@article {pmid34570180,
year = {2021},
author = {Mintzer, J and Lanctôt, KL and Scherer, RW and Rosenberg, PB and Herrmann, N and van Dyck, CH and Padala, PR and Brawman-Mintzer, O and Porsteinsson, AP and Lerner, AJ and Craft, S and Levey, AI and Burke, W and Perin, J and Shade, D and , },
title = {Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3356},
pmid = {34570180},
issn = {2168-6157},
abstract = {Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.

Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.

This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.

Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo.

Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.

Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.

Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.

Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.},
}

@article {pmid34570178,
year = {2021},
author = {Fredericks, C},
title = {Methylphenidate for Apathy in Alzheimer Disease-Why Should We Care?.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2942},
pmid = {34570178},
issn = {2168-6157},
}

@article {pmid34570177,
year = {2021},
author = {Vossel, K and Ranasinghe, KG and Beagle, AJ and La, A and Ah Pook, K and Castro, M and Mizuiri, D and Honma, SM and Venkateswaran, N and Koestler, M and Zhang, W and Mucke, L and Howell, MJ and Possin, KL and Kramer, JH and Boxer, AL and Miller, BL and Nagarajan, SS and Kirsch, HE},
title = {Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3310},
pmid = {34570177},
issn = {2168-6157},
abstract = {Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).

Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.

The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.

Interventions: Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.

Main Outcomes and Measures: The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.

Results: Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.

Conclusions and Relevance: In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02002819.},
}

@article {pmid34569963,
year = {2021},
author = {Katz, J and Gao, H},
title = {The Alzheimer-E. coli Axis: What Can We Learn from an Electronic Health Record Platform.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-215004},
pmid = {34569963},
issn = {1875-8908},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with unclear etiology. Recent studies have demonstrated a potential role for gut microbiome. There is, however, a significant dearth in epidemiological correlation between gut bacteria and AD.

OBJECTIVE: To investigate the association between Escherichia coli (E. coli) infection and AD.

METHODS: Counts of patients with ICD 10 diagnoses of AD, E. coli, urinary tract infection, and comorbidities were retrieved from the electronic health records at the University of Florida Health Center.

RESULTS: The relative risk for AD with a previous event of E. coli was 5.17 (95%CI 4.0786 to 6.5446, p < 0.0001). In the unadjusted association, patients with E. coli infection had odds ratio (OR) of 20.83 to have AD (95%CI, 17.7-24.34; p < 0.0001); after adjusting for gender (OR = 12.71; 95%CI, 10.82-14.83; p < 0.0001), race (OR = 13.97; 95%CI, 11.84-16.36; p < 0.0001), age group (OR = 11.51; 95%CI, 9.73-13.54; p < 0.0001), diabetes (OR = 9.23; 95%CI, 7.79-10.87; p < 0.0001), stroke (OR = 5.31; 95%CI, 4.47-6.28; p < 0.0001), and hypertension (OR = 4.55; 95%CI, 3.86-5.32; p < 0.0001).

CONCLUSION: These results should be taken cautiously. This retrospective cross-sectional study cannot infer causality and had used aggregate data that did not allow simultaneous adjustments of covariates. Future studies are warranted to investigate the link between gut bacteria and AD.},
}

@article {pmid34569854,
year = {2021},
author = {Hairu, R and Close, JCT and Lord, SR and Delbaere, K and Wen, W and Jiang, J and Taylor, ME},
title = {The association between white matter hyperintensity volume and cognitive/physical decline in older people with dementia: A one-year longitudinal study.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/13607863.2021.1980859},
pmid = {34569854},
issn = {1364-6915},
abstract = {OBJECTIVES: Understanding the relationship between white matter hyperintensities (WMHs) and cognitive and physical decline in people with dementia will assist in determining potential treatment strategies. Currently there is conflicting evidence describing the association between WMHs and cognitive decline and, WMHs association with declines in objective measures of physical function have not been examined. We examined the relationship between baseline WMH volume and physical/cognitive decline over one-year in older people with dementia.

METHODS: Twenty-six community-dwelling older people with dementia (mean age = 81 ± 8 years; 35% female) were assessed at baseline and follow-up (one-year) using the Addenbrooke's Cognitive Examination-Revised (including verbal fluency), Trail Making Test A, the Physiological Profile Assessment (PPA), timed-up-and-go (TUG) and gait speed. WMH volumes were quantified using a fully automated segmentation toolbox, UBO Detector.

RESULTS: In analyses adjusted for baseline performance, higher baseline WMH volume was associated with decline in executive function (verbal fluency), sensorimotor function (PPA) and mobility (TUG). Executive function (semantic/category fluency) was the only domain association that withstood adjustment for age, and additionally hippocampal volume.

CONCLUSIONS: In unadjusted analyses, WMH volume was associated with one-year declines in cognitive and physical function in older people with dementia. The association with executive function decline withstood adjustment for age. More research is needed to confirm these findings and explore whether vascular risk reduction strategies can reduce WMH volume and associated cognitive and physical impairments in this group.},
}

@article {pmid34567426,
year = {2021},
author = {Skok, M},
title = {Mesenchymal stem cells as a potential therapeutic tool to cure cognitive impairment caused by neuroinflammation.},
journal = {World journal of stem cells},
volume = {13},
number = {8},
pages = {1072-1083},
doi = {10.4252/wjsc.v13.i8.1072},
pmid = {34567426},
issn = {1948-0210},
abstract = {An established contribution of neuroinflammation to multiple brain pathologies has raised the requirement for therapeutic strategies to overcome it in order to prevent age- and disease-dependent cognitive decline. Mesenchymal stem cells (MSCs) produce multiple growth and neurotrophic factors and seem to evade immune rejection due to low expression of major histocompatibility complex class I molecules. Therefore, MSCs are widely used in experiments and clinical trials of regenerative medicine. This review summarizes recent data concerning the optimization of MSC use for therapeutic purposes with the emphasis on the achievements of the last 2 years. Specific attention is paid to extracellular vesicles secreted by MSCs and to the role of α7 nicotinic acetylcholine receptors. The reviewed data demonstrate that MSCs have a significant therapeutic potential in treating neuroinflammation-related cognitive disfunctions including age-related neurodegenerative diseases. The novel data demonstrate that maximal therapeutic effect is being achieved when MSCs penetrate the brain and produce their stimulating factors in situ. Consequently, therapeutic application using MSCs should include measures to facilitate their homing to the brain, support the survival in the brain microenvironment, and stimulate the production of neurotrophic and anti-inflammatory factors. These measures include but are not limited to genetic modification of MSCs and pre-conditioning before transplantation.},
}

@article {pmid34565625,
year = {2021},
author = {Jacus, JP and Voltzenlogel, V and Mayelle, A and Antoine, P and Cuervo-Lombard, CV},
title = {Awareness dimensions and associated factors in Alzheimer's disease.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2021.05.011},
pmid = {34565625},
issn = {0035-3787},
abstract = {OBJECTIVES: We recently reported the major role depression and apathy in awareness among Alzheimer patients, using the stage of the disease as an exposure factor and exploring different assessment methods. Using the same patient data, we aimed here to explore the different dimensions of awareness assessed by different sub-scales in awareness scales.

METHOD: Sixty-one Alzheimer patients were examined using four awareness scales relating to three assessment methods: (a) patient-caregiver discrepancy; (b) clinical rating; and (c) prediction of performance discrepancy. Global cognition, executive functioning, autonomy, depression and apathy were also assessed. Multivariate logistic models were performed using disease stage as an exposure factor for awareness scales and sub-scales. Correlations across the different factors and patient and caregiver awareness ratings were computed.

RESULTS: The patient-caregiver discrepancy and clinical rating methods (a, b) both identified the factors associated with awareness in the overall scales and the sub-scales as being depression and/or apathy. Depression correlated with patient self-ratings while apathy correlated with caregiver ratings. The prediction of performance discrepancy method (c) identified different factors in the overall scale, executive factors in three sub-scales involving executive domains and the memory factor in a sub-scale involving the mnesic domain.

DISCUSSION: The awareness scales using a referential based on a human rating (a, b) suggest that awareness is unidimensional, with depression impacting self-reports and apathy influencing caregiver/clinical reports. Scales based on a test rating (c) appear to be more closely associated with the dimensions assessed. This highlights the role of the reference system for awareness assessment in Alzheimer's disease.},
}

@article {pmid34563212,
year = {2021},
author = {Preman, P and Tcw, J and Calafate, S and Snellinx, A and Alfonso-Triguero, M and Corthout, N and Munck, S and Thal, DR and Goate, AM and De Strooper, B and Arranz, AM},
title = {Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques.},
journal = {Molecular neurodegeneration},
volume = {16},
number = {1},
pages = {68},
pmid = {34563212},
issn = {1750-1326},
support = {G0D9817N//Fonds Wetenschappelijk Onderzoek/ ; ZEN-17-441253/ALZ/Alzheimer's Association/United States ; ERC-CELLPHASE-AD -834682//H2020 European Research Council/ ; GSKE//UCB/ ; RTI2018-101850-A-100//Ministerio de Ciencia, Innovación y Universidades/ ; startup funds//Ikerbasque, Basque Foundation for Science/ ; },
abstract = {BACKGROUND: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.

RESULTS: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background.

CONCLUSIONS: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.},
}

@article {pmid34401683,
year = {2021},
author = {Benjamin, LA and Paterson, RW and Moll, R and Pericleous, C and Brown, R and Mehta, PR and Athauda, D and Ziff, OJ and Heaney, J and Checkley, AM and Houlihan, CF and Chou, M and Heslegrave, AJ and Chandratheva, A and Michael, BD and Blennow, K and Vivekanandam, V and Foulkes, A and Mummery, CJ and Lunn, MP and Keddie, S and Spyer, MJ and Mckinnon, T and Hart, M and Carletti, F and Jäger, HR and Manji, H and Zandi, MS and Werring, DJ and Nastouli, E and Simister, R and Solomon, T and Zetterberg, H and Schott, JM and Cohen, H and Efthymiou, M and , },
title = {Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.},
journal = {EClinicalMedicine},
volume = {39},
number = {},
pages = {101070},
doi = {10.1016/j.eclinm.2021.101070},
pmid = {34401683},
issn = {2589-5370},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear.

Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG.

Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2.

Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.

Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.},
}

@article {pmid34560903,
year = {2021},
author = {Coley, N and Coniasse-Brioude, D and Igier, V and Fournier, T and Poulain, JP and Andrieu, S and , },
title = {Disparities in the participation and adherence of older adults in lifestyle-based multidomain dementia prevention and the motivational role of perceived disease risk and intervention benefits: an observational ancillary study to a randomised controlled trial.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {157},
pmid = {34560903},
issn = {1758-9193},
abstract = {BACKGROUND: Preventive interventions for dementia are urgently needed and must be tested in randomised controlled trials (RCTs). Selection (volunteer) bias may limit efficacy, particularly in trials testing multidomain interventions and may also be indicative of disparities in intervention uptake in real-world settings. We identified factors associated with participation and adherence in a 3-year RCT of multidomain lifestyle intervention and/or omega-3 supplementation for prevention of cognitive decline and explored reasons for (non-) participation.

METHODS: Ancillary study during recruitment and follow-up of the 3-year Multidomain Alzheimer Preventive Trial (MAPT) conducted in in 13 memory centres in France and Monaco, involving 1630 community-dwelling dementia-free individuals aged ≥ 70 who were pre-screened for MAPT (1270 participated in MAPT; 360 declined to participate).

RESULTS: Response rates were 76% amongst MAPT participants and 53% amongst non-participants. Older individuals (odds ratio 0.94 [95% confidence interval 0.91-0.98] and those with higher anxiety (0.61 [0.47-0.79]) were less likely to participate in the trial. Those with higher income (4.42 [2.12-9.19]) and family history (1.60 [1.10-2.32]) or greater fear (1.73 [1.30-2.29]) of dementia were more likely to participate, as were those recruited via an intermediary (e.g. pension funds, local Alzheimer's associations, University of the 3rd Age, sports clubs) (2.15 [1.45-3.20]). MAPT participants living in larger towns (0.71 [0.55-0.92]) and with higher depressive symptoms (0.94 [0.90-0.99]) were less likely to adhere to the interventions. Greater perceived social support (1.21 [1.03-1.43]) and cognitive function (1.37 [1.13-1.67]) predicted better adherence. Descriptively, the most frequent reasons for accepting and refusing to participate were, respectively, altruism and logistical constraints, but underlying motivations mainly related to (lack of) perceived benefits.

CONCLUSIONS: Disparities in uptake of health interventions persist in older age. Those most at risk of dementia may not participate in or adhere to preventive interventions. Barriers to implementing lifestyle changes for dementia prevention include lack of knowledge about potential benefits, lack of support networks, and (perceived) financial costs.

TRIAL REGISTRATION: NCT00672685 (ClinicalTrials.gov).},
}

@article {pmid34559097,
year = {2021},
author = {Wang, W and Diwu, Y and Liu, Q and Zhou, Y and Sayed, TI and Wang, D and Gou, Y},
title = {Chinese herbal medicine for mild cognitive impairment using mini-mental state examination: A systematic review and meta-analysis.},
journal = {Medicine},
volume = {100},
number = {38},
pages = {e27034},
pmid = {34559097},
issn = {1536-5964},
support = {82074503//National Natural Science Foundation of China/ ; No.2019-QN05//the Disciplinary Innovation Team of Shaanxi University of Traditional Chinese Medicine/ ; },
abstract = {INTRODUCTION: The prevalence of mild cognitive impairment (MCI) in the elderly population aged 60 to 84 years ranges from 6.7% to 25.2%, and the effective prevention and reversal of MCI progression to Alzheimer disease (AD) is crucial. The mini mental state examination (MMSE) is the most commonly used screening tool in Chinese outpatient clinics, with sufficient sensitivity and specificity to allow useful stratification from average to abnormal with adequate consideration of age and education.

OBJECTIVE: To investigate the clinical significance of Chinese herbs on MMSE scores in MCI patients and discuss the effectiveness of Chinese herbs through pharmacology.

METHODS: Three English databases and 4 Chinese databases we have searched, and the risk of bias was assessed according to the Cochrane tool. Statistics will be used for heterogeneity assessment, sensitivity analysis, data synthesis, funnel plot generation and subgroup analysis. If sufficiently homogeneous studies are found, a Meta-analysis will be performed, with subgroups describing any differences.

RESULTS: A total of 21 studies were included, 4 studies were placebo-controlled, 14 Chinese Herbal Medicines (CHMs) were compared with other cognitive improvements, 3 CHMs were combined with other medications, and the results of 17 studies favored the herbal group.

CONCLUSION: The results indicate that herbal medicine can improve MMSE scores, and herbal medicine combined with other drugs that can improve cognition can significantly improve MMSE scores, but there are methodological flaws in the study. Experimental studies have found a basis for the ability of herbs to improve cognition and memory impairment, and herbal medicine has great potential to improve MCI cognition. Keywords mild cognitive impairment, herbal medicine, MMSE, systematic evaluation, meta-analysis. PROSPERO international prospective register of systematic reviews protocol registration number: CRD42020202368.},
}

@article {pmid34558138,
year = {2021},
author = {Erekat, NS},
title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.23792},
pmid = {34558138},
issn = {1098-2353},
abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.},
}

@article {pmid34557567,
year = {2021},
author = {Hanczyc, P and Fita, P},
title = {Laser Emission of Thioflavin T Uncovers Protein Aggregation in Amyloid Nucleation Phase.},
journal = {ACS photonics},
volume = {8},
number = {9},
pages = {2598-2609},
pmid = {34557567},
issn = {2330-4022},
abstract = {There is currently no definitive test for early detection of neurodegeneration which is linked with protein aggregation. Finding methods capable of detecting intermediate states of protein aggregates, named oligomers, is critical for the early stage diagnosis of over 30 neurodegenerative diseases including Alzheimer's or Parkinson's. Currently, fluorescence-based imaging using Thioflavin T (ThT) dye is the gold standard for detecting protein aggregation. It is used to detect aggregation in vitro and in various tissues, including the cerebrospinal fluid (CSF), whereby the disease-related protein recombinant is seeded with the patient's fluid. The major drawback of ThT is its lack of sensitivity to oligomeric forms of protein aggregates. Here, we overcome this limitation by transferring a ThT-oligomer mixture into solid state thin films and detecting fluorescence of ThT amplified in the process of stimulated emission. By monitoring the amplified spontaneous emission (ASE) we achieved a remarkable recognition sensitivity to prefibrillar oligomeric forms of insulin and lysozyme aggregates in vitro, to Aβ42 oligomers in the human protein recombinants seeded with CSF and to Aβ42 oligomers doped into brain tissue. Seeding with Alzheimer patient's CSF containing Aβ42 and Tau aggregates revealed that only Aβ42 oligomers allowed generating ASE. Thus, we demonstrated that, in contrast to the current state-of-the-art, ASE of ThT, a commonly used histological dye, can be used to detect and differentiate amyloid oligomers and evaluate the risk levels of neurodegenerative diseases to potential patients before the clinical symptoms occur.},
}

@article {pmid34557314,
year = {2021},
author = {Lopez-Gutierrez, L and García-Alberca, JM and Mendoza, S and Gris, E and De la Guía, MP and Marin-Carmona, JM and Alarcón-Martín, E and Lobato, A and Cruz-Gamero, JM and Cura, L and Ocejo, O and Torrecilla, J and Nieto, MD and Urbano, C and Pareja, N and Luque, M and García-Peralta, M and Carrillejo, R and Royo, JL},
title = {The Genetic Research in Alzheimer Disease (GERALD) Initiative Finds rs9320913 as a Neural eQTL of lincRNA AL589740.1.},
journal = {International journal of Alzheimer's disease},
volume = {2021},
number = {},
pages = {3064224},
pmid = {34557314},
issn = {2090-8024},
abstract = {Alzheimer's disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer's disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer's disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex (beta = -0.15, p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline.},
}

@article {pmid34556565,
year = {2021},
author = {Milà-Alomà, M and Brinkmalm, A and Ashton, NJ and Kvartsberg, H and Shekari, M and Operto, G and Salvadó, G and Falcon, C and Gispert, JD and Vilor-Tejedor, N and Arenaza-Urquijo, EM and Grau-Rivera, O and Sala-Vila, A and Sanchez-Benavides, G and González-de-Echávarri, JM and Minguillon, C and Fauria, K and Niñerola-Baizán, A and Perissinotti, A and Kollmorgen, G and Suridjan, I and Zetterberg, H and Molinuevo, JL and Blennow, K and Suárez-Calvet, M and , },
title = {CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012853},
pmid = {34556565},
issn = {1526-632X},
abstract = {OBJECTIVE: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer's continuum and associated with Alzheimer's disease (AD) risk factors, primary pathology, and neurodegeneration markers.

METHODS: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker NfL were also measured. Participants underwent structural MRI, and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.

RESULTS: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE-ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values) and, importantly, the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism, but lower cortical thickness in AD-related brain regions.

CONCLUSION: CSF synaptic biomarkers increase in early preclinical stages of the Alzheimer's continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE-ε4, and markers of neurodegeneration.},
}

@article {pmid34556345,
year = {2021},
author = {Fathi, M and Taghizadeh, F and Mojtahedi, H and Zargar Balaye Jame, S and Markazi Moghaddam, N},
title = {The effects of Alzheimer's and Parkinson's disease on 28-day mortality of COVID-19.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
pmid = {34556345},
issn = {0035-3787},
abstract = {We compared the prognosis of inpatients with a known diagnosis of Alzheimer's or Parkinson's disease who have COVID-19 infection with other hospitalized patients with COVID-19. Our cohort study started in October 2020 and ended in May 2021 and included inpatients with COVID-19 infection who were admitted to hospitals. From a total of 67,871 patients with a confirmed diagnosis of COVID-19, a sample of 3732 individuals were selected of which 363 had Alzheimer's, and 259 had Parkinson's disease. All patients had both positive RT-PCR test and positive chest CT for COVID-19. The outcome was dead within 28 days of admission and the predictors were a large number of demographic and clinical features, and comorbidities recorded at patients' bedside. Mortality were 37.5%, 35.1%, and 29.5% in patients with Alzheimer's disease, Parkinson's disease; and in other patients, respectively. The hazard ratio for Alzheimer's disease was 1.27 (95% CI, 1.06-1.53, p=0.010) and for Parkinson's disease was 1.17 (95% CI, 0.94-1.46, p=0.171). Age was a predictor of mortality, hazard ratio=1.04 (95% CI, 1.03-1.05, p<0.001). Patients with Alzheimer's disease and COVID-19 infection were older and more likely to have a loss of consciousness on admission (both p≤0.001). We concluded that inpatients with Alzheimer's disease have an increased risk for 28-day mortality from COVID-19 and healthcare settings should be ready to provide critical care for them such as early intubation and immediate O2 therapy. However, Parkinson's disease does not significantly predict higher mortality of COVID-19.},
}

@article {pmid34556089,
year = {2021},
author = {Jiang, Z and Shi, Y and Zhao, W and Zhou, L and Zhang, B and Xie, Y and Zhang, Y and Tan, G and Wang, Z},
title = {Association between chronic periodontitis and the risk of Alzheimer's disease: combination of text mining and GEO dataset.},
journal = {BMC oral health},
volume = {21},
number = {1},
pages = {466},
pmid = {34556089},
issn = {1472-6831},
support = {3502Z20209005//Xiamen Municipal Bureau of Science and Technology/ ; 2020J02063//Natural Science Foundation of Fujian Province/ ; 82072777//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Although chronic periodontitis has previously been reported to be linked with Alzheimer's disease (AD), the pathogenesis between the two is unclear. The purpose of this study is to analyze and screen the relevant and promising molecular markers between chronic periodontitis and Alzheimer's disease (AD).

METHODS: In this paper, we analyzed three AD expression datasets and extracted differentially expressed genes (DEGs), then intersected them with chronic periodontitis genes obtained from text mining, and finally obtained integrated DEGs. We followed that by enriching the matching the matching cell signal cascade through DAVID analysis. Moreover, the MCODE of Cytoscape software was employed to uncover the protein-protein interaction (PPI) network and the matching hub gene. Finally, we verified our data using a different independent AD cohort.

RESULTS: The chronic periodontitis gene set acquired from text abstracting was intersected with the previously obtained three AD groups, and 12 common genes were obtained. Functional enrichment assessment uncovered 12 cross-genes, which were mainly linked to cell morphogenesis involved in neuron differentiation, leading edge membrane, and receptor ligand activity. After PPI network creation, the ten hub genes linked to AD were retrieved, consisting of SPP1, THY1, CD44, ITGB1, HSPB3, CREB1, SST, UCHL1, CCL5 and BMP7. Finally, the function terms in the new independent dataset were used to verify the previous dataset, and we found 22 GO terms and one pathway, "ECM-receptor interaction pathways", in the overlapping functional terms.

CONCLUSIONS: The establishment of the above-mentioned candidate key genes, as well as the enriched signaling cascades, provides promising molecular markers for chronic periodontitis-related AD, which may help the diagnosis and treatment of AD patients in the future.},
}

@article {pmid34556008,
year = {2021},
author = {LaPlume, AA and Paterson, TSE and Gardner, S and Stokes, KA and Freedman, M and Levine, B and Troyer, AK and Anderson, ND},
title = {Interindividual and intraindividual variability in amnestic mild cognitive impairment (aMCI) measured with an online cognitive assessment.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/13803395.2021.1982867},
pmid = {34556008},
issn = {1744-411X},
abstract = {INTRODUCTION: Mean cognitive performance is worse in amnestic mild cognitive impairment (aMCI) compared to control groups. However, studies on variability of cognitive performance in aMCI have yielded inconclusive results, with many differences in variability measures and samples from one study to another.

METHODS: We examined variability in aMCI using an existing older adult sample (n = 91; 51 with aMCI, 40 with normal cognition for age), measured with an online self-administered computerized cognitive assessment (Cogniciti's Brain Health Assessment). Our methodology extended past findings by using pure measures of variability (controlling for confounding effects of group performance or practice), and a clinically representative aMCI sample (reflecting the continuum of cognitive performance between normal cognition and aMCI).

RESULTS: Between-group t-tests showed significantly greater between-person variability (interindividual variability or diversity) in overall cognitive performance in aMCI than controls, although the effect size was with a small to moderate effect size, d = 0.44. No significant group differences were found in within-person variability (intraindividual variability) across cognitive tasks (dispersion) or across trials of a response time task (inconsistency), which may be because we used a sample measuring the continuum of cognitive performance. Exploratory correlation analyses showed that a worse overall score was associated with greater inter- and intraindividual variability, and that variability measures were correlated with each other, indicating people with worse cognitive performance were more variable.

DISCUSSION: The current study demonstrates that self-administered online tests can be used to remotely assess different types of variability in people at risk of Alzheimer`s. Our findings show small but significantly more interindividual differences in people with aMCI. This diversity is considered as "noise" in standard assessments of mean performance, but offers an interesting and cognitively informative "signal" in itself.},
}

@article {pmid34555025,
year = {2021},
author = {Carcaillon-Bentata, L and Quintin, C and Boussac-Zarebska, M and Elbaz, A},
title = {Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system.},
journal = {PLoS medicine},
volume = {18},
number = {9},
pages = {e1003801},
doi = {10.1371/journal.pmed.1003801},
pmid = {34555025},
issn = {1549-1676},
abstract = {BACKGROUND: Dementia onset in those aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences. In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources. Few studies have provided precise frequency estimates of YOD. The aim of this study is to provide YOD prevalence and incidence estimates in France and to study the contribution of comorbidities to YOD incidence.

METHODS AND FINDINGS: Using data from the French national health data system (Système National des Données de Santé, SNDS) for 76% of the French population aged 40 to 64 years in 2016 (n = 16,665,795), we identified all persons with dementia based on at least 1 of 3 criteria: anti-Alzheimer drugs claims, hospitalization with the International Classification of Diseases-10th Revision (ICD-10) dementia code (F00 to F03, G30, G31.0, G31.1, or F05.1), or registration for free healthcare for dementia. We estimated prevalence rate (PR) and incidence rate (IR) and estimated the association of comorbidities with incident YOD. Sex differences were investigated. We identified 18,466 (PRstandardized = 109.7/100,000) and 4,074 incident (IRstandardized = 24.4/100,000 person-years) persons with prevalent and incident YOD, respectively. PR and IR sharply increased with age. Age-adjusted PR and IR were 33% (95% confidence interval (CI) = 29 to 37) and 39% (95% CI = 31 to 48) higher in men than women (p < 0.001 both for PR and IR). Cardio- and cerebrovascular, neurological, psychiatric diseases, and traumatic brain injury prevalence were associated with incident YOD (age- and sex-adjusted p-values <0.001 for all comorbidities examined, except p = 0.109 for antihypertensive drug therapy). Adjustment for all comorbidities explained more than 55% of the sex difference in YOD incidence. The lack of information regarding dementia subtypes is the main limitation of this study.

CONCLUSIONS: We estimated that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016. The higher YOD frequency in men may be partly explained by higher prevalence of cardiovascular and neurovascular diseases, substance abuse disorders, and traumatic brain injury and warrants further investigation.},
}

@article {pmid34551697,
year = {2021},
author = {Mengr, A and Hrubá, L and Exnerová, A and Holubová, M and Popelová, A and Železná, B and Kuneš, J and Maletínská, L},
title = {Palmitoylated prolactin-releasing peptide reduced Aβ plaques and microgliosis in the cerebellum: APP/PS1 mice study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567205018666210922110652},
pmid = {34551697},
issn = {1875-5828},
abstract = {BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated type 2 diabetes mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex.

OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD.

METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice.

RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker glial fibrillary acidic protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice.

CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.},
}

@article {pmid34551374,
year = {2021},
author = {Whitwell, JL and Tosakulwong, N and Weigand, SD and Graff-Radford, J and Ertekin-Taner, N and Machulda, MM and Duffy, JR and Schwarz, CG and Senjem, ML and Jack, CR and Lowe, VJ and Josephs, KA and , },
title = {Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease.},
journal = {Neurobiology of aging},
volume = {108},
number = {},
pages = {90-98},
doi = {10.1016/j.neurobiolaging.2021.08.012},
pmid = {34551374},
issn = {1558-1497},
abstract = {The apolipoprotein E (APOE) ε4 allele is the most well-established risk factor for Alzheimer's disease (AD), although its relationship to age at onset and clinical phenotype is unclear. We aimed to assess relationships between APOE genotype and age at onset, amyloid-beta (Aβ) deposition and typical versus atypical clinical presentations in AD. Frequency of APOE ε4 carriers by age at onset was assessed in 447 AD patients, 138 atypical AD patients recruited by the Neurodegenerative Research Group at Mayo Clinic, and 309 with typical AD from ADNI. APOE ε4 frequency increased with age at onset in atypical AD but showed a bell-shaped curve in typical AD where highest frequencies were observed between 65 and 70 years. Typical AD showed higher APOE ε4 frequencies than atypical AD only between the ages of 57 and 69 years. Global Aβ standard uptake value ratios did not differ according to APOE e4 status in either group. APOE genotype varies by both age at onset and clinical phenotype in AD, highlighting the heterogeneous nature of AD.},
}

@article {pmid34550903,
year = {2021},
author = {Jutten, RJ and Sikkes, SAM and Van der Flier, WM and Scheltens, P and Visser, PJ and Tijms, BM and , },
title = {Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.},
journal = {Neurology},
volume = {96},
number = {22},
pages = {e2673-e2684},
pmid = {34550903},
issn = {1526-632X},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.

METHODS: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.

RESULTS: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).

CONCLUSIONS: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.},
}

@article {pmid34550902,
year = {2021},
author = {Buckley, RF and Knopman, DS},
title = {Cognitive Heterogeneity in Alzheimer Clinical Trials: Harnessing Noise to Achieve Meaningfulness.},
journal = {Neurology},
volume = {96},
number = {22},
pages = {1017-1018},
doi = {10.1212/WNL.0000000000012027},
pmid = {34550902},
issn = {1526-632X},
}

@article {pmid34550082,
year = {2021},
author = {Betz, ME and Polzer, E and Nearing, K and Knoepke, CE and Johnson, RL and Meador, L and Matlock, DD},
title = {Feasibility and Acceptability of a Web-Based Caregiver Decision Aid (Safety in Dementia) for Firearm Access: Pilot Randomized Controlled Trial.},
journal = {JMIR formative research},
volume = {5},
number = {9},
pages = {e30990},
doi = {10.2196/30990},
pmid = {34550082},
issn = {2561-326X},
abstract = {BACKGROUND: Firearms are common in the households of persons with Alzheimer disease and related dementias (ADRD). Safety in Dementia (SiD) is a free web-based decision aid that was developed to support ADRD caregivers in addressing firearm access.

OBJECTIVE: We aimed to evaluate the feasibility and acceptability of SiD among a web-based sample of ADRD caregivers.

METHODS: SiD was tested in 2 phases by using participants who were recruited from a web-based convenience sample (Amazon Mechanical Turk participants). In phase 1, caregivers were randomized to view either the intervention (SiD) or the control (Alzheimer's Association materials), and the blinding of participants to the study arms was conducted. In phase 2, caregivers of individuals with ADRD and firearm access were recruited; all of these participants viewed the firearm section of SiD. In both phases, participants viewed SiD independently for as long as they wanted. Measures for evaluating decision-making and SiD acceptability were used, and these were assessed via a self-administered web-based questionnaire.

RESULTS: Participants were recruited for phases 1 (n=203) and 2 (n=54). Although it was feasible to collect the study outcome data in a web-based format, in phase 1, there were no significant differences between SiD and the control in terms of decision-making and self-efficacy. The majority (137/203, 67.5%) of phase 1 participants spent between 5 and 10 minutes reviewing the resources. In phase 2, 61% (33/54) of participants spent 5 to 10 minutes viewing the firearm section, and 31% (17/54) spent 10 to 20 minutes viewing this section. Usability and acceptability were high across the phases.

CONCLUSIONS: SiD represents a new resource for promoting safety among people with dementia, and high acceptability was achieved in a pilot trial. In this sample, SiD performed similarly to Alzheimer's Association materials in supporting decision-making and self-efficacy.},
}

@article {pmid34549475,
year = {2021},
author = {Lessard-Beaudoin, M and M Gonzales, L and AlOtaibi, M and Chouinard-Watkins, R and Plourde, M and Calon, F and Graham, RK},
title = {Diet enriched in omega-3 fatty acids alleviates olfactory system deficits in APOE4 transgenic mice.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.15472},
pmid = {34549475},
issn = {1460-9568},
abstract = {Olfactory dysfunction is observed in several neurological disorders including Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). These deficits occur early and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite extensive human studies, there has been little characterization of the olfactory system in models of AD. In order to determine if olfactory structural and/or molecular phenotypes are observed in a model expressing a genetic risk factor for AD, we assessed the olfactory bulb (OB) in APOE4 transgenic mice. A significant decrease in OB weight was observed at 12 months of age in APOE4 mice concurrent with inflammation and decreased NeuN expression. In order to determine if a diet rich in omega-3s may alleviate the olfactory system phenotypes observed we assessed WT and APOE4 mice on a docosahexaenoic acid (DHA) diet. APOE4 mice on a DHA diet did not present with atrophy of the OB and the alterations in NeuN and IBA-1 expression were alleviated. Furthermore, alterations in caspase mRNA and protein expression in the APOE4 OB were not observed with a DHA diet. Similar to the human AD condition, OB atrophy is an early phenotype in the APOE4 mice and concurrent with inflammation. These data support a link between the structural olfactory brain region atrophy and the olfactory dysfunction observed in AD and suggest that inflammation and cell death pathways may contribute to the olfactory deficits observed. Furthermore, the results suggest that diets enriched in DHA may provide benefit to APOE4 allele carriers.},
}

@article {pmid34548654,
year = {2021},
author = {McDade, E and Voytyuk, I and Aisen, P and Bateman, RJ and Carrillo, MC and De Strooper, B and Haass, C and Reiman, EM and Sperling, R and Tariot, PN and Yan, R and Masters, CL and Vassar, R and Lichtenthaler, SF},
title = {The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34548654},
issn = {1759-4766},
abstract = {Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.},
}

@article {pmid34548629,
year = {2021},
author = {Chen, Z and Schwulst, SJ and Mentis, AA},
title = {Correction: APOE4-mediated Alzheimer disease and "Vascular"-"Meningeal Lymphatic" components: towards a novel therapeutic era?.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-021-01307-7},
pmid = {34548629},
issn = {1476-5578},
}

@article {pmid34545700,
year = {2021},
author = {Smirnova, TA and Viskin, A and Hoskova, M and Habartova, L and Setnicka, V and Cejnar, P and Kuckova, S},
title = {Comparison of proteomic approaches used for the detection of potential biomarkers of Alzheimer's disease in blood plasma.},
journal = {Journal of separation science},
volume = {},
number = {},
pages = {},
doi = {10.1002/jssc.202100468},
pmid = {34545700},
issn = {1615-9314},
abstract = {At present, Alzheimer´s disease is detected mainly using psychological tests, which, can only confirm the disease in its more advanced phases. Therefore, bioanalytical possibilities for detecting this disease earlier are being investigated. To date, the results of analyses, which focus mainly on the study of lipids and proteins either in cerebrospinal fluid or much less often in blood plasma, do not provide satisfactory results. In addition, cerebrospinal fluid sampling is uncomfortable for the patients and involves many health risks. In this work, we deal with proteomic analysis using Matrix-Assisted Laser Desorption/Ionisation - Time Of Flight and Liquid Chromatography coupled to tandem Mass Spectrometry of blood plasma with a focus on various ways of pre-analytical sample treatments. This should lead to results improvement and facilitate the subsequent evaluation using principal component analysis and partial least squares discriminant analysis. The obtained results indicate the direction of further research, namely the study of interactions between proteins and lipids contained in blood plasma. These substances may be regarded as potential biomarkers allowing for the diagnosis of Alzheimer´s disease even in its early stages. This article is protected by copyright. All rights reserved.},
}

@article {pmid34545424,
year = {2021},
author = {Kanel, P and Bedard, MA and Aghourian, M and Rosa-Neto, P and Soucy, JP and Albin, RL and Bohnen, NI},
title = {Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views.},
journal = {Current neurology and neuroscience reports},
volume = {21},
number = {10},
pages = {52},
pmid = {34545424},
issn = {1534-6293},
support = {P01 NS015655/NH/NIH HHS/United States ; R01 NS070856/NH/NIH HHS/United States ; P50 NS091856/NH/NIH HHS/United States ; I01 RX001631/RX/RRD VA/United States ; },
abstract = {PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented.

RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.},
}

@article {pmid34544751,
year = {2021},
author = {Arnaud, K and Oliveira Moreira, V and Vincent, J and Dallerac, G and Dubreuil, C and Dupont, E and Richter, M and Müller, UC and Rondi-Reig, L and Prochiantz, A and Di Nardo, AA},
title = {Choroid plexus APP regulates adult brain proliferation and animal behavior.},
journal = {Life science alliance},
volume = {4},
number = {11},
pages = {},
doi = {10.26508/lsa.202000703},
pmid = {34544751},
issn = {2575-1077},
abstract = {Elevated amyloid precursor protein (APP) expression in the choroid plexus suggests an important role for extracellular APP metabolites such as sAPPα in cerebrospinal fluid. Despite widespread App brain expression, we hypothesized that specifically targeting choroid plexus expression could alter animal physiology. Through various genetic and viral approaches in the adult mouse, we show that choroid plexus APP levels significantly impact proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Given the role of Aβ peptides in Alzheimer disease pathogenesis, we also tested whether favoring the production of Aβ in choroid plexus could negatively affect niche functions. After AAV5-mediated long-term expression of human mutated APP specifically in the choroid plexus of adult wild-type mice, we observe reduced niche proliferation, reduced hippocampus APP expression, behavioral defects in reversal learning, and deficits in hippocampal long-term potentiation. Our findings highlight the unique role played by the choroid plexus in regulating brain function and suggest that targeting APP in choroid plexus may provide a means to improve hippocampus function and alleviate disease-related burdens.},
}

@article {pmid34542571,
year = {2021},
author = {Janelidze, S and Teunissen, CE and Zetterberg, H and Allué, JA and Sarasa, L and Eichenlaub, U and Bittner, T and Ovod, V and Verberk, IMW and Toba, K and Nakamura, A and Bateman, RJ and Blennow, K and Hansson, O},
title = {Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3180},
pmid = {34542571},
issn = {2168-6157},
abstract = {Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.

Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.

This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.

Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.

Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.

Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.},
}

@article {pmid34542418,
year = {2021},
author = {Saredakis, D and Keage, HA and Corlis, M and Ghezzi, ES and Loffler, H and Loetscher, T},
title = {The Effect of Reminiscence Therapy Using Virtual Reality on Apathy in Residential Aged Care: Multisite Nonrandomized Controlled Trial.},
journal = {Journal of medical Internet research},
volume = {23},
number = {9},
pages = {e29210},
doi = {10.2196/29210},
pmid = {34542418},
issn = {1438-8871},
abstract = {BACKGROUND: Apathy is a frequent and underrecognized neurological disorder symptom. Reduced goal-directed behavior caused by apathy is associated with poor outcomes for older adults in residential aged care. Recommended nonpharmacological treatments include person-centered therapy using information and communication technology. Virtual reality (VR) in the form of head-mounted displays (HMDs) is a fully immersive technology that provides access to a wide range of freely available content. The use of VR as a therapy tool has demonstrated promise in the treatment of posttraumatic stress disorder and anxiety. In addition, VR has been used to improve conditions including depression, anxiety, cognitive function, and balance in older adults with memory deficits, Alzheimer disease, and Parkinson disease. Research using VR for the symptoms of apathy in older adults living in residential aged care facilities is limited.

OBJECTIVE: This study aims to examine whether using HMDs as a tool for reminiscence therapy improves the symptoms of apathy compared with using a laptop computer and physical items with older adults living in residential aged care.

METHODS: In this multisite trial, 43 participants were allocated to one of three groups: reminiscence therapy intervention using VR in the form of HMDs, reminiscence therapy using a laptop computer supplemented by physical items if required (active control), and a usual care (passive control) group. The primary outcome was apathy, and the secondary outcomes included cognition and depression. The side effects of using HMDs were also measured in the VR group.

RESULTS: Mixed model analyses revealed no significant group interaction over time in outcomes between the VR and laptop groups (estimate=-2.24, SE 1.89; t40=-1.18; P=.24). Pooled apathy scores in the two intervention groups compared with the passive control group also revealed no significant group interaction over time (estimate=-0.26, SE 1.66; t40=-0.16; P=.88). There were no significant secondary outcomes. Most participants in the VR group stated that they would prefer to watch content in VR than on a flat screen (Χ22=11.2; P=.004), side effects from HMD use were negligible to minimal according to the Simulator Sickness Questionnaire cutoff scores.

CONCLUSIONS: Although there were no significant results in outcome measures, this study found that participants engaged in the research and enjoyed the process of reminiscing using both forms of technology. It was found that VR can be implemented in an aged care setting with correct protocols in place. Providing residents in aged care with a choice of technology may assist in increasing participation in activities. We cannot dismiss the importance of immediate effects while the therapy was in progress, and this is an avenue for future research.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001510134; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378564.

RR2-DOI: 10.1136/bmjopen-2020-046030.},
}

@article {pmid34541458,
year = {2021},
author = {Laudicella, R and Burger, IA and Panasiti, F and Longo, C and Scalisi, S and Minutoli, F and Baldari, S and Grimaldi, LME and Alongi, P},
title = {Subcutaneous Uptake on [18F]Florbetaben PET/CT: a Case Report of Possible Amyloid-Beta Immune-Reactivity After COVID-19 Vaccination.},
journal = {SN comprehensive clinical medicine},
volume = {},
number = {},
pages = {1-3},
pmid = {34541458},
issn = {2523-8973},
abstract = {Introduction: Large-scale worldwide COVID-19 vaccination programs are being rapidly deployed, and high-risk patients with comorbidity are now receiving the first doses of the vaccine. Physicians should be, therefore, aware of new pitfalls associated with the current pandemic vaccination program, also in the case of [18F]Florbetaben PET/CT.Case PresentationWe described the first image of [18F]Florbetaben PET/CT in the evaluation of a 70-year-old male with suspicious Alzheimer disease and unclear history of heart disease. We detailed the diagnostic imaging PET/CT workup with different findings.

Conclusion: In this case, [18F]Florbetaben PET/CT can demonstrate potential beta-amyloid immune-reactivity and deposition associated with the current COVID-19 pandemic vaccination programs.},
}

@article {pmid34540049,
year = {2021},
author = {Xie, L and Pu, M and Liu, Y},
title = {The effect of individual nursing on improving the living ability and blood sugar control of Alzheimer disease patients with diabetes mellitus.},
journal = {American journal of translational research},
volume = {13},
number = {8},
pages = {9324-9331},
pmid = {34540049},
issn = {1943-8141},
abstract = {OBJECTIVE: To explore the effect of individual nursing on Alzheimer disease (AD) patients with diabetes mellitus.

METHODS: A total of 119 patients with AD complicated with diabetes admitted to our hospital from January 2017 to January 2019 were selected for prospective analysis, and 64 patients received individual nursing mode, which were regarded as the personality group (PG). Another 55 patients received routine nursing mode and were regarded as the regular group (RG). The curative effect of AD, blood glucose, living ability, cognitive function, self-care ability and nursing satisfaction of the two groups were investigated.

RESULTS: There was no difference between the two groups in AD curative effect and cognitive function (P > 0.05), and the blood sugar control, living ability, self-care ability and nursing satisfaction of the PG were higher than those of the RG (P < 0.05).

CONCLUSION: Individual nursing can effectively improve the ability of blood sugar control and daily life of AD patients with diabetes mellitus, and greatly enhance the patients' trust, dependence, and satisfaction with medical staff, which is worth popularizing in clinical practice.},
}

@article {pmid34539565,
year = {2021},
author = {Malek-Ahmadi, M and Su, Y and Jansen, WJ},
title = {Editorial: Vascular Factors and Vascular Lesions in Pre-clinical Alzheimer's Disease.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {738465},
pmid = {34539565},
issn = {1664-2295},
}

@article {pmid34539551,
year = {2021},
author = {Vaismoradi, M and Behboudi-Gandevani, S and Lorenzl, S and Weck, C and Paal, P},
title = {Needs Assessment of Safe Medicines Management for Older People With Cognitive Disorders in Home Care: An Integrative Systematic Review.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {694572},
pmid = {34539551},
issn = {1664-2295},
abstract = {Background and Objectives: The global trend of healthcare is to improve the quality and safety of care for older people with cognitive disorders in their own home. There is a need to identify how medicines management for these older people who are cared by their family caregivers can be safeguarded. This integrative systematic review aimed to perform the needs assessment of medicines management for older people with cognitive disorders who receive care from their family caregivers in their own home. Methods: An integrative systematic review of the international literature was conducted to retrieve all original qualitative and quantitative studies that involved the family caregivers of older people with cognitive disorders in medicines management in their own home. MeSH terms and relevant keywords were used to search four online databases of PubMed (including Medline), Scopus, CINAHL, and Web of Science and to retrieve studies published up to March 2021. Data were extracted by two independent researchers, and the review process was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Given that selected studies were heterogeneous in terms of the methodological structure and research outcomes, a meta-analysis could not be performed. Therefore, narrative data analysis and knowledge synthesis were performed to report the review results. Results: The search process led to retrieving 1,241 studies, of which 12 studies were selected for data analysis and knowledge synthesis. They involved 3,890 older people with cognitive disorders and 3,465 family caregivers. Their methodologies varied and included cohort, randomised controlled trial, cross-sectional studies, grounded theory, qualitative framework analysis, and thematic analysis. The pillars that supported safe medicines management with the participation of family caregivers in home care consisted of the interconnection between older people's needs, family caregivers' role, and collaboration of multidisciplinary healthcare professionals. Conclusion: Medicines management for older people with cognitive disorders is complex and multidimensional. This systematic review provides a comprehensive image of the interconnection between factors influencing the safety of medicines management in home care. Considering that home-based medicines management is accompanied with stress and burden in family caregivers, multidisciplinary collaboration between healthcare professionals is essential along with the empowerment of family caregivers through education and support.},
}

@article {pmid34539542,
year = {2021},
author = {Wu, D and Kumal, JPP and Lu, X and Li, Y and Mao, D and Tang, X and Nie, M and Liu, X and Sun, L and Liu, B and Zhang, Y},
title = {Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer's-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {666430},
pmid = {34539542},
issn = {1664-2295},
abstract = {An increasing number of studies have suggested that traumatic brain injury (TBI) is associated with some neurodegenerative diseases, including Alzheimer's disease (AD). Various aspects of the mechanism of TBI-induced AD have been elucidated. However, there are also studies opposing the view that TBI is one of the causes of AD. In the present study, we demonstrated that TBI exacerbated the disruption of hippocampal-dependent learning and memory, worsened the reductions in neuronal cell density and synapse formation, and aggravated the deposition of Aβ plaques in the hippocampi of APP/PS1 mice. We also found that TBI rapidly activated microglia in the central nervous system (CNS) and that this effect lasted for at least for 3 weeks. Furthermore, TBI boosted Aβ-related microglia-mediated neuroinflammation in the hippocampi of APP/PS1 mice and the transformation of microglia toward the proinflammatory phenotype. Therefore, our experiments suggest that TBI accelerates the onset of cognitive dysfunction and Alzheimer-like pathology in the APP/PS1 mouse model, at least partly by altering microglial reactions and polarization.},
}

@article {pmid34539382,
year = {2021},
author = {Li, B and Zhang, M and Jang, I and Ye, G and Zhou, L and He, G and Lin, X and Meng, H and Huang, X and Hai, W and Chen, S and Li, B and Liu, J},
title = {Amyloid-Beta Influences Memory via Functional Connectivity During Memory Retrieval in Alzheimer's Disease.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {721171},
pmid = {34539382},
issn = {1663-4365},
abstract = {Objective: Amnesia in Alzheimer's disease (AD) appears early and could be caused by encoding deficiency, consolidation dysfunction, and/or impairment in the retrieval of stored memory information. The relationship between AD pathology biomarker β-amyloid and memory dysfunction is unclear. Method: The memory task functional MRI and amyloid PET were simultaneously performed to investigate the relationship between memory performance, memory phase-related functional connectivity, and cortical β-amyloid deposition. We clustered functional networks during memory maintenance and compared network connectivity between groups in each memory phase. Mediation analysis was performed to investigate the mediator between β-amyloid and related cognitive performance. Results: Alzheimer's disease was primarily characterized by decreased functional connectivity in a data-driven network composed of an a priori default mode network, limbic network, and frontoparietal network during the memory maintenance (0.205 vs. 0.236, p = 0.04) and retrieval phase (0.159 vs. 0.183, p = 0.017). Within the network, AD had more regions with reduced connectivity during the retrieval than the maintenance and encoding phases (chi-square p = 0.01 and < 0.001). Furthermore, the global cortical β-amyloid negatively correlated with network connectivity during the memory retrieval phase (R = - 0.247, p = 0.032), with this relationship mediating the effect of cortical β-amyloid on memory performance (average causal mediation effect = - 0.05, p = 0.035). Conclusion: We demonstrated that AD had decreased connectivity in specific networks during the memory retrieval phase. Impaired functional connectivity during memory retrieval mediated the adverse effect of β-amyloid on memory. These findings help to elucidate the involvement of cortical β-amyloid (Aβ) in the memory performance in the early stages of AD.},
}

@article {pmid34538654,
year = {2021},
author = {Sáinz Pelayo, MDP and Pelayo Vergara, R and Albu, S and Figueira, C},
title = {[Experience with 4 clinical cases. Traumatic encephalopathy may be associated with a single traumatic brain injury?].},
journal = {Rehabilitacion},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.rh.2021.04.004},
pmid = {34538654},
issn = {1578-3278},
abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that affects people who had repetitive head trauma. Also, in single traumatic brain injury (TBI), changes may be found during the follow-up visits. We present four clinical cases of patients visited at the Institut Guttmann clinic between 2017 and 2019. They were affected by mild sequelae of severe and unique TBI who have subsequently developed a neurodegenerative disease without a specific diagnosis, and who could meet clinical criteria for chronic traumatic encephalopathy syndrome. Rehabilitation doctors are the professionals with the greatest possibility of identifying a suggestive clinic of this pathology, they can order the appropriate studies and indicate the new rehabilitation goals according to the new neurological situation.},
}

@article {pmid34538105,
year = {2021},
author = {de Heus, RAA and Tzourio, C and Lee, EJL and Opozda, M and Vincent, AD and Anstey, KJ and Hofman, A and Kario, K and Lattanzi, S and Launer, LJ and Ma, Y and Mahajan, R and Mooijaart, SP and Nagai, M and Peters, R and Turnbull, D and Yano, Y and , and Claassen, JAHR and Tully, PJ},
title = {Association Between Blood Pressure Variability With Dementia and Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {},
number = {},
pages = {HYPERTENSIONAHA12117797},
doi = {10.1161/HYPERTENSIONAHA.121.17797},
pmid = {34538105},
issn = {1524-4563},
abstract = {Research links high blood pressure variability (BPV) with stroke and cerebrovascular disease, however, its association with cognition remains unclear. Moreover, it remains uncertain which BP-derived parameter (ie, variability or mean) holds more significance in understanding vascular contributions to cognitive impairment. We searched PubMed, Embase, PsycINFO, and Scopus and performed a meta-analysis of studies that quantified the association between resting BPV with dementia or cognitive impairment in adults. Two authors independently reviewed all titles, abstracts, and full-texts and extracted data, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Study quality was assessed using the (modified) Newcastle-Ottawa Scale. A multilevel meta-analysis was used, which included effect sizes for both BPV and mean BP, with a combined end point of dementia or cognitive impairment as primary outcome. In the primary analysis, 54 effect sizes were extracted from 20 studies, with a total analytical sample of n=7 899 697. Higher systolic BPV (odds ratio [OR], 1.25 [95% CI, 1.16-1.35]), mean systolic pressure (OR, 1.12 [95% CI, 1.02-1.29]), diastolic BPV (OR, 1.20 [95% CI, 1.12-1.29]), and mean diastolic pressure (OR, 1.16 [95% CI, 1.04-1.29]) were associated with dementia and cognitive impairment. A direct comparison showed that mean BP effect sizes were less strong than BPV effect sizes (OR, 0.92 [95% CI, 0.87-0.97], P<0.01), indicating that the relative contribution of BPV exceeded that of mean BP. Methodological and statistical heterogeneity was high. Secondary analyses were less consistent as to whether BPV and mean BP were differentially associated with dementia subtypes and cognitive domains. Future studies are required to investigate BPV as a target for dementia prevention.},
}

@article {pmid34537810,
year = {2021},
author = {Chen, SD and Lu, JY and Li, HQ and Yang, YX and Jiang, JH and Cui, M and Zuo, CT and Tan, L and Dong, Q and Yu, JT and , },
title = {Staging tau pathology with tau PET in Alzheimer's disease: a longitudinal study.},
journal = {Translational psychiatry},
volume = {11},
number = {1},
pages = {483},
pmid = {34537810},
issn = {2158-3188},
abstract = {A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.},
}

@article {pmid34536437,
year = {2021},
author = {Naghibi, S and Shariatzadeh Joneydi, M and Barzegari, A and Davoodabadi, A and Ebrahimi, A and Eghdami, E and Fahimpour, N and Ghorbani, M and Mohammadikia, E and Rostami, M and Salari, AA},
title = {Treadmill exercise sex-dependently alters susceptibility to depression-like behaviour, cytokines and BDNF in the hippocampus and prefrontal cortex of rats with sporadic Alzheimer-like disease.},
journal = {Physiology & behavior},
volume = {241},
number = {},
pages = {113595},
doi = {10.1016/j.physbeh.2021.113595},
pmid = {34536437},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is associated with increased depression-related behaviours. Previous studies have reported a greater risk of AD and depression in women. In recent years, we and others have provided evidence that exercise during life could be used as a therapeutic strategy for stress-related disorders such as depression. The main goal of the current study was to determine whether treadmill exercise during life can reduce depression-related behaviours in male and female Wistar rats with sporadic Alzheimer-like disease (ALD). Animals were subjected to treadmill exercise eight weeks before and four weeks after ALD induction by streptozocin (STZ). We measured body weight, food intake, and depression-related symptoms in rats using five behavioural tests. We measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the hippocampus and prefrontal cortex of animals. Our findings showed that exercise but not ALD induction decreased body weight and food intake in male and female rats. ALD induction increased depression-related symptoms and hippocampal TNF-α in male and female rats. Besides, treadmill exercise alone decreased depression-related behaviours and increased hippocampal BDNF in females but not males. We also found that treadmill exercise decreased depression-related behaviours and TNF-α in the hippocampus and prefrontal cortex, and increased IL-10 in the prefrontal cortex and BDNF in the hippocampus of female ALD-induced rats. However, treadmill exercise only reduced anhedonia-like behaviour and hippocampal TNF-α in male ALD-induced rats. Overall, the evidence from this study suggests that treadmill exercise alters depression-related behaviours, brain BDNF and cytokines in a sex-dependant manner in rats with sporadic Alzheimer-like disease.},
}

@article {pmid34535787,
year = {2021},
author = {Liu, KY and Howard, R},
title = {Can we learn lessons from the FDA's approval of aducanumab?.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34535787},
issn = {1759-4766},
abstract = {On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field.},
}

@article {pmid34532569,
year = {2021},
author = {Gerring, ZF and Gamazon, ER and White, A and Derks, EM},
title = {Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease.},
journal = {Neurology. Genetics},
volume = {7},
number = {5},
pages = {e622},
pmid = {34532569},
issn = {2376-7839},
support = {R01 HG011138/HG/NHGRI NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; },
abstract = {Background and Objectives: To integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease.

Methods: We integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene coexpression networks from brain tissue samples in the Genotype-Tissue Expression study. We identified gene coexpression networks enriched with genetic signals for Alzheimer disease and characterized the associated networks using biological pathway analysis. The disease-implicated modules were subsequently used as a molecular substrate for a computational drug repositioning analysis, in which we (1) imputed genetically regulated gene expression within Alzheimer disease implicated modules; (2) integrated the imputed gene expression levels with drug-gene signatures from the connectivity map to identify compounds that normalize dysregulated gene expression underlying Alzheimer disease; and (3) prioritized drug compounds and mechanisms of action based on the extent to which they normalize dysregulated expression signatures.

Results: Genetic factors for Alzheimer disease are enriched in brain gene coexpression networks involved in the immune response. Computational drug repositioning analyses of expression changes within the disease-associated networks retrieved known Alzheimer disease drugs (e.g., memantine) as well as biologically meaningful drug categories (e.g., glutamate receptor antagonists).

Discussion: Our results improve the biological interpretation of genetic data for Alzheimer disease and provide a list of potential antidementia drug repositioning candidates for which the efficacy should be investigated in functional validation studies.},
}

@article {pmid34532568,
year = {2021},
author = {Grangeon, L and Cassinari, K and Rousseau, S and Croisile, B and Formaglio, M and Moreaud, O and Boutonnat, J and Le Meur, N and Miné, M and Coste, T and Pipiras, E and Tournier-Lasserve, E and Rovelet-Lecrux, A and Campion, D and Wallon, D and Nicolas, G},
title = {Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.},
journal = {Neurology. Genetics},
volume = {7},
number = {5},
pages = {e609},
pmid = {34532568},
issn = {2376-7839},
abstract = {Background and Objective: To report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).

Methods: Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.

Results: Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.

Discussion: Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.},
}

@article {pmid34531734,
year = {2021},
author = {Zecca, C and Pasculli, G and Tortelli, R and Dell'Abate, MT and Capozzo, R and Barulli, MR and Barone, R and Accogli, M and Arima, S and Pollice, A and Brescia, V and Logroscino, G},
title = {The Role of Age on Beta-Amyloid1-42 Plasma Levels in Healthy Subjects.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {698571},
pmid = {34531734},
issn = {1663-4365},
abstract = {Beta-amyloid (Aβ) plaques have been observed in the brain of healthy elderlies with frequencies strongly influenced by age. The aim of the study is to evaluate the role of age and other biochemical and hematological parameters on Aβ1-42 plasma levels in cognitively and neurologically normal individuals. Two-hundred and seventy-five normal subjects stratified by age groups (<35 years, 35-65 years, and >65 years) were included in the study. Aβ1-42 plasma levels significantly correlated with age (rs = 0.27; p < 0.0001) in the whole sample, inversely correlated with age in the first age group (rs = -0.25, p = 0.01), positively correlated in the second group (rs = 0.22, p = 0.03), while there was no significant correlation in the older group (rs = 0.02, p = 0.86). Both age (β-estimate = 0.08; p < 0.001) and cholesterol (β-estimate = 0.03; p = 0.009) were significantly associated with Aβ1-42 plasma level in multivariable analysis. However, only the association with age survived post hoc adjustment for multiple comparisons. The different effects of age on the Aβ level across age groups should be explored in further studies to better understand the age-dependent variability. This could better define the value of plasma Aβ as a biomarker of the Alzheimer neuropathology.},
}

@article {pmid34531308,
year = {2021},
author = {Lopez-Grancha, M and Bernardelli, P and Moindrot, N and Genet, E and Vincent, C and Roudieres, V and Krick, A and Sabuco, JF and Machnik, D and Ibghi, D and Pradier, L and Taupin, V},
title = {A Novel Selective PKR Inhibitor Restores Cognitive Deficits and Neurodegeneration in Alzheimer Disease Experimental Models.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {378},
number = {3},
pages = {262-275},
doi = {10.1124/jpet.121.000590},
pmid = {34531308},
issn = {1521-0103},
abstract = {In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR)/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-β oligomers (AβOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, 1-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AβO-injected male mice, a 2-week administration of SAR439883 in diet dose-dependently ameliorated the AβO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins, and reduced levels of the proinflammatory cytokine interleukin-1β In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology, suggesting that inhibition of PKR is a potential therapeutic approach for AD. SIGNIFICANCE STATEMENT: This study reports the identification of a new small molecule potent and selective protein kinase R (PKR) inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer disease (AD) experimental models, including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD.},
}

@article {pmid34530925,
year = {2021},
author = {Marazuela, P and Solé, M and Bonaterra-Pastra, A and Pizarro, J and Camacho, J and Martínez-Sáez, E and Kuiperij, HB and Verbeek, MM and de Kort, AM and Schreuder, FHBM and Klijn, CJM and Castillo-Ribelles, L and Pancorbo, O and Rodríguez-Luna, D and Pujadas, F and Delgado, P and Hernández-Guillamon, M},
title = {MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {154},
pmid = {34530925},
issn = {2051-5960},
support = {R01 NS104147/NS/NINDS NIH HHS/United States ; },
abstract = {Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.},
}

@article {pmid34530113,
year = {2021},
author = {Gao, F and Liu, T and Tuo, M and Chi, S},
title = {The role of orexin in Alzheimer disease: From sleep-wake disturbance to therapeutic target.},
journal = {Neuroscience letters},
volume = {765},
number = {},
pages = {136247},
doi = {10.1016/j.neulet.2021.136247},
pmid = {34530113},
issn = {1872-7972},
abstract = {Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD.},
}

@article {pmid34530075,
year = {2021},
author = {Barone, E and Di Domenico, F and Perluigi, M and Butterfield, DA},
title = {The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease.},
journal = {Free radical biology & medicine},
volume = {176},
number = {},
pages = {16-33},
doi = {10.1016/j.freeradbiomed.2021.09.006},
pmid = {34530075},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.},
}

@article {pmid34529902,
year = {2021},
author = {Aleem, M},
title = {Phytochemistry and pharmacology of Celastrus paniculatus Wild.: a nootropic drug.},
journal = {Journal of complementary & integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1515/jcim-2021-0251},
pmid = {34529902},
issn = {1553-3840},
abstract = {OBJECTIVES: Celastrus paniculatus Wild is an evergreen climbing shrub. The plant is of great significance in the traditional Indian System of Medicine, such as Ayurveda, Unani, and Siddha. The seeds and their oil are extensively used to treat neurological disorders such as cognitive dysfunction, paralysis, epilepsy, insomnia, and other ailments like rheumatism, arthritis, sciatica, and leprosy. This paper aims to highlight the nootropic activity of C. paniculatus and explore its phytochemistry, traditional uses, and other pharmacological activities.

METHODS: All available information concerning C. paniculatus has been searched in the internationally accepted scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. Additional knowledge was gathered from the classical Textbooks and Unani Pharmacopoeia.

RESULTS: C. paniculatus is a rich source of several secondary metabolites, such as β-Dihydroagarofuranoids sesquiterpenes, alkaloids (Celastrine, Celapanin, Celapagin, and paniculatin), flavonoids, terpenoid (β-amyrin, Lupeol, Pristimerin), sterols (β-sitosterol, campesterol, stigmasterol, α-tocopherol, γ-Tocopherol), fatty acid (palmitic, stearic, oleic, linoleic, linolenic acids) and non-fatty acids (Benzoic acid, Cinnamic acid). The various study shows that the extracts and active constituent of this plant possess potent nootropic activity. Besides nootropic activity, it has also been reported for anti-Alzheimer, anticonvulsant, antidepressant, antioxidant, analgesic, anti-inflammatory, antiarthritic, gastroprotective, anti-psoriatic, wound healing, antibacterial, antimalarial, and several other properties.

CONCLUSIONS: Several in vitro and in vivo trials confirm the conventional use of C. paniculatus in cognitive dysfunction. However, the relations between the possible mechanisms of other activities and traditional uses of the C. paniculatus remain indistinct. Still, pharmacological studies also explored the effects of C. paniculatus, which were not recognized in ancient times, such as cytotoxic, ACE inhibitor, and antidiabetic activities. These discoveries are may be beneficial in the development of the new drug to treat various diseases. It is also confirmed that the β-dihydroagarofuranoids exhibit significant AChE inhibitory, cytotoxic, antibacterial, and insecticidal effects. This versatile medicine is truly a life elixir. Considering the therapeutic importance of the C. paniculatus and the absence of any reported clinical studies, extensive clinical trials are needed to explore its memory enhancing and other activities.},
}

@article {pmid34526539,
year = {2021},
author = {Benseny-Cases, N and Álvarez-Marimon, E and Aso, E and Carmona, M and Klementieva, O and Appelhans, D and Ferrer, I and Cladera, J},
title = {In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer's disease transgenic mice using synchrotron-based infrared imaging.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {18368},
pmid = {34526539},
issn = {2045-2322},
support = {IH18MIRAS//ALBA Synchrotron/ ; LCF/PR/HR19/52160007//"la Caixa" Foundation/ ; SAF2017-844-R//Spanish Ministerio de Cienia, Innovación y Universidades/ ; },
abstract = {Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer's disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.},
}

@article {pmid34526343,
year = {2021},
author = {Bollinger, RM and Keleman, A and Thompson, R and Westerhaus, E and Fagan, AM and Benzinger, TL and Schindler, SE and Xiong, C and Balota, D and Morris, JC and Ances, BM and Stark, SL},
title = {Falls: a marker of preclinical Alzheimer disease: a cohort study protocol.},
journal = {BMJ open},
volume = {11},
number = {9},
pages = {e050820},
doi = {10.1136/bmjopen-2021-050820},
pmid = {34526343},
issn = {2044-6055},
abstract = {INTRODUCTION: Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility changes seen with AD.

METHODS AND ANALYSIS: This longitudinal cohort study will be conducted at the Knight Alzheimer Disease Research Center. Approximately 350 cognitively normal participants (with and without preclinical AD) will complete an in-home visit every year for 4 years. During each yearly assessment, functional mobility will be assessed using the Performance Oriented Mobility Assessment, Timed Up and Go, and Timed Up and Go dual task. Data regarding falls (including number and severity) will be collected monthly by self-report and confirmed through interviews. This study will leverage ongoing neuropsychological assessments and neuroimaging (including molecular imaging using positron emission tomography and MRI) performed by the Knight Alzheimer Disease Research Center. Relationships between falls and biomarkers of amyloid, tau and neurodegeneration will be evaluated.

ETHICS AND DISSEMINATION: This study was approved by the Washington University in St. Louis Institutional Review Board (reference number 201807135). Written informed consent will be obtained in the home prior to the collection of any study data. Results will be published in peer-reviewed publications and presented at national and international conferences.

TRIAL REGISTRATION NUMBER: NCT04949529; Pre-results.},
}

@article {pmid34525960,
year = {2021},
author = {Khanassov, V and Rojas-Rozo, L and Sourial, R and Yang, XQ and Vedel, I},
title = {Needs of patients with dementia and their caregivers in primary care: lessons learned from the Alzheimer plan of Quebec.},
journal = {BMC family practice},
volume = {22},
number = {1},
pages = {186},
pmid = {34525960},
issn = {1471-2296},
support = {//CIHR/Canada ; },
mesh = {Aged ; *Alzheimer Disease/therapy ; Caregivers ; Cross-Sectional Studies ; *Dementia/therapy ; Humans ; Primary Health Care ; Quebec ; },
abstract = {BACKGROUND: Persons living with dementia have various health and social care needs and expectations, some which are not fully met by health providers, including primary care clinicians. The Quebec Alzheimer plan, implemented in 2014, aimed to cover these needs, but there is no research on the effect this plan had on the needs and expectations of persons living with dementia. The objective of this study is to identify persons living with dementia and caregivers' met and unmet needs and to describe their experience.

METHODS: This is a sequential mixed methods explanatory design: Phase 1: cross-sectional study to describe the met and unmet health and social care needs of community-dwelling persons living with dementia using Camberwell Assessment of Need of the Elderly and Carers' Assessment for Dementia tools. Phase 2: qualitative descriptive study to explore and understand the experiences of persons living with dementia and caregivers with the use of social and healthcare services, using semi-structured interviews. Data from phase 1 was analyzed with descriptive statistics, and from phase 2, with inductive thematic analysis. Results from phases 1 and 2 were compared, contrasted and interpreted together.

RESULTS: The mean total number of needs reported by the patients was 5.03 (4.48 and 0.55 met and unmet needs, respectively). Caregivers had 0.52 met needs (3.16 unmet needs). The main needs for both were memory, physical health, eyesight/hearing/communication, medication, looking after home, money/budgeting. Three categories were mentioned by the participants: Persons living with dementia and caregiver's attitude towards memory decline, their perception of community health services and of the family medicine practice.

CONCLUSIONS: Our study confirms the findings of other studies on the most common unmet needs of the patients and caregivers that are met partially or not at all. In addition, the participants were satisfied with access to care, and medical services in primary practices, being confident in their family. Our results indicate persons living with dementia and their caregivers need a contact person, a clear explanation of their dementia diagnosis, a care plan, written information on available services, and support for the caregivers.},
}

Aged
*Alzheimer Disease/therapy
Caregivers
Cross-Sectional Studies
*Dementia/therapy
Humans
Primary Health Care
Quebec

@article {pmid34525093,
year = {2021},
author = {Kauwe, G and Tracy, TE},
title = {Amyloid beta emerges from below the neck to disable the brain.},
journal = {PLoS biology},
volume = {19},
number = {9},
pages = {e3001388},
pmid = {34525093},
issn = {1545-7885},
abstract = {Accumulation of amyloid beta (Aβ) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aβ from the liver can promote brain pathology, supporting that peripheral Aβ can contribute to neurodegeneration.},
}

@article {pmid34524968,
year = {2021},
author = {Chiong, W and Tsou, AY and Simmons, Z and Bonnie, RJ and Russell, JA and , },
title = {Ethical Considerations in Dementia Diagnosis and Care: AAN Position Statement.},
journal = {Neurology},
volume = {97},
number = {2},
pages = {80-89},
doi = {10.1212/WNL.0000000000012079},
pmid = {34524968},
issn = {1526-632X},
abstract = {Alzheimer disease and other dementias present unique practical challenges for patients, their families, clinicians, and health systems. These challenges reflect not only the growing public health effect of dementia in an aging global population, but also more specific ethical complexities including early loss of patients' capacity to make decisions regarding their own care, the stigma often associated with a dementia diagnosis, the difficulty of balancing concern for patients' welfare with respect for patients' remaining independence, and the effect on the physical, emotional, and financial well-being of family caregivers. Caring for patients with dementia requires respecting patient autonomy while acknowledging progressively diminishing decisional capacity and continuing to provide care in accordance with other core ethical principles (beneficence, justice, and nonmaleficence). Whereas these ethical principles remain unchanged, neurologists must reconsider how to apply them given changes across multiple domains including our understanding of disease, clinical and legal tools for addressing manifestations of illness, our expanding awareness of the crucial role of family caregivers in providing care and maintaining patient quality of life, and societal conceptions of dementia and individuals' personal expectations for aging. This revision to the American Academy of Neurology's 1996 position statement summarizes ethical considerations that often arise in caring for patients with dementia; although it addresses how such considerations influence patient management, it is not a clinical practice guideline.},
}

@article {pmid34524654,
year = {2021},
author = {Parker, K and Vincent, B and Rhee, Y and Choi, BJ and Robinson-Lane, SG and Hamm, JM and Klawitter, L and Jurivich, DA and McGrath, R},
title = {The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
pmid = {34524654},
issn = {1720-8319},
abstract = {BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis.

AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization.

METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years.

RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%).

DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless.

CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.},
}

@article {pmid34522196,
year = {2021},
author = {Hassanzadeh, M and Hassanzadeh, F and Khodarahmi, GA and Rostami, M and Azimi, F and Nadri, H and Homayouni Moghadam, F},
title = {Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.},
journal = {Research in pharmaceutical sciences},
volume = {16},
number = {5},
pages = {482-492},
pmid = {34522196},
issn = {1735-5362},
abstract = {Background and purpose: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects.

Experimental approach: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds.

Findings/Results: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 μM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 μM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons.

Conclusion and implications: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.},
}

@article {pmid34522195,
year = {2021},
author = {Teymuori, M and Yegdaneh, A and Rabbani, M},
title = {Effects of Piper nigrum fruit and Cinnamum zeylanicum bark alcoholic extracts, alone and in combination, on scopolamine-induced memory impairment in mice.},
journal = {Research in pharmaceutical sciences},
volume = {16},
number = {5},
pages = {474-481},
pmid = {34522195},
issn = {1735-5362},
abstract = {Background and purpose: Alzheimer's disease is a progressive brain disorder that is thought to be triggered via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, antioxidant phytochemicals with the ability to fortify cholinergic function should help in preventing the progress of the disease. This study aimed at evaluating the combinational effects of two popular herbs one with anticholinesterase activity namely Piper nigrum and the other with antioxidant capacity, Cinnamomum zeylanicum.

Experimental approach: In this study, P. nigrum extract (PN) (50, 100 mg/kg, ip) and C. zeylanicum extract (CZ) (100, 200, 400 mg/kg, ip) and their combinations were administered for 8 days before the injection of scopolamine (1 mg/kg, ip). Mice were then tested for their memory using two behavioral models, namely the object recognition test and the passive avoidance task.

Findings/Results: Administration of scopolamine significantly impaired memory performance in both memory paradigms. In the passive avoidance test (PAT) model, PN at doses up to 100 mg/kg and CZ at doses up to 400 mg/kg did not significantly alter the memory impairment induced by scopolamine. The combination of these two plant extracts did not change the PAT parameters. In the object recognition test (ORT) model, however, administration of 100 mg/kg CZ alone and a combination of PN (50 mg/kg) with CZ (400 mg/kg), significantly increased the recognition index (P < 0.05).

Conclusion and implications: Two plant extracts when administered alone or in combinations affected the memory performance differently in two memory paradigms. In the PAT model, the extracts did not show any memory improvement, in ORT, however, some improvements were observed after plant extracts.},
}

@article {pmid34522039,
year = {2021},
author = {Bettcher, BM and Tansey, MG and Dorothée, G and Heneka, MT},
title = {Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34522039},
issn = {1759-4766},
abstract = {Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates that pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.},
}

@article {pmid34521342,
year = {2021},
author = {Wen, J and Zhao, M and Sun, W and Cheng, X and Yu, L and Cao, D and Li, P},
title = {Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.},
journal = {BMC neuroscience},
volume = {22},
number = {1},
pages = {53},
pmid = {34521342},
issn = {1471-2202},
support = {81660620//National Natural Science Foundation/ ; },
abstract = {BACKGROUND: The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.

RESULTS: In this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important "carrier" for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.

CONCLUSIONS: This is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.},
}

@article {pmid34520451,
year = {2021},
author = {Lam, V and Takechi, R and Hackett, MJ and Francis, R and Bynevelt, M and Celliers, LM and Nesbit, M and Mamsa, S and Arfuso, F and Das, S and Koentgen, F and Hagan, M and Codd, L and Richardson, K and O'Mara, B and Scharli, RK and Morandeau, L and Gauntlett, J and Leatherday, C and Boucek, J and Mamo, JCL},
title = {Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.},
journal = {PLoS biology},
volume = {19},
number = {9},
pages = {e3001358},
pmid = {34520451},
issn = {1545-7885},
abstract = {Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.},
}

@article {pmid34519052,
year = {2021},
author = {Kozlowska, U and Nichols, C and Wiatr, K and Figiel, M},
title = {From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.15509},
pmid = {34519052},
issn = {1471-4159},
abstract = {The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.},
}

@article {pmid34518345,
year = {2021},
author = {Watt, JA and Marple, R and Hemmelgarn, B and Straus, SE},
title = {Should Canadian patients look forward to aducanumab for Alzheimer disease?.},
journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne},
volume = {193},
number = {36},
pages = {E1430-E1431},
pmid = {34518345},
issn = {1488-2329},
}

@article {pmid34517889,
year = {2021},
author = {Hassenstab, J and Nicosia, J and LaRose, M and Aschenbrenner, AJ and Gordon, BA and Benzinger, TLS and Xiong, C and Morris, JC},
title = {Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {153},
pmid = {34517889},
issn = {1758-9193},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P01AG03991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; K01 AG 053474/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.

METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer's Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness.

RESULTS: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong's test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = - 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15-0.16, ps < 0.007).

CONCLUSIONS: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.},
}

@article {pmid34516970,
year = {2021},
author = {Di Lauro, C and Bianchi, C and Sebastián-Serrano, Á and Soria-Tobar, L and Alvarez-Castelao, B and Nicke, A and Díaz-Hernández, M},
title = {P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102173},
doi = {10.1016/j.pneurobio.2021.102173},
pmid = {34516970},
issn = {1873-5118},
abstract = {Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2X7 receptors (P2X7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2X7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2X7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2X7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2X7 overexpression caused a significant worsening of Tau-induced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2X7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies.},
}

@article {pmid34515788,
year = {2021},
author = {Schwartz, JB and Weintraub, S},
title = {Treatment for Alzheimer Disease-Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials.},
journal = {JAMA network open},
volume = {4},
number = {9},
pages = {e2124386},
doi = {10.1001/jamanetworkopen.2021.24386},
pmid = {34515788},
issn = {2574-3805},
}

@article {pmid34515784,
year = {2021},
author = {Martinkova, J and Quevenco, FC and Karcher, H and Ferrari, A and Sandset, EC and Szoeke, C and Hort, J and Schmidt, R and Chadha, AS and Ferretti, MT},
title = {Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis.},
journal = {JAMA network open},
volume = {4},
number = {9},
pages = {e2124124},
doi = {10.1001/jamanetworkopen.2021.24124},
pmid = {34515784},
issn = {2574-3805},
abstract = {Importance: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.

Objective: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.

Data Sources: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020.

Study Selection: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment.

Data Extraction and Synthesis: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model.

Main Outcomes and Measures: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied.

Results: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P < .001) and Europe (68.2%; difference, -10.67% [95% CI, -12.39% to -8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03).

Conclusions and Relevance: In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.},
}

@article {pmid34515750,
year = {2021},
author = {Planche, V and Villain, N},
title = {US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3126},
pmid = {34515750},
issn = {2168-6157},
}

@article {pmid34513285,
year = {2021},
author = {Ford, JN and Sweeney, EM and Skafida, M and Glynn, S and Amoashiy, M and Lange, DJ and Lin, E and Chiang, GC and Osborne, JR and Pahlajani, S and de Leon, MJ and Ivanidze, J},
title = {Heuristic scoring method utilizing FDG-PET statistical parametric mapping in the evaluation of suspected Alzheimer disease and frontotemporal lobar degeneration.},
journal = {American journal of nuclear medicine and molecular imaging},
volume = {11},
number = {4},
pages = {313-326},
pmid = {34513285},
issn = {2160-8407},
abstract = {Distinguishing frontotemporal lobar degeneration (FTLD) and Alzheimer Disease (AD) on FDG-PET based on qualitative review alone can pose a diagnostic challenge. SPM has been shown to improve diagnostic performance in research settings, but translation to clinical practice has been lacking. Our purpose was to create a heuristic scoring method based on statistical parametric mapping z-scores. We aimed to compare the performance of the scoring method to the initial qualitative read and a machine learning (ML)-based method as benchmarks. FDG-PET/CT or PET/MRI of 65 patients with suspected dementia were processed using SPM software, yielding z-scores from either whole brain (W) or cerebellar (C) normalization relative to a healthy cohort. A non-ML, heuristic scoring system was applied using region counts below a preset z-score cutoff. W z-scores, C z-scores, or WC z-scores (z-scores from both W and C normalization) served as features to build random forest models. The neurological diagnosis was used as the gold standard. The sensitivity of the non-ML scoring system and the random forest models to detect AD was higher than the initial qualitative read of the standard FDG-PET [0.89-1.00 vs. 0.22 (95% CI, 0-0.33)]. A categorical random forest model to distinguish AD, FTLD, and normal cases had similar accuracy than the non-ML scoring model (0.63 vs. 0.61). Our non-ML-based scoring system of SPM z-scores approximated the diagnostic performance of a ML-based method and demonstrated higher sensitivity in the detection of AD compared to qualitative reads. This approach may improve the diagnostic performance.},
}

@article {pmid34512509,
year = {2021},
author = {Finneran, DJ and Njoku, IP and Flores-Pazarin, D and Ranabothu, MR and Nash, KR and Morgan, D and Gordon, MN},
title = {Toward Development of Neuron Specific Transduction After Systemic Delivery of Viral Vectors.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {685802},
pmid = {34512509},
issn = {1664-2295},
abstract = {Widespread transduction of the CNS with a single, non-invasive systemic injection of adeno-associated virus is now possible due to the creation of blood-brain barrier-permeable capsids. However, as these capsids are mutants of AAV9, they do not have specific neuronal tropism. Therefore, it is necessary to use genetic tools to restrict expression of the transgene to neuronal tissues. Here we compare the strength and specificity of two neuron-specific promoters, human synapsin 1 and mouse calmodulin/calcium dependent kinase II, to the ubiquitous CAG promoter. Administration of a high titer of virus is necessary for widespread CNS transduction. We observed the neuron-specific promoters drive comparable overall expression in the brain to the CAG promoter. Furthermore, the neuron-specific promoters confer significantly less transgene expression in peripheral tissues compared with the CAG promoter. Future experiments will utilize these delivery platforms to over-express the Alzheimer-associated pathological proteins amyloid-beta and tau to create mouse models without transgenesis.},
}

@article {pmid34512506,
year = {2021},
author = {Tsolaki, M and Tsatali, M and Gkioka, M and Poptsi, E and Tsolaki, A and Papaliagkas, V and Tabakis, IM and Lazarou, I and Makri, M and Kazis, D and Papagiannopoulos, S and Kiryttopoulos, A and Koutsouraki, E and Tegos, T},
title = {Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {683131},
pmid = {34512506},
issn = {1664-2295},
abstract = {Background: This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. Methods: The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. Results: In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. Conclusion: In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.},
}

@article {pmid34512305,
year = {2021},
author = {Sevinc, G and Rusche, J and Wong, B and Datta, T and Kaufman, R and Gutz, SE and Schneider, M and Todorova, N and Gaser, C and Thomalla, G and Rentz, D and Dickerson, BD and Lazar, SW},
title = {Mindfulness Training Improves Cognition and Strengthens Intrinsic Connectivity Between the Hippocampus and Posteromedial Cortex in Healthy Older Adults.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {702796},
pmid = {34512305},
issn = {1663-4365},
abstract = {Maintaining optimal cognitive functioning throughout the lifespan is a public health priority. Evaluation of cognitive outcomes following interventions to promote and preserve brain structure and function in older adults, and associated neural mechanisms, are therefore of critical importance. In this randomized controlled trial, we examined the behavioral and neural outcomes following mindfulness training (n = 72), compared to a cognitive fitness program (n = 74) in healthy, cognitively normal, older adults (65-80 years old). To assess cognitive functioning, we used the Preclinical Alzheimer Cognitive Composite (PACC), which combines measures of episodic memory, executive function, and global cognition. We hypothesized that mindfulness training would enhance cognition, increase intrinsic functional connectivity measured with magnetic resonance imaging (MRI) between the hippocampus and posteromedial cortex, as well as promote increased gray matter volume within those regions. Following the 8-week intervention, the mindfulness training group showed improved performance on the PACC, while the control group did not. Furthermore, following mindfulness training, greater improvement on the PACC was associated with a larger increase in intrinsic connectivity within the default mode network, particularly between the right hippocampus and posteromedial cortex and between the left hippocampus and lateral parietal cortex. The cognitive fitness training group did not show such effects. These findings demonstrate that mindfulness training improves cognitive performance in cognitively intact older individuals and strengthens connectivity within the default mode network, which is particularly vulnerable to aging affects. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT02628548], identifier [NCT02628548].},
}

@article {pmid34511072,
year = {2021},
author = {Islam, MS and Mia, MAK and Rahman, MS and Arefin, MS and Dhar, PK and Koshiba, T},
title = {Frequent contiguous pattern mining over biological sequences of protein misfolded diseases.},
journal = {BMC bioinformatics},
volume = {22},
number = {1},
pages = {435},
pmid = {34511072},
issn = {1471-2105},
mesh = {Amino Acid Sequence ; Amino Acids ; Humans ; *Retinitis Pigmentosa ; Rhodopsin ; },
abstract = {BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools.

RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method.

CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.},
}

Amino Acid Sequence
Amino Acids
Humans
*Retinitis Pigmentosa
Rhodopsin

@article {pmid34510664,
year = {2021},
author = {Maayan, G and Behar, AE and Sabater, L and Baskin, M and Hureau, C},
title = {A Water-Soluble Peptoid Chelator that Can Remove Cu2+ from Amyloid-β and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {},
doi = {10.1002/anie.202109758},
pmid = {34510664},
issn = {1521-3773},
abstract = {Cu bound to Amyloid-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer's disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn2+ ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex. Herein we describe P3, a water-soluble peptidomimetic chelator that selectively removes Cu(II) from Cu-Aβ in the presence of Zn and prevent the formation of ROS even in a reductive environment. We demonstrate, based on extensive spectroscopic analysis, that although P3 extracts Zn from Cu,Zn-Aβ faster than in removes Cu, the formed Zn complexes are kinetic products that further dissociate, while CuP3 is formed as an exclusive stable thermodynamic product. Our unique findings, combined with the bioavailability of peptoids, make P3 an excellent drug candidate in the context of AD.},
}

@article {pmid34509621,
year = {2021},
author = {George, KM and Peterson, RL and Gilsanz, P and Barnes, LL and Mayeda, ER and Glymour, MM and Mungas, DM and DeCarli, CS and Whitmer, RA},
title = {Stroke Belt Birth State and Late-life Cognition in The Study of Healthy Aging in African Americans (STAR).},
journal = {Annals of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annepidem.2021.09.001},
pmid = {34509621},
issn = {1873-2585},
abstract = {PURPOSE: We examined the association of Stroke Belt birth state with late-life cognition in The Study of Healthy Aging in African Americans (STAR).

METHODS: STAR enrolled 764 Black Americans ages 50+ who were long-term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check-ups (MHC;1964-1985) where early-life overweight/obesity, hypertension, diabetes, and hyperlipidemia were measured. At STAR (2018), birth state, self-reported early-life socioeconomic status (SES), and executive function, verbal episodic memory, and semantic memory scores were collected. We used linear regression to examine the association between Stroke Belt birth and late-life cognition adjusting for birth year, gender, and parental education. We evaluated early-life SES and cardiovascular risk factors (CVRF) as potential mechanisms.

RESULTS: Twenty-seven percent of participants were born in the Stroke Belt with a mean age of 69(SD=9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β(95% CI):-0.18(-0.33,-0.02)) and semantic memory (-0.37(-0.53, -0.21)), but not verbal episodic memory (-0.04(-0.20, 0.12)). Adjustment for SES and CVRF attenuated associations of Stroke Belt birth with cognition (executive function (-0.05(-0.25, 0.14)); semantic memory (-0.28(-0.49, -0.07))).

CONCLUSION: Black Americans born in the Stroke Belt had worse late-life cognition than those born elsewhere, underscoring the importance of early-life exposures on brain health.},
}

@article {pmid34509401,
year = {2021},
author = {Bello-Medina, PC and González-Franco, DA and Vargas-Rodríguez, I and Díaz-Cintra, S},
title = {Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.},
journal = {Neurologia (Barcelona, Spain)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nrleng.2019.06.008},
pmid = {34509401},
issn = {2173-5808},
abstract = {INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response.

DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address 2 factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment.

CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.},
}

@article {pmid34508753,
year = {2021},
author = {Baldinotti, R and Fronza, MG and Fetter, J and Silva, L and Bender, CB and Lüdtke, DS and Seixas, FK and Collares, T and Alves, D and Savegnago, L},
title = {Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {910},
number = {},
pages = {174499},
doi = {10.1016/j.ejphar.2021.174499},
pmid = {34508753},
issn = {1879-0712},
abstract = {Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.},
}

@article {pmid34507341,
year = {2021},
author = {Flugon, SJ and Jøranson, N and Tangen, GG},
title = {Mobility and Depressive Symptoms in Persons With Mild Cognitive Impairment and Alzheimer Dementia.},
journal = {Journal of neurologic physical therapy : JNPT},
volume = {},
number = {},
pages = {},
doi = {10.1097/NPT.0000000000000378},
pmid = {34507341},
issn = {1557-0584},
abstract = {BACKGROUND AND PURPOSE: Persons with mild cognitive impairment (MCI) and Alzheimer dementia (AD) often experience gait and balance disturbances and depressive symptoms alongside their cognitive impairment. The aim of this study was to explore the relationship between mobility and depressive symptoms in community-dwelling persons with MCI and mild to moderate AD.

METHODS: Ninety-nine participants with MCI and AD from the memory clinic at Oslo University Hospital, Ullevål, Norway, were included. The Balance Evaluation Systems Test (BESTest), 10-m walk test regular (gait speed), and dual task (naming animals, dual-task cost in percent) were used to assess mobility. The Cornell Scale for Depression in Dementia, with validated cut-off 5/6 points, was used to assess presence of depressive symptoms. Multiple regression analysis was used to explore the relationship between mobility (3 separate models) and depressive symptoms, controlled for demographic factors, comorbidity, and Mini-Mental State Examination.

RESULTS: One-third of the participants had depressive symptoms, mean (SD) gait speed was 1.09 (0.3) m/s, and median (interquartile range) BESTest percent score was 81.5 (17.6). No statistically significant associations were found between depression and BESTest, gait speed or dual-task cost, neither in the simple models (P = 0.15-0.85), nor in the 3 multivariate models (P = 0.57-0.69).

DISCUSSION AND CONCLUSIONS: In this study, we found no associations between mobility and depressive symptoms in persons with MCI and AD recruited at a memory clinic. Few participants had major symptoms of depression, which may have influenced the results. Longitudinal studies are needed to explore the long-time associations between mobility and depression.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A366).},
}

@article {pmid34507318,
year = {2021},
author = {Brenowitz, WD and Xiang, Y and McEvoy, CT and Yang, C and Yaffe, K and Le, WD and Leng, Y},
title = {Current Alzheimer disease research highlights: evidence for novel risk factors.},
journal = {Chinese medical journal},
volume = {134},
number = {18},
pages = {2150-2159},
pmid = {34507318},
issn = {2542-5641},
mesh = {*Alzheimer Disease/epidemiology/etiology ; Amyloid ; Amyloid beta-Peptides ; Humans ; Risk Factors ; tau Proteins ; },
abstract = {ABSTRACT: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.},
}

*Alzheimer Disease/epidemiology/etiology
Amyloid
Amyloid beta-Peptides
Humans
Risk Factors
tau Proteins

@article {pmid34506904,
year = {2021},
author = {Sanders, OD and Rajagopal, L and Rajagopal, JA},
title = {The oxidatively damaged DNA and amyloid-β oligomer hypothesis of Alzheimer's disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2021.08.019},
pmid = {34506904},
issn = {1873-4596},
abstract = {The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still dominates the field, yet the clinical trial evidence does not robustly support it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should be elevated in the brain regions and at the disease stages where and when neuron death and synaptic protein loss begin and are the most severe, but we review previous evidence to demonstrate that this is not consistently the case. To rescue the Aβ oligomer hypothesis from falsification, we propose the novel ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally produce Aβ peptides even in healthily aging individuals, and hippocampal oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate and drive Aβ peptide aggregation into oligomers and spreading, neuron death, synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight additional evidence consistent with the underwhelming efficacy of Aβ oligomer-lowering agents, such as aducanumab, and of antioxidants, such as vitamin E, versus the so far isolated case report that DNase-I treatment for 2 months resulted in a severe AD patient's Mini-Mental State Exam score increasing from 3 to 18, reversing his diagnosis to moderate AD, according to the Mini-Mental State Exam.},
}

@article {pmid34506082,
year = {2021},
author = {Xiromerisiou, G and Bourinaris, T and Houlden, H and Lewis, PA and Senkevich, K and Hammer, M and Federoff, M and Khan, A and Spanaki, C and Hadjigeorgiou, GM and Bonstanjopoulou, S and Fidani, L and Ermolaev, A and Gan-Or, Z and Singleton, A and Vandrovcova, J and Hardy, J},
title = {SORL1 mutation in a Greek family with Parkinson's disease and dementia.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.51433},
pmid = {34506082},
issn = {2328-9503},
support = {PDF-IRGP-1102//Parkinson's Disease Foundation/United States ; },
abstract = {Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.},
}

@article {pmid34505123,
year = {2021},
author = {Kshirsagar, S and Sawant, N and Morton, H and Reddy, AP and Reddy, PH},
title = {Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddab262},
pmid = {34505123},
issn = {1460-2083},
abstract = {The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy enhancers treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, & mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aβ-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with ad.},
}

@article {pmid34505007,
year = {2021},
author = {Aguilar-Pineda, JA and Vera-Lopez, KJ and Shrivastava, P and Chávez-Fumagalli, MA and Nieto-Montesinos, R and Alvarez-Fernandez, KL and Goyzueta Mamani, LD and Davila Del-Carpio, G and Gomez-Valdez, B and Miller, CL and Malhotra, R and Lindsay, ME and Lino Cardenas, CL},
title = {Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease.},
journal = {iScience},
volume = {24},
number = {9},
pages = {102993},
pmid = {34505007},
issn = {2589-0042},
abstract = {Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD.},
}

@article {pmid34504414,
year = {2021},
author = {Nascimento, FP and Macedo-Júnior, SJ and Lapa-Costa, FR and Cezar-Dos-Santos, F and Santos, ARS},
title = {Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {703783},
pmid = {34504414},
issn = {1662-4548},
abstract = {Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.},
}

@article {pmid34504028,
year = {2021},
author = {Schindler, S and Li, Y and Buckles, VD and Gordon, BA and Benzinger, TLS and Wang, G and Coble, D and Klunk, WE and Fagan, AM and Holtzman, D and Bateman, RJ and Morris, JC and Xiong, C},
title = {Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012775},
pmid = {34504028},
issn = {1526-632X},
abstract = {OBJECTIVE: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).

METHODS: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale using longitudinal data.

RESULTS: Amyloid accumulation was evaluated in 236 individuals who underwent more than one amyloid PET scan. The average age was 66.5 ± 9.2 years and twelve individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the twenty-two individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R2=0.54, p<0.0001, root mean square error (RMSE) 4.5 years); the model was more accurate after exclusion of three likely misdiagnoses (R2=0.84, p<0.0001, RMSE of 2.8 years).

CONCLUSIONS: The age of symptom onset in sporadic AD is strongly correlated with the age that an individual reaches a tipping point in amyloid accumulation.},
}

@article {pmid34504027,
year = {2021},
author = {Buciuc, M and Josephs, KA and Jones, DT and Whitwell, JL and Graff-Radford, J},
title = {Progressive Auditory Verbal Agnosia Secondary to Alzheimer Disease.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012783},
pmid = {34504027},
issn = {1526-632X},
}

@article {pmid34501947,
year = {2021},
author = {Lee, YY and Chen, CL and Lee, IC and Lee, IC and Chen, NC},
title = {History of Falls, Dementia, Lower Education Levels, Mobility Limitations, and Aging Are Risk Factors for Falls among the Community-Dwelling Elderly: A Cohort Study.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {17},
pages = {},
pmid = {34501947},
issn = {1660-4601},
abstract = {BACKGROUND: Falling is a serious issue among elderly community dwellers, often resulting in disability. We aimed to investigate the risk factors for falls among elderly community dwellers.

METHODS: We recruited 232 participants from multiple community learning and care centers, who provided their information through questionnaires. They were divided into two groups, according to their falling events after a 1-year follow-up. Univariate and multivariate logistic regressions were used for statistical analysis.

RESULTS: A total of 64 participants reported a fall at the 1-year follow-up. The falling group comprised older and single people with lower education levels, higher rates of dementia, a history of falls, lower scores on the Mini-Mental State Examination, and more disability functions when compared to the non-falling group (all p < 0.05). The regression model showed that a history of falls (OR: 62.011; p < 0.0001), lower education levels (OR: 4.088; p = 0.039), mild dementia (OR: 20.729; p = 0.028), older age (OR: 1.176; p < 0.0001), walking for 300 m (OR: 4.153; p = 0.030), and running for 30 m (OR: 3.402; p = 0.015) were 1-year risk factors for falls.

CONCLUSION: A history of falling, low education levels, aging, mild dementia, and certain mobility limitations were strong risk factors for future falling accidents in elderly Taiwanese community dwellers.},
}

@article {pmid34500640,
year = {2021},
author = {Purgatorio, R and Gambacorta, N and de Candia, M and Catto, M and Rullo, M and Pisani, L and Nicolotti, O and Altomare, CD},
title = {First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {17},
pages = {},
pmid = {34500640},
issn = {1420-3049},
support = {PRIN, Grant 201744BN5T_004//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; PRIN, Grant 2017RPHBCW_002//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/metabolism ; Animals ; Butyrylcholinesterase/metabolism ; Cattle ; Cholinesterase Inhibitors/*pharmacology ; Factor Xa/metabolism ; Factor Xa Inhibitors/pharmacology ; Humans ; Molecular Docking Simulation ; Piperidines/pharmacology ; Structure-Activity Relationship ; Thrombin/*metabolism ; },
abstract = {Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.},
}

Acetylcholinesterase/metabolism
Alzheimer Disease/*drug therapy/metabolism
Animals
Butyrylcholinesterase/metabolism
Cattle
Cholinesterase Inhibitors/*pharmacology
Factor Xa/metabolism
Factor Xa Inhibitors/pharmacology
Humans
Molecular Docking Simulation
Piperidines/pharmacology
Structure-Activity Relationship
Thrombin/*metabolism

@article {pmid34499725,
year = {2021},
author = {Anderson, TS and Ayanian, JZ and Souza, J and Landon, BE},
title = {Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
pmid = {34499725},
issn = {1538-3598},
}

@article {pmid34499406,
year = {2021},
author = {Ryan, KC and Ashkavand, Z and Sarasija, S and Laboy, JT and Samarakoon, R and Norman, KR},
title = {Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e13472},
doi = {10.1111/acel.13472},
pmid = {34499406},
issn = {1474-9726},
support = {AG064175/AG/NIA NIH HHS/United States ; GM088213/GM/NIGMS NIH HHS/United States ; },
abstract = {Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.},
}

@article {pmid34498439,
year = {2021},
author = {Heger, I and Köhler, S and Boxtel, MV and Vugt, M and Hajema, K and Verhey, F and Deckers, K},
title = {[Raising awareness for dementia risk reduction through a public health campaign: a pre-post study].},
journal = {Tijdschrift voor gerontologie en geriatrie},
volume = {52},
number = {2},
pages = {},
doi = {10.36613/tgg.1875-6832/2021.02.01},
pmid = {34498439},
issn = {0167-9228},
mesh = {*Dementia/prevention & control ; Health Knowledge, Attitudes, Practice ; *Health Promotion ; Humans ; Mass Media ; Risk Reduction Behavior ; },
abstract = {This study evaluates a public health campaign initiated by the Alzheimer Center Limburg of Maastricht University. The aim was to increase awareness of the influence of a healthy lifestyle on lowering the risk of dementia in community-dwelling inhabitants of the Province of Limburg (aged 40 - 75 years). The campaign used mass media and public events, supported by a campaign website and mobile application (MijnBreincoach app). An additional district-oriented approach was chosen in the municipalities of Roermond, Landgraaf and Brunssum, in which local stakeholders were involved in the design and execution of campaign-related events. Population-level difference in awareness before and after the campaign was assessed in two independent samples. No pre-post difference was observed in the level of awareness of dementia risk reduction. An additional analyses in the post-campaign sample revealed that the group that reported to have heard of the campaign, was more often aware of dementia risk reduction and reported higher motivation for behavioural change than the group that had not heard of the campaign. The district-oriented approach resulted in better recognition of campaign-material and the mobile application. With regard to the individual lifestyle factors, healthy diet and physical activity were identified more often post-campaign. Cognitive activity was identified most often at both pre- and post-assessment, but there was no increase in awareness after the campaign.},
}

*Dementia/prevention & control
Health Knowledge, Attitudes, Practice
*Health Promotion
Humans
Mass Media
Risk Reduction Behavior

@article {pmid34498073,
year = {2021},
author = {Fernandes, AR and Dujardin, S and Maté de Gérando, A and Hyman, BT and Frosch, MP},
title = {Impact of Sterilization Methods on the Seeding Ability of Human Tau Proteopathic Seeds.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab087},
pmid = {34498073},
issn = {1554-6578},
abstract = {The protein tau, when misfolded in neurodegenerative diseases, has several prion-like properties including being able to spread by cell-to-cell transfer, induce templated seeding, and exist in distinct conformational strains. These properties of transmission may present health hazards when lesion-containing biospecimens are used in research and neuropathology laboratories. We evaluated the impact standard sterilization and cleaning methods have on the capacity of tau seeds to induce aggregation. We employed a previously developed, highly sensitive FRET-based biosensor assay to assess remnant tau seeding after exposure to these procedures. For tau species derived from human Alzheimer disease tissue (brain homogenate and sarkosyl-insoluble fibrils), both autoclaving and incubation in 90.6% formic acid were sufficient to reduce tau bioactivity. By contrast, boiling was not always effective in completely blocking bioactivity in the seeding assay. Notably, only formic acid incubation was able to produce a similar reduction in tissue from a P301L mutant tau mouse model of tauopathy. Our study highlights nuances in methods for inactivation of tau seeding which may support adapted tissue processing procedures, especially in research settings. These findings also highlight the importance of universal precautions when handling human neuropathological and research laboratory materials.},
}

@article {pmid34496627,
year = {2021},
author = {Lee, SR and Choi, EK and Park, SH and Jung, JH and Han, KD and Oh, S and Lip, GYH},
title = {Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.},
journal = {Stroke},
volume = {},
number = {},
pages = {STROKEAHA120033338},
doi = {10.1161/STROKEAHA.120.033338},
pmid = {34496627},
issn = {1524-4628},
abstract = {BACKGROUND AND PURPOSE: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin.

METHODS: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant-naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia.

RESULTS: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709-0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820-0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740-0.931]).

CONCLUSIONS: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.},
}

@article {pmid34496377,
year = {2021},
author = {Sternin, A and McGarry, LM and Owen, AM and Grahn, JA},
title = {The Effect of Familiarity on Neural Representations of Music and Language.},
journal = {Journal of cognitive neuroscience},
volume = {33},
number = {8},
pages = {1595-1611},
doi = {10.1162/jocn_a_01737},
pmid = {34496377},
issn = {1530-8898},
support = {300292//Canadian Institutes for Health Research/ ; 160728116, 215063, RGPIN-2016-05834, Postgraduate Scholarship - Doctoral//Natural Sciences and Engineering Research Council of Canada/ ; //McDonnell Foundation Scholar Award/ ; },
abstract = {We investigated how familiarity alters music and language processing in the brain. We used fMRI to measure brain responses before and after participants were familiarized with novel music and language stimuli. To manipulate the presence of language and music in the stimuli, there were four conditions: (1) whole music (music and words together), (2) instrumental music (no words), (3) a capella music (sung words, no instruments), and (4) spoken words. To manipulate participants' familiarity with the stimuli, we used novel stimuli and a familiarization paradigm designed to mimic "natural" exposure, while controlling for autobiographical memory confounds. Participants completed two fMRI scans that were separated by a stimulus training period. Behaviorally, participants learned the stimuli over the training period. However, there were no significant neural differences between the familiar and unfamiliar stimuli in either univariate or multivariate analyses. There were differences in neural activity in frontal and temporal regions based on the presence of language in the stimuli, and these differences replicated across the two scanning sessions. These results indicate that the way we engage with music is important for creating a memory of that music, and these aspects, over and above familiarity on its own, may be responsible for the robust nature of musical memory in the presence of neurodegenerative disorders such as Alzheimer disease.},
}

@article {pmid34496036,
year = {2021},
author = {Mahmoudi, E and Lin, P and Kamdar, N and Gonzales, G and Norcott, A and Peterson, MD},
title = {Risk of early- and late-onset Alzheimer disease and related dementia in adults with cerebral palsy.},
journal = {Developmental medicine and child neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/dmcn.15044},
pmid = {34496036},
issn = {1469-8749},
support = {AARG-NTF-20-685960/ALZ/Alzheimer's Association/United States ; 90RTHF0001-01-00//National Institute on Disability, Independent Living, and Rehabilitation Research/ ; },
abstract = {AIM: To examine the risk of Alzheimer disease and related dementia (ADRD) among adults with cerebral palsy (CP).

METHOD: Using administrative insurance claims data for 2007 to 2017 in the USA, we identified adults (45y or older) with a diagnosis of CP (n=5176). Adults without a diagnosis of CP were included as a typically developing comparison group (n=1 119 131). Using age, sex, ethnicity, other demographic variables, and a set of chronic morbidities, we propensity-matched individuals with and without CP (n=5038). Cox survival models were used to estimate ADRD risk within a 3-year follow up.

RESULTS: The unadjusted incidence of ADRD was 9 and 2.4 times higher among cohorts of adults 45 to 64 years (1.8%) and 65 years and older (4.8%) with CP than the respective unmatched individuals without CP (0.2% and 2.0% among 45-64y and 65y or older respectively). Fully adjusted survival models indicated that adults with CP had a greater hazard for ADRD (among 45-64y: unmatched hazard ratio 7.48 [95% confidence interval {CI}
6.05-9.25], matched hazard ratio 4.73 [95% CI 2.72-8.29]; among 65y or older: unmatched hazard ratio 2.21 [95% CI 1.95-2.51], matched hazard ratio 1.73 [1.39-2.15]).

INTERPRETATION: Clinical guidelines for early screening of cognitive function among individuals with CP need updating, and preventative and/or therapeutic services should be used to reduce the risk of ADRD.},
}

@article {pmid34491277,
year = {2021},
author = {Elliott, CL and Ryan, L and Silverberg, N},
title = {Building Inclusive and Open Alzheimer Disease and Alzheimer Disease-Related Dementias Research Programs.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2941},
pmid = {34491277},
issn = {2168-6157},
}

@article {pmid34489759,
year = {2021},
author = {Wang, Y and Chi, I and Zhan, Y and Chen, W and Li, T},
title = {Effectiveness of Resilience Interventions on Psychosocial Outcomes for Persons With Neurocognitive Disorders: A Systematic Review and Meta-Analysis.},
journal = {Frontiers in psychiatry},
volume = {12},
number = {},
pages = {709860},
pmid = {34489759},
issn = {1664-0640},
abstract = {Background: Neurocognitive disorders, such as mild cognitive impairment (MCI), dementia, and Alzheimer's disease, not only harm people's cognitive function but also lead to negative emotions, poor quality of life (QOL), and unsatisfactory level of well-being. Resilience can be defined as a dynamic and amendable process, which maintains or improves life satisfaction and quick recovery from own dilemma. However, no meta-analysis of randomized controlled trials (RCTs) has thus far examined the effectiveness of resilience interventions among persons with neurocognitive disorders, and the results of RCTs were inconsistent. This systematic review aimed to assess the effectiveness of resilience interventions on psychosocial outcomes among persons with neurocognitive disorders. Methods: Nine electronic Chinese and English databases (the Cochrane Library, PsycINFO, Web of Science, PubMed, Medline, Eric, JSTOR, CNKI, and WANGFANG) were searched through April 2021. Only RCTs were included, and the quality of the included studies was assessed by the Cochrane "Risk of Bias" tool. Meta-analysis was carried out on psychosocial outcomes, and heterogeneity was investigated by subgroup and sensitivity analysis. RevMan 5.4 was used for meta-analysis. Results: Fourteen RCT studies were identified, representing a total of 2,442 participants with neurocognitive disorders. The risk of bias was high or unclear for most included studies in the domains of allocation concealment, blinding participants, and interventionists. Meta-analysis showed that heterogeneity was low or moderate. There were significant differences in favor of resilience interventions compared with control on the outcome of QOL, using the Quality of Life-Alzheimer Disease scale (QOL-AD) [I 2 = 36%, standardized mean difference (SMD) = 0.14, 95% CI (0.02, 0.26), p = 0.02], and no significant differences on depression, using the Cornell Scale for Depression in Dementia (CSDD) [I 2 = 41%, SMD = -0.14, 95% CI (-0.34, 0.05), p = 0.16], and neuropsychiatric symptoms using the Neuropsychiatric Inventory Questionnaire (NPI-Q) [I 2 = 62%, SMD = -0.10, 95% CI (-0.37, -0.16), p ≤ 0.46]. Conclusions: Resilience interventions had a significant benefit on QOL but no significant benefit on depression and neuropsychiatric behavioral symptoms. More evidence is needed to answer questions about how to implement resilience interventions and how to evaluate their effectiveness.},
}

@article {pmid34489674,
year = {2021},
author = {Ou, H and Chien, WC and Chung, CH and Chang, HA and Kao, YC and Wu, PC and Tzeng, NS},
title = {Association Between Antibiotic Treatment of Chlamydia pneumoniae and Reduced Risk of Alzheimer Dementia: A Nationwide Cohort Study in Taiwan.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {701899},
pmid = {34489674},
issn = {1663-4365},
abstract = {Background: Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284-1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.},
}

@article {pmid34489627,
year = {2021},
author = {Sim, AY and Barua, S and Kim, JY and Lee, YH and Lee, JE},
title = {Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {708547},
pmid = {34489627},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.},
}