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Bibliography on: Alzheimer Disease — Current Literature

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 14 Nov 2022 at 01:30 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2022-10-20
CmpDate: 2022-10-20

Sandhoff R, K Sandhoff (2023)

Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease : Cascades of Secondary Metabolic Errors Can Generate Complex Pathologies (in LSDs).

Advances in neurobiology, 29:333-390.

Glycosphingolipids (GSLs) are a diverse group of membrane components occurring mainly on the surfaces of mammalian cells. They and their metabolites have a role in intercellular communication, serving as versatile biochemical signals (Kaltner et al, Biochem J 476(18):2623-2655, 2019) and in many cellular pathways. Anionic GSLs, the sialic acid containing gangliosides (GGs), are essential constituents of neuronal cell surfaces, whereas anionic sulfatides are key components of myelin and myelin forming oligodendrocytes. The stepwise biosynthetic pathways of GSLs occur at and lead along the membranes of organellar surfaces of the secretory pathway. After formation of the hydrophobic ceramide membrane anchor of GSLs at the ER, membrane-spanning glycosyltransferases (GTs) of the Golgi and Trans-Golgi network generate cell type-specific GSL patterns for cellular surfaces. GSLs of the cellular plasma membrane can reach intra-lysosomal, i.e. luminal, vesicles (ILVs) by endocytic pathways for degradation. Soluble glycoproteins, the glycosidases, lipid binding and transfer proteins and acid ceramidase are needed for the lysosomal catabolism of GSLs at ILV-membrane surfaces. Inherited mutations triggering a functional loss of glycosylated lysosomal hydrolases and lipid binding proteins involved in GSL degradation cause a primary lysosomal accumulation of their non-degradable GSL substrates in lysosomal storage diseases (LSDs). Lipid binding proteins, the SAPs, and the various lipids of the ILV-membranes regulate GSL catabolism, but also primary storage compounds such as sphingomyelin (SM), cholesterol (Chol.), or chondroitin sulfate can effectively inhibit catabolic lysosomal pathways of GSLs. This causes cascades of metabolic errors, accumulating secondary lysosomal GSL- and GG- storage that can trigger a complex pathology (Breiden and Sandhoff, Int J Mol Sci 21(7):2566, 2020).

RevDate: 2022-10-18

Sherazi SAM, Abbasi A, Jamil A, et al (2023)

Molecular hallmarks of long non-coding RNAs in aging and its significant effect on aging-associated diseases.

Neural regeneration research, 18(5):959-968.

Aging is linked to the deterioration of many physical and cognitive abilities and is the leading risk factor for Alzheimer's disease. The growing aging population is a significant healthcare problem globally that researchers must investigate to better understand the underlying aging processes. Advances in microarrays and sequencing techniques have resulted in deeper analyses of diverse essential genomes (e.g., mouse, human, and rat) and their corresponding cell types, their organ-specific transcriptomes, and the tissue involved in aging. Traditional gene controllers such as DNA- and RNA-binding proteins significantly influence such programs, causing the need to sort out long non-coding RNAs, a new class of powerful gene regulatory elements. However, their functional significance in the aging process and senescence has yet to be investigated and identified. Several recent researchers have associated the initiation and development of senescence and aging in mammals with several well-reported and novel long non-coding RNAs. In this review article, we identified and analyzed the evolving functions of long non-coding RNAs in cellular processes, including cellular senescence, aging, and age-related pathogenesis, which are the major hallmarks of long non-coding RNAs in aging.

RevDate: 2022-08-26

Chudobová J, H Zempel (2023)

Microtubule affinity regulating kinase (MARK/Par1) isoforms differentially regulate Alzheimer-like TAU missorting and Aβ-mediated synapse pathology.

Neural regeneration research, 18(2):335-336.

RevDate: 2018-12-02
CmpDate: 2018-05-22

Hou M, Fu YJ, Liu C, et al (2016)

[Effects of extractionfrom raspberry on hippocampus proteomics of mice suffered from ovariectomized-induced AD].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 41(15):2895-2900.

This paper was aimed to investigate the impact of the extraction from raspberry on the Alzheimer disease model protein expression. According to weight, the ovariectomized mice were randomly divided into shame operation group, model group, estrogen positive control group(0.1 g•L[-1]) and ethyl acetate extraction part control group(in dose of 18 g•kg[-1]). Each mouse in positive control group was subcutaneous injected of estradiol with 0.2 mL every two days. Raspberry effective parts group were given 0.01 mL•g[-1] raspberry ethylacetate extracts, model group and control group were given 0.01 mL•g[-1] saline once a day. The drug administration lasted for 32 days. Proteins from mice's hippocampus were extracted, then Nanol-ESI liquid-mass spectrometry system was used for detection and ProteinDiscovery software was used for identification to qualitative analysis different groups of hippocampal proteins by using the software of SIEVE. The results showed that model group compared with the mice of ethyl acetate extraction part control group have 66 differentially expressed proteins including heat shock protein, microtubule protein, protein involved in energy metabolism and protein of brain protection related proteins associated with AD. Those differences protein may be the target that Raspberry prevention and treatment of AD.

RevDate: 2020-09-30

van Hoof J, Douven B, Janssen BM, et al (2016)

Losing Items in the Psychogeriatric Nursing Home: The Perspective of Residents and Their Informal Caregivers.

Gerontology & geriatric medicine, 2:2333721416669895.

Introduction: Losing items is a time-consuming occurrence in nursing homes that is ill described. An explorative study was conducted to investigate which items got lost by nursing home residents, and how this affects the residents and family caregivers. Method: Semi-structured interviews and card sorting tasks were conducted with 12 residents with early-stage dementia and 12 family caregivers. Thematic analysis was applied to the outcomes of the sessions. Results: The participants stated that numerous personal items and assistive devices get lost in the nursing home environment, which had various emotional, practical, and financial implications. Significant amounts of time are spent on trying to find items, varying from 1 hr up to a couple of weeks. Numerous potential solutions were identified by the interviewees. Discussion: Losing items often goes together with limitations to the participation of residents. Many family caregivers are reluctant to replace lost items, as these items may get lost again.

RevDate: 2018-12-02
CmpDate: 2018-07-30

Todder D, Levartovsky M, T Dwolatzky (2016)

[MEASURING THE EFFECT OF MULTI-SENSORY STIMULATION IN THE SNOEZELEN ROOM ON SLEEP QUALITY OF ALZHEIMER PATIENTS USING ACTIGRAPH].

Harefuah, 155(12):727-730.

BACKGROUND: The most common cause of dementia is Alzheimer's disease. The major manifestation of the disease is the cognitive impairment which appears at the onset of the disease. In addition to the cognitive impairment there are behavioral dysfunctions such as apathy, anxiety, depression and sleep disturbances. The treatment for the manifestations of Alzheimer is currently pharmacological and behavioral. One of the newest behavioral treatments for Alzheimer is the multi-sensory treatment using the Snoezelen room.

METHODS: The study group included 16 hospitalized Alzheimer patients. A device called the ActiGraph, which reads movement level, was placed on the subjects' non-dominant wrist. The measurements took place continually for five nights: two nights before snoezelen treatment, the day of treatment and two nights after the treatment. This protocol was repeated after a week of rest.

RESULTS: The results showed that snoezelen treatment has a positive effect on the quality of sleep during the first week but not on the second week.

CONCLUSIONS: Snoezelen treatment should be considered as part of the treatment regimen of Alzheimer patients, in addition to the pharmacological treatments in order to improve their quality of sleep and quality of life. Larger sample size and longer periods of time are needed to confirm the effectiveness of the treatment.

RevDate: 2022-01-29

Patel S (2016)

Deviant lysosomal Ca[2+] signalling in neurodegeneration. An introduction.

Messenger (Los Angeles, Calif. : Print), 5(1-2):24-29.

Lysosomes are key acidic Ca[2+] stores. The principle Ca[2+]-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca[2+] store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann-Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease. Cellular phenotypes, underpinned by endo-lysosomal trafficking defects, are reversed by chemical or molecular targeting of TRPMLs and TPCs. Lysosomal Ca[2+] channels therefore emerge as potential druggable targets in combatting neurodegeneration.

RevDate: 2018-11-13
CmpDate: 2017-06-05

Chen D (2016)

NEUROPROTECTIVE EFFECT OF AMORPHOPHALLUS CAMPANULATUS IN STZ INDUCED ALZHEIMER RAT MODEL.

African journal of traditional, complementary, and alternative medicines : AJTCAM, 13(4):47-54.

BACKGROUND: The present investigation deals with the assessment of neuroprotective effect Amorphophallus campanulatus (AC) tuber in alzheimer diseased (AD) rat and also postulates its possible mechanism of action.

MATERIAL AND METHODS: AD was induced by administering streptozotocin i.e. STZ (3 mg/kg, ICV) day one and 3[rd] day after surgery. Surgery was performed on anesthetized rats by the help of stereotaxic apparatus. STZ induced AD rats were treated with petroleum ether extract of AC (100, 200 and 500 mg/kg, p.o.) for 14 days. Effect of AC tuber in AD rats were assessed by estimating the alteration in the behavior (Y maze apparatus and single trail passive avoidance), biochemical parameter in the brain tissue {Oxidative stress parameters (SOD, CAT and LPO), amyloid β peptide (Aβ) and acetylcholinesterase (AchE)} and histopathological study of brain tissue.

RESULT: Treatment with AC shows significant (p<0.01) increased in the % of alteration in the behavior and step through latency in Y maze task and single trial passive avoidance test compared to AD rats. AC significantly (p<0.01) decreases the Aβ1-40, Aβ1-42 peptides and AchE in the brain tissue compared to AD rats. Whereas, treatment with AC significantly reduces the oxidative stress level in AD rats. Histopathological study reveals that treatment with AC extract reduces the amyloid plaque formation in the brain tissue of AD rat.

CONCLUSION: The present study concludes the neuroprotective effect of AC extract in AD rats by reducing oxidative stress, Aβ and AchE in the brain tissue.

RevDate: 2020-10-01

Sadeghi M, Ganji F, Taghizadeh SM, et al (2016)

Preparation and Characterization of Rivastigmine Transdermal Patch Based on Chitosan Microparticles.

Iranian journal of pharmaceutical research : IJPR, 15(3):283-294.

Here we report a novel approach for preparation of a 6-day transdermal drug delivery system (TDDS) as treatment for mild to moderate Alzheimer's disease. The spray drying method was used to prepare microparticles containing the anti-Alzheimer drug, Rivastigmine, in combination with the natural polymer, chitosan, for transdermal drug delivery applications. The content of the drug was determined by High Performance Liquid Chromatography (HPLC) method which was validated as per FDA guidelines. The morphology and size range of the microparticles were determined; and the effect of drug concentration in the solution injected into the spray dryer on the particles characterizations was studied. The stability of Rivastigmine at high temperature was confirmed using FTIR analysis as well as a validate HPLC assay. The obtained results show that the drug was stable at high temperatures with 7 to 42% loading in the microparticles, and the higher drug concentrations of the solution injected into the spray dryer resulted in increase of the drug loading, surface drug and microparticles distortion. The TDDS containing the microparticles was also prepared with microparticle to dry adhesive ratios of 5, 10 and 15% using acrylic adhesive. Based on adhesion properties of the patches, gained from the probe tack and the peel adhesion 180° tests, and the 15% patch by having more drug content per unit area of the patch, and still having similar adhesion properties was compared to the microparticles-free patch of 5.1% Rivastigmine salt (equivalent to the drug content of the 15% patch) from the permeation point of view by using Franz cell diffusion over 6 days. The drug permeation rate from the microparticle-free patch was slower than the 15% microparticles patch, which is the result of crystallization of Rivastigmine salt in the acrylic adhesive. The 6-day-prepared TDDS can be considered as an alternative for one-week application of 6 Exelon patches.

RevDate: 2018-11-13
CmpDate: 2018-01-30

Abd El-Kader SM, OH Al-Jiffri (2016)

Aerobic exercise improves quality of life, psychological well-being and systemic inflammation in subjects with Alzheimer's disease.

African health sciences, 16(4):1045-1055.

BACKGROUND: Alzheimer's disease has a destructive drawbacks on the patient and his/her entire family as this disease badly af fects the behavior, cognition and abilities to do activities of daily living (ADL). The physical and mental benefits of exercise are widely known but seldom available to persons suffering from Alzheimer's disease.

OBJECTIVE: The aim of this study was to measure quality of life, systemic inflammation and psychological well-being response to aerobic exercises in Alzheimer's.

METHODS: Forty Alzheimer elderly subjects were enrolled in two groups; the first group received treadmill aerobic exercise, while the second group was considered as a control group and received no training intervention for two months. Assessment of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), Rosenberg Self-Esteem Scale (RSES),Beck Depression Inventory (BDI), Profile of Mood States(POMS) and SF-36 health quality of life (SF-36 HRQL) were taken before and at the end of the study.

RESULTS: There was a 25.2%, 19.4%, 23.5%, 21.3%, 17.7% , 11.7%, 12.5% and 10.1 % reduction in mean values of TNF-α, IL-6, BDI, POMS, health transition SF-36 subscale, bodily pain SF-36 subscale, role functioning: emotional SF-36 subscale and mental health SF-36 subscale respectively in addition to 15.7%, 13.1%, 12.6%, 11.1%, 13.2% and 11.2 % increase in mean values of RSES, physical functioning SF-36 subscale, role functioning:physical SF-36 subscale, general health SF-36 subscale, Vitality SF-36 subscale and Social functioning SF-36 subscale respectively in group (A) received aerobic exercise training, so that there was a significant reduction in the mean values of TNF-α, IL-6, BDI & POMS and increase in the mean values of SF-36 HRQL subscale scores, RSES in group (A) as a result of aerobic exercise training, while the results of group (B) who received no training intervention were not significant. Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study (P<0.05).

CONCLUSION: Treadmill walking exercise training is an effective treatment policy to improve quality of life, systemic inflammation and psychological wellbeing in Alzheimer's.

RevDate: 2022-03-21

Cummings J, Aisen P, Barton R, et al (2016)

Re-Engineering Alzheimer Clinical Trials: Global Alzheimer's Platform Network.

The journal of prevention of Alzheimer's disease, 3(2):114-120.

Alzheimer's disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer's Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.

RevDate: 2020-10-01

Lima CO, da Rocha VM, Ferreira EO, et al (2016)

Clostridium baratii: a rare case of pneumonia associated with an Alzheimer patient in Rio de Janeiro, Brazil.

JMM case reports, 3(4):e005041.

INTRODUCTION: Clostridium baratii is rarely associated with human diseases. Infection is usuallcaused by ingestion of contaminated food, and infant botulism is the most common clinical presentation.

CASE REPORT: Here we report a case of pneumonia by a non-toxigenic strain of C. baratii in an Alzheimer 70-year-old male with sepsis in Rio de Janeiro, Brazil. The micro-organism was identified by phenotypical tests, mass spectrometry (MALDI-TOF), DNA amplification (PCR) and sequencing of the 16S rRNA gene. Testing for the presence of botulinum F toxin was made using multiplex PCR. Bioassay for a large number of colonies was performed in mice to evaluate the production of any lethal toxin, but the results were negative.

CONCLUSION: To our knowledge, there are no cases of C. baratii infection reported in Brazil and we highlight the importance of anaerobic lab tests in the standard routine of diagnosis.

RevDate: 2022-04-09
CmpDate: 2017-11-06

Rasmussen KL (2016)

Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review.

Atherosclerosis, 255:145-155.

Dementia is one of the major causes of disability in later life, and ischemic heart disease is a leading cause of morbidity and mortality. Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated in both dementia and ischemic heart disease. Peripherally, liver-derived apoE is the main source of plasma apoE. Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the low density lipoprotein (LDL) receptor and the LDL receptor Related Protein (LRP). In the brain, apoE is produced mainly by astrocytes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of β-amyloid, a major pathological hallmark of Alzheimer disease. Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the ε4 allele is a strong genetic risk factor for Alzheimer disease. The characteristics of the APOE polymorphism thus suggest the qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism. Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established. The aim of this review is to summarize and discuss the current epidemiological and biological evidence for an association of plasma levels of apoE with risk of dementia and ischemic heart disease.

RevDate: 2018-11-13
CmpDate: 2017-10-23

Barrera-Ocampo A, F Lopera (2016)

Amyloid-beta immunotherapy: the hope for Alzheimer disease?.

Colombia medica (Cali, Colombia), 47(4):203-212.

Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

RevDate: 2018-01-09
CmpDate: 2018-01-09

Rubinstein W, Cossini F, D Politis (2016)

[Impact of facial emotional recognition alterations in Dementia of the Alzheimer type].

Vertex (Buenos Aires, Argentina), XXVII(128):263-269.

Face recognition of basic emotions is independent of other deficits in dementia of the Alzheimer type. Among these deficits, there is disagreement about what emotions are more difficult to recognize. Our aim was to study the presence of alterations in the process of facial recognition of basic emotions, and to investigate if there were differences in the recognition of each type of emotion in Alzheimer's disease. With three tests of recognition of basic facial emotions we evaluated 29 patients who had been diagnosed with dementia of the Alzheimer type and 18 control subjects. Significant differences were obtained in tests of recognition of basic facial emotions and between each. Since the amygdala, one of the brain structures responsible for emotional reaction, is affected in the early stages of this disease, our findings become relevant to understand how this alteration of the process of emotional recognition impacts the difficulties these patients have in both interpersonal relations and behavioral disorders.

RevDate: 2018-01-23
CmpDate: 2018-01-23

Labos E, Trojanowski S, Schapira M, et al (2016)

[New predictors in prodromal Alzheimer: Deferred phase in word recall of MIS test].

Vertex (Buenos Aires, Argentina), XXVII(129):339-353.

BACKGROUND: The Memory Impairment Screen (MIS-A) is a validated test to detect Alzheimer's Disease (AD) and other dementias. We have modified this test to suit a Spanish speaking population and added a new component, delayed recall (MIS-D).

OBJECTIVES: 1) To test a Spanish version of MIS-A and MIS-D. 2) To assess the discriminative validity of MIS-D as a screening tool for the amnestic variant of Mild Cognitive Impairment (aMCI).

METHODS: A case-control study of a cohort of 739 aged 65 years old and over, of whom 436 were healthy controls and 303 had a diagnosis of aMCI. The MCI group was patients from the Geriatric Unit for the Elderly at the Italian Hospital of Buenos Aires staffed by geriatricians.

MEASUREMENTS: ANOVA test and test t de Student mean comparison. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NVP) were estimated for MIS-D and MIS-A.

RESULTS: Normative values for MIS-A and MIS-D were obtained from the control population. Both age and education significantly affected these values (p<0.0001). The cut-off for MIS-A should be 7.5 and for MIS-D, 5.5. Comparison between control population and aMCI population using ROC curve gave a result of 5.5 in MIS-D, with 97% specificity and 76% sensitivity.

CONCLUSION: MIS-D was positively predictive of Amci. An extension of the sample in other health care contexts would enable us to verify its clinical validity for other populations.

RevDate: 2020-09-28
CmpDate: 2017-08-02

Martinez-Cancino DP, Azpiroz-Leehan J, Jimenez-Angeles L, et al (2016)

Effects of high frequency rTMS on sleep deprivation: A pilot study.

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, 2016:5937-5940.

Transcranial magnetic stimulation is a neurostimulation technique which has the potential to serve as a unique research tool for investigating a wide variety of fields in cognitive neuroscience. TMS has been approved by the FDA to serve as a treatment to depression and has also been used to evaluate its effects among several conditions such as Alzheimer, Parkinson disease, chronic pain and stroke. High frequency TMS has been previously used with the intention to measure and modulate the negative effects of sleep deprivation in cognitive performance, but there is no consensus about the ideal protocol yet. In this pilot study, we attempt to test high frequency rTMS in different brain targets in order to determine the effects in remediation of working memory due to sleep deprivation. These results provide preliminary evidence of the potential effectiveness of TMS for the treatment of cognitive impairment.

RevDate: 2017-06-20
CmpDate: 2017-06-20

Stara V, Navarova J, Ujhazy E, et al (2016)

Progressive increase of lysosomal enzyme activities in hippocampus associated with reduction of population spike in a rat model of neurodegeneration.

Neuro endocrinology letters, 37(Suppl1):111-117.

OBJECTIVES: Extensive effort has been made to identify early markers of neurodegeneration as late stages have no chance of treatment. Recently, many experimental models have been used to study hallmarks of neuronal injury. One of them is the model of trimethyltin (TMT)-induced damage associated with cognitive decline, thus called a model of Alzheimer-like disease.

OBJECTIVE AND METHODS: Our aim was to study neuronal transmission in hippocampal slices of male Wistar rats affected with a single dose of TMT (7.5 mg/kg, i.p.) during the first three weeks of its action. The monitored time periods after TMT administration were days 1-3; 8-10 and 15-17. At the same time periods, right hippocampi were collected for determination of changes in specific activities of two lysosomal enzymes. Electrophysiological measurements were based on stimulation of Schäffer collaterals and registration of evoked responses in the stratum pyramidale and the stratum radiatum at the CA3-CA1 synapse. Specific activities of N-acetyl-β-D-glucosaminidase (NAGA) and cathepsin D (Cat D) were determined spectrophotometrically.

RESULTS: During three weeks after i.p. TMT administration to rats, we found a time-dependent reduction of postsynaptic neuronal firing, expressed by diminished population spike (PoS) amplitude recorded in the stratum pyramidale accompanied with marked increase in specific activity of NAGA to respective 111%, 163% and 252% in the 1st, 2nd and 3rd week compared to unaffected rats. In the stratum radiatum, reduction of the slope of excitatory postsynaptic potential was not time-dependent but almost constantly reduced from the 1st to 3rd week after TMT administration (55-60%) compared to control rats. Specific activity of lysosomal enzyme Cat D was significantly increased in the 3rd week after TMT administration.

CONCLUSION: This work demonstrates a time-dependent reduction of somatic response in the hippocampus of TMT affected rats during the first three weeks. This reduction of neuronal firing was later accompanied with increase of specific activity of NAGA and Cat D, supporting evidence that lysosomal dysfunction may be one of the primary contributors to TMT-induced neurodegeneration.

RevDate: 2020-09-30

Maity S, YL Lyubchenko (2016)

Probing of Amyloid Aβ (14-23) Trimers by Single-Molecule Force Spectroscopy.

Jacobs journal of molecular and translational medicine, 1(1):.

Self-assembly and aggregation of amyloid peptides, such as Aβ(1-40) and Aβ(1-42), lead to the development of Alzheimer disease and similar neurodegenerative disorders associated with protein aggregation. The structures of large aggregates, specifically fibrils, are well characterized. However, our understanding about the structure of oligomeric forms of amyloids is incomplete and needs to be expanded, particularly given the finding that oligomeric rather than fibrillar amyloid morphologies are neurotoxic. This lack of knowledge is primarily due to the existence of transient oligomeric forms that require the use of non-traditional approaches capable of probing transiently existing amyloid forms. We have recently developed the Single-Molecule Force Spectroscopy (SMFS) approach enabling us to probe dimeric forms of amyloids. These studies suggest that the assembly of amyloid proteins into dimers leads to extremely stabilized amyloids in non-native, misfolded states [1]. Herein, we applied the SMFS approach to probe amyloid trimers. We used the Aβ(14-23) segment of Aβ42 protein that is responsible for full-size protein aggregation. The dimerization of this peptide was recently characterized [2]. The dimeric form of Aβ (14-23) was assembled by the use of a tandem Aβ(14-23)-YNGK-Aβ(14-23), in which the YNGK motif between the two Aβ(14-23) monomers makes a β turn to form a hairpin loop with an antiparallel arrangement of Aβ(14-23) monomers[3]. The Aβ(14-23) monomer was tethered to the AFM tip, and trimers were formed by approaching the tip to the mica surface on which the Aβ(14-23)-YNGK-Aβ(14-23) dimer was immobilized via a polyethylene glycol tether. We identified trimers by rupture forces that were considerably larger than those for dimers. Models for the trimer assembly process are discussed.

RevDate: 2022-03-21

Faizi M, Seydi E, Abarghuyi S, et al (2016)

A Search for Mitochondrial Damage in Alzheimer's Disease Using Isolated Rat Brain Mitochondria.

Iranian journal of pharmaceutical research : IJPR, 15(Suppl):185-195.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects regions of the brain that control cognition, memory, language, speech and awareness to one's physical surroundings. The pathological initiation and progression of AD is highly complex and its prevalence is on the rise. In his study, Alzheimer's disease was induced with single injection of amyloid-β (Aβ) peptides (30ng, by stereotaxy) in each hemisphere of the Wistar rat brain. Then memory dysfunction, oxidative stress and apoptosis induced by Aβ peptide were investigated on isolated brain mitochondria obtained from infected rat. Our results showed memory impairment in rats after receiving an Aβ peptide. We also found significant rise (P<0.05) at ROS formation, mitochondrial membrane depolarization, mitochondria swelling, cytochrome c release and significant decrease in ATP/ADP ratio on mitochondria isolated from brain of these memory impaired rats compared with those of untreated control rat group. Activation of caspase-3 the final mediator of apoptosis in the brain homogenate of the memory impaired rats was another justification for occurrence of neuron loss in the experimental model of AD. Our results suggest that oxidative stress and mitochondria mediated apoptosis in brain neurons play very important role in initiation of AD.

RevDate: 2018-03-08
CmpDate: 2018-02-08

Kulkarni S, Mukherjee S, Pandey A, et al (2016)

Bacillus Calmette-Guérin Confers Neuroprotection in a Murine Model of Japanese Encephalitis.

Neuroimmunomodulation, 23(5-6):278-286.

OBJECTIVE: Japanese encephalitis (JE) is a debilitating disease caused by infection with the JE virus (JEV; family: Flaviviridae), which leaves neurological sequelae in survivors but more often leads to mortality. Neurodegeneration caused by inflammation is the primary pathology behind the clinical manifestation of encephalitis caused by JEV. Bacillus Calmette-Guérin (BCG) has been used in immunoprophylaxis for tuberculosis and in the adjuvant therapy of many malignancies, and has exhibited neuroprotective activities in experimental models of Parkinson and Alzheimer disease. This study aimed at assessing the neuroprotective role of BCG in a murine model of JE.

METHODS: Suckling mice were inoculated with 106 CFU of BCG and at 18 days postinoculation were challenged with 100 LD50 of JEV. PBS-inoculated mice were used as controls. Mice were sacrificed on days 2, 4, 6, and 8. Brain tissue was homogenized for RNA extraction. One-step real-time RT-PCR was performed to assess the relative gene expressions of TNF-α, IL-6, and iNOS.

RESULTS: The BCG-inoculated (BCG+JEV) group exhibited a significant delay in the presentation of neuropathological symptoms, longer survival, and a downregulation in the expression of TNF-α, IL-6, and iNOS on days 2, 4, and 6 post-JEV challenge compared to the JEV group.

CONCLUSION: These findings indicate that the administration of BCG offers neuroprotection in the murine model of JE. BCG should therefore be further investigated as an adjuvant in the management of JE. BCG is an accepted vaccine for tuberculosis in many countries that are endemic for JEV. This approach may have a significant impact on the public health burden in these countries.

RevDate: 2022-04-08
CmpDate: 2017-09-15

Podcasy JL, CN Epperson (2016)

Considering sex and gender in Alzheimer disease and other dementias.

Dialogues in clinical neuroscience, 18(4):437-446.

Suffering related to dementia is multifaceted because cognitive and physical functioning slowly deteriorates. Advanced age and sex, two of the most prominent risk factors for dementia, are not modifiable. Lifestyle factors such as smoking, excessive alcohol use, and poor diet modulate susceptibility to dementia in both males and females. The degree to which the resulting health conditions (eg, obesity, type 2 diabetes, and cardiovascular disease) impact dementia risk varies by sex. Depending on the subtype of dementia, the ratio of male to female prevalence differs. For example, females are at greater risk of developing Alzheimer disease dementia, whereas males are at greater risk of developing vascular dementia. This review examines sex and gender differences in the development of dementia with the goal of highlighting factors that require further investigation. Considering sex as a biological variable in dementia research promises to advance our understanding of the pathophysiology and treatment of these conditions.

RevDate: 2020-10-01

Baek SS, SH Kim (2016)

Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats.

Journal of exercise rehabilitation, 12(6):526-534.

Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation.

RevDate: 2017-04-11
CmpDate: 2017-04-11

Al-Shaikhli SD, Yang MY, B Rosenhahn (2016)

Alzheimer's disease detection via automatic 3D caudate nucleus segmentation using coupled dictionary learning with level set formulation.

Computer methods and programs in biomedicine, 137:329-339.

BACKGROUND AND OBJECTIVE: This paper presents a novel method for Alzheimer's disease classification via an automatic 3D caudate nucleus segmentation.

METHODS: The proposed method consists of segmentation and classification steps. In the segmentation step, we propose a novel level set cost function. The proposed cost function is constrained by a sparse representation of local image features using a dictionary learning method. We present coupled dictionaries: a feature dictionary of a grayscale brain image and a label dictionary of a caudate nucleus label image. Using online dictionary learning, the coupled dictionaries are learned from the training data. The learned coupled dictionaries are embedded into a level set function. In the classification step, a region-based feature dictionary is built. The region-based feature dictionary is learned from shape features of the caudate nucleus in the training data. The classification is based on the measure of the similarity between the sparse representation of region-based shape features of the segmented caudate in the test image and the region-based feature dictionary.

RESULTS: The experimental results demonstrate the superiority of our method over the state-of-the-art methods by achieving a high segmentation (91.5%) and classification (92.5%) accuracy.

CONCLUSIONS: In this paper, we find that the study of the caudate nucleus atrophy gives an advantage over the study of whole brain structure atrophy to detect Alzheimer's disease.

RevDate: 2018-10-23
CmpDate: 2018-01-23

Massano J, Leão M, Garrett C, et al (2016)

[Investigation of Genetic Etiology in Neurodegenerative Dementias: Recommendations from the Centro Hospitalar São João Neurogenetics Group].

Acta medica portuguesa, 29(10):675-679.

In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of Alzheimer disease and frontotemporal dementia in clinical practice, based on international consensus documents (currently containing partly outdated information) and published scientific evidence on this topic. Alzheimer disease may be caused by mutations in PSEN1, PSEN2 and APP. APOE genotyping is not recommended for the diagnostic or genetic counseling purposes in Alzheimer disease. Frontotemporal dementia may be caused by mutations in several genes such as c9orf72, PGRN, MAPT, TBK1, VCP, SQSTM1, and UBQLN2. This paper pragmatically approaches the process of genetic diagnosis in Alzheimer disease and frontotemporal dementia, with specific recommendations for both disorders.

RevDate: 2020-10-01

Arjmand Abbassi Y, Mohammadi MT, Sarami Foroshani M, et al (2016)

Captopril and Valsartan May Improve Cognitive Function Through Potentiation of the Brain Antioxidant Defense System and Attenuation of Oxidative/Nitrosative Damage in STZ-Induced Dementia in Rat.

Advanced pharmaceutical bulletin, 6(4):531-539.

Purpose: Previous findings have shown the crucial roles of brain renin-angiotensin system (RAS) in pathogenesis of Alzheimer's disease (AD). Since RAS inhibitors may have beneficial effects on dementia and cognitive function in elderly people, the aim of present study was to examine the neuroprotective actions of captopril and valsartan on memory function and neuronal damage in experimental model of AD. Methods: Adult forty male Wistar rats (220-280g) were randomly divided into 5 groups; Control, Vehicle, Alzheimer and treatment groups. AD was induced by the injections of streptozotocin (3mg/kg, bilateral intracerebroventricular) at days 1&3. Treated rats received orally captopril (50mg/kg/day) and valsartan (30mg/kg/day). Memory function and histological assessments were done at termination of experiment. Finally, superoxide dismutase (SOD) and catalase (CAT) activities as well as malondialdehyde (MDA) and NOx contents were determined. Results: There was a significant increase in the mean value of latency in Alzheimer group (66%). Captopril and valsartan considerably decreased this value in both treatment groups (45% and 72%, respectively). In Alzheimer group the activities of brain's SOD and CAT reduced (40% and 47%, respectively) in accompany with an increase in MDA and NOx contents (49% and 50%, respectively). Captopril and valsartan significantly increased the activities of brain's SOD and CAT concomitant reduction in MDA and NOx contents. Also, histopathological damages noticeably decreased in both treatment groups. Conclusion: Our findings indicate that RAS inhibition by using captopril and valsartan potentiates the antioxidant defense system of brain and reduces oxidative/nitrosative stress in accompany with neuronal damage during AD.

RevDate: 2022-03-11

Borba EM, Duarte JA, Bristot G, et al (2016)

Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease.

Dementia and geriatric cognitive disorders extra, 6(3):559-567.

BACKGROUND/AIMS: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]).

METHODS: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®.

RESULTS: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants.

DISCUSSION: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.

RevDate: 2020-10-01

Barbe C, Morrone I, Novella JL, et al (2016)

Predictive Factors of Rapid Cognitive Decline in Patients with Alzheimer Disease.

Dementia and geriatric cognitive disorders extra, 6(3):549-558.

AIM: To determine predictive factors associated with rapid cognitive decline (RCD) in elderly patients suffering from Alzheimer disease (AD).

METHODS: Patients suffering from mild to moderate AD were included. RCD was defined as the loss of at least 3 points on the Mini-Mental State Examination (MMSE) over 12 months. Factors associated with RCD were identified by logistic regression.

RESULTS: Among 123 patients included, 61 were followed up until 12 months. RCD occurred in 46% of patients (n = 28). Polymedication (p < 0.0001), the fact that the caregiver was the child or spouse of the patient (p < 0.0001) and autonomy for washing (p < 0.0001) were protective factors against RCD, while the presence of caregiver burden (p < 0.0001) was shown to be a risk factor for RCD.

CONCLUSION: Early detection of the RCD risk in AD patients could make it possible to anticipate the patient's medical needs and adjust the care plan for caregiver burden.

RevDate: 2022-03-11

Mahmoudvand H, Sheibani V, Keshavarz H, et al (2016)

Acetylcholinesterase Inhibitor Improves Learning and Memory Impairment Induced by Toxoplasma gondii Infection.

Iranian journal of parasitology, 11(2):177-185.

BACKGROUND: Here, we established the mouse models of chronic toxoplasmosis by T. gondii Tehran strain to provide a good understanding about defining the possible association between T. gondii exposure and learning and memory impairments. Moreover, as secondary objective of the present study, we hypothesized whether administration of an acetylcholinesterase (AChE) inhibitor could reduce learning and memory impairments induced by T. gondii infection.

METHODS: Twenty-four male BALB/c mice were used to establishment of latent toxoplasmosis. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii. Donepezil (2 mg/kg) an AChE inhibitor to treat Alzheimer disease was injected intraperitoneally once a day for two weeks starting from post-infection day 90. Morris water maze (MWM) task was used to assay spatial learning and short term spatial memory in all groups. One-way ANOVA with Tukey's post-hoc test was used to assess differences between experimental groups. P<0.05 was considered statistically significant.

RESULTS: Toxoplasma infection impaired spatial leaning and short term spatial memory of the infected BALB/c mice, whereas donepezil, an AChE inhibitor, improved impairments induced by Toxoplasma infection.

CONCLUSION: T. gondii infection through increasing AChE reduces the level of Acetylcholine (Ach) and consequently affects learning and memory activity in infected hosts, whereas, donepezil as an AChE inhibitor improves these impairments by restoring ACh levels at synapses of neurons in brain.

RevDate: 2018-11-13
CmpDate: 2017-06-05

Weamer EA, DeMichele-Sweet MA, Cloonan YK, et al (2016)

Incident Psychosis in Subjects With Mild Cognitive Impairment or Alzheimer's Disease.

The Journal of clinical psychiatry, 77(12):e1564-e1569.

OBJECTIVE: To estimate the incidence of psychotic symptoms in Alzheimer's disease.

METHODS: The study consists of 776 elderly subjects presenting to the Alzheimer Disease Research Center at the University of Pittsburgh (Pittsburgh, Pennsylvania) between May 9, 2000, and August 19, 2014. All participants were diagnosed with mild cognitive impairment (National Institute on Aging-Alzheimer's Association workgroup criteria) or possible or probable Alzheimer's disease (National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) and were without psychosis at entry. Psychotic symptoms were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Behavioral Rating Scale every 6 months. One-, 3- and 5-year cumulative incidences of psychosis were calculated.

RESULTS: The 1-year psychosis incidence was 10% (95% CI, 8%-12%), and this annual rate remained remarkably consistent at 3 and 5 years. Psychosis incidence was related to cognitive status at all time points. However, the incidence rate reached a plateau during the disease course. Cumulative psychosis incidence at 5 years was 61% (95% CI, 52%-69%) in individuals with moderate to severe Alzheimer's disease, not statistically significantly different from the cumulative incidence at 3 years in this group, which was 48% (95% CI, 40%-55%) or from the 5-year incidence in individuals who entered the study with mild Alzheimer's disease, which was 48% (95% CI, 41%-56%).

CONCLUSIONS: Psychosis in Alzheimer's disease has been associated with a number of adverse clinical outcomes. We provide estimates of the risk of psychosis onset within clinically defined subgroups of individuals, a tool clinicians can use in treatment planning. Anticipating which subjects are at high risk for psychosis and the poor outcomes associated with it can help with family education and support decisions to implement nonpharmacologic strategies that may reduce or prevent symptoms.

RevDate: 2020-10-01

Jiraungkoorskul W (2016)

Review of Neuro-nutrition Used as Anti-Alzheimer Plant, Spinach, Spinacia oleracea.

Pharmacognosy reviews, 10(20):105-108.

Neuro-nutrition is the nutrition needed to achieve health brain and neurocognitive function. Diets rich in antioxidants, vitamins, flavonoids, and polyphenolic compounds will help suppress the onset of Alzheimer's disease. Spinacia oleracea (Family: Amaranthaceae) commonly known as spinach or Buai Leng (in Thai), one of the traditional medicinal plants with high in those mention nutrients. The micronutrients in spinach include a range of vitamins and minerals, which can prevent deficiency diseases and are essential for normal physiological function. Its phytochemicals are carotenoids, flavonoids, and phenolic compounds, which can prevent chronic health problems, as well as other diseases associated with aging. The objective of this article was to conduct a review on various ethnomedicinal uses of the spinach and its influences on the pathophysiology of Alzheimer's disease based on a literature review.

RevDate: 2020-10-01

Yousefirad N, Kaygısız Z, Y Aydın (2016)

Amyloid beta peptide 22-35 induces a negative inotropic effect on isolated rat hearts.

International journal of physiology, pathophysiology and pharmacology, 8(4):146-151.

Evidences indicate that deposition of amyloid beta peptides (Aβs) plays an important role in the pathogenesis of Alzheimer disease. Aβs may influence cardiovascular system and ileum contractions. But the effect of amyloid beta peptide 22-35 (Aβ22-35) on cardiovascular functions and contractions of ileum has not been studied. Therefore, the present study aimed to investigate the possible effects of this peptide on isolated rat heart and ileum smooth muscle. Langendorff-perfused rat heart preparations were established. The hearts were perfused under constant pressure (60 mmHg) with modified Krebs-Henseleit solution. Aβ22-35 at doses of 1, 10 and 100 nM significantly decreased left ventricular developed pressure (LVDP; an index of cardiac contractility) and maximal rate of pressure development of left ventricle (+dP/dtmax; another index of cardiac contractility). This peptide at doses studied had no significant effect on heart rate, coronary flow, monophasic action potential amplitude (MAPamp), MAP duration at 90% repolarization (MAP90) and ileum contractions. We suggest that Aβ22-35 exerts a negative inotropism on isolated rat hearts with unchanged heart rate, coronary flow, MAPamp, MAP90 and smooth muscle contractility of ileum.

RevDate: 2020-10-01

Cardona-Gómez GP, F Lopera (2016)

Dementia, Preclinical Studies in Neurodegeneration and its Potential for Translational Medicine in South America.

Frontiers in aging neuroscience, 8:304.

Latin-American people with dementia will increase to an astounding 368% in 2050, higher than USA and Europe. In addition, to sporadic dementia type like Alzheimer, and vascular dementia (VaD) progression after Cerebrovascular disease is also found. These incidences are increased in Colombia by specific populations affected with pure Neurodegenerative and VaDs like Autosomical Dominant familial Alzheimer's disease (AD) and Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). In spite of the enormous human effort with and economical effort and investment costs, neither sporadic nor genetic kinds of dementia progression have been prevented or blocked yet. Currently, there exist several animal models that partially solve the understanding of the neurodegenerative etiopathogenesis and its treatment. However, when the potential therapies are translated to humans, those do not work or present a limited action. Main difficulties are the diverse comorbility associated to the cause and/or several affected brain regions, reducing the efficacy of some therapies which are limited to a tissue-specific action or modulating a kind of neurotransmission. Global investigation suggests that a general prevention could be achieved with the improvement in the quality of lifestyle, including healthy diet, physical and mental activity, and avoiding mechanical or chemical pro-inflammatory events in an early stage in the most of non-communicable diseases. In this review article, we present some molecular targets and preclinical studies in animal models to propose strategies that could be useful in a future translation to prevent or block neurodegeneration: one is gene therapy; silencing pathogenic genes in critical brain areas where excitotoxicity arise and spread. Another is to take advantage of the natural source and its wide biodiversity of natural products that are capable of identifying, by the blocking and prevention of neurodegeneration. On the other side, the casuistic of pure dementias in the Latin-American region gives an exceptional opportunity to understand the pathogenesis in these human populations. Further, this is in support of the basic and clinical researchers working on an interaction for a better understanding and medical care of mixed dementias, which have more complex factors than pure ones. However, to promote the translation of any therapeutical alternative is necessary to clarify the normative and the protocols for developing clinical trials with original candidates or work upon strategies proposed from South-American countries.

RevDate: 2020-10-01

Seipold L, P Saftig (2016)

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein.

Frontiers in molecular neuroscience, 9:149.

Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.

RevDate: 2017-03-21
CmpDate: 2017-03-21

Khmeleva SA, Kozin SA, Kiseleva YY, et al (2016)

[Zinc-induced interactions of the metal-binding domain of beta-amyloid with nucleic acids and glycosaminoglycans].

Molekuliarnaia biologiia, 50(6):1049-1052.

Zinc ions form complexes with β-amyloid peptides and play an important role in Alzheimer's disease pathogenesis. It has been demonstrated by turbidimetry and correlation spectroscopy that synthetic peptide Aβ16 representing the metal-binding domain of β-amyloid is able to interact with nucleic acids, chondroitin polysulfate, and dextran sulfates in the presence of zinc ions. The amino acid D7H substitution enhanced the peptide binding to polyanions, whereas the H6R and H6A-H13A substitutions abolished this interaction. It is suggested that the metal-binding domain may serve as a zinc-dependent site of β-amyloid interaction with biological polyanions including DNA, RNA, and glycosaminoglycans.

RevDate: 2020-10-01

Deak F, Kapoor N, Prodan C, et al (2016)

Memory loss: Five new things.

Neurology. Clinical practice, 6(6):523-529.

PURPOSE OF REVIEW: Memory loss can be due to a wide variety of causes. We provide new information about the biology of common genetic and acquired causes of memory loss in older adults.

RECENT FINDINGS: New data are available about the genetics of Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia. Amyloid PET, FDG-PET, and MRI have improved our understanding of how mild cognitive impairment evolves to AD. Several studies have shown links between concussion and chronic traumatic encephalopathy. Healthy eating and regular exercise have been demonstrated to slow cognitive decline in older adults. Randomized trials continue to show benefits for cholinesterase inhibitors and memantine in patients with AD and DLB.

SUMMARY: New causes of memory loss are still being identified. More sophisticated diagnostic tools have improved our ability to make earlier diagnoses in older adults with memory loss.

RevDate: 2020-09-28

Stage E, Duran T, Risacher SL, et al (2016)

The effect of the top 20 Alzheimer disease risk genes on gray-matter density and FDG PET brain metabolism.

Alzheimer's & dementia (Amsterdam, Netherlands), 5:53-66.

INTRODUCTION: We analyzed the effects of the top 20 Alzheimer disease (AD) risk genes on gray-matter density (GMD) and metabolism.

METHODS: We ran stepwise linear regression analysis using posterior cingulate hypometabolism and medial temporal GMD as outcomes and all risk variants as predictors while controlling for age, gender, and APOE ε4 genotype. We explored the results in 3D using Statistical Parametric Mapping 8.

RESULTS: Significant predictors of brain GMD were SLC24A4/RIN3 in the pooled and mild cognitive impairment (MCI); ZCWPW1 in the MCI; and ABCA7, EPHA1, and INPP5D in the AD groups. Significant predictors of hypometabolism were EPHA1 in the pooled, and SLC24A4/RIN3, NME8, and CD2AP in the normal control group.

DISCUSSION: Multiple variants showed associations with GMD and brain metabolism. For most genes, the effects were limited to specific stages of the cognitive continuum, indicating that the genetic influences on brain metabolism and GMD in AD are complex and stage dependent.

RevDate: 2020-10-01

Raman MR, Kantarci K, Murray ME, et al (2016)

Imaging markers of cerebrovascular pathologies: Pathophysiology, clinical presentation, and risk factors.

Alzheimer's & dementia (Amsterdam, Netherlands), 5:5-14.

Cerebrovascular pathologies (CVPs) are common pathologies associated with age-related cognitive decline along with Alzheimer disease pathologies. The impact of CVP on the prevalence of dementia is increasingly being recognized. The goal of this review is to improve our understanding of the pathophysiological underpinnings and the multimodal magnetic resonance imaging and positron emission tomography imaging changes that are associated with the hallmarks of CVP. This knowledge will facilitate the development of early detection, intervention, and prevention strategies that may contribute to lowering the risk of dementia. In this review, we will first discuss currently known risk factors of CVPs including cardiovascular, lifestyle, genetic, sex differences, and head injury. Next, we will focus on the pathophysiology of CVPs and their impact on neurodegeneration and downstream cognitive impairment. Specifically, we will discuss three of the most common cerebrovascular lesions seen on MRI: white-matter hyperintensity, microbleeds, and infarcts. Finally, we will discuss the unanswered open questions in this field.

RevDate: 2020-10-01

Han MH, Lee EH, SH Koh (2016)

Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function.

International neurourology journal, 20(4):276-287.

Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports.

RevDate: 2020-10-01

Cacciottolo M, Morgan TE, CE Finch (2016)

Rust on the Brain from Microbleeds and Its Relevance to Alzheimer Studies: Invited Commentary on Cacciottolo Neurobiology of Aging, 2016.

Journal of Alzheimer's disease & Parkinsonism, 6(6):.

Cerebral microbleeds (MB) and small vessel disease (SVD) with congophilic arterial angiopathy (CAA) are increasingly recognized as a variable factor in AD cognitive impairments. This commentary on our recent report on sex-ApoE interactions in MBs published this February, briefly explores three aspects of MBs that could not be fully discussed therein: I, A possible gap between the prevalence of MBs as detected by MRI and post mortem analysis; II, The role of hemoglobin-degradation products in amyloid-attributed neurodegenerative changes; and III, Possible assessment of MB by cerebrospinal fluid (CSF) assays for iron-related markers to better screen patient subgroups for AD interventions.

RevDate: 2020-10-01

Bisht K, Sharma K, Lacoste B, et al (2016)

Dark microglia: Why are they dark?.

Communicative & integrative biology, 9(6):e1230575.

Using transmission electron microscopy (TEM) we recently characterized a microglial phenotype that is induced by chronic stress, fractalkine receptor deficiency, aging, or Alzheimer disease pathology. These 'dark' microglia appear overly active compared with the normal microglia, reaching for synaptic clefts, and extensively engulfing pre-synaptic axon terminals and post-synaptic dendritic spines. From these findings we hypothesized that dark microglia could be specifically implicated in the pathological remodeling of neuronal circuits, which impairs learning, memory, and other essential cognitive functions. In the present addendum we further discuss about the possible causes of their dark appearance under TEM.

RevDate: 2018-11-13
CmpDate: 2017-02-21

Crunkhorn S (2016)

Alzheimer disease: BACE1 inhibitor reduces β-amyloid production in humans.

Nature reviews. Drug discovery, 16(1):18.

RevDate: 2017-08-17
CmpDate: 2017-02-21

Mullard A (2016)

Alzheimer amyloid hypothesis lives on.

Nature reviews. Drug discovery, 16(1):3-5.

RevDate: 2018-11-13
CmpDate: 2017-07-03

Dammers C, Yolcu D, Kukuk L, et al (2016)

Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease.

PloS one, 11(12):e0167432.

A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d-enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.

RevDate: 2018-11-13
CmpDate: 2017-07-28

Schaefer PM, von Einem B, Walther P, et al (2016)

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration.

PloS one, 11(12):e0168157.

One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.

RevDate: 2018-11-13
CmpDate: 2018-06-15

Randino R, Grimaldi M, Persico M, et al (2016)

Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of β-Amyloid Peptide with Single Curcuminoids.

Scientific reports, 6:38846.

A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer's disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the Aβ CD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a model for the curcuminoid-Aβ interaction, highlighting the importance of a constrained "semi-folded" conformation to interact with Aβ analogously to the pattern observed in α-helical coiled-coil peptide structures. This combined approach led to a better understanding of the intriguing in vitro and in vivo activity of curcuminoids as anti-Alzheimer agents, paving a new path for the rational design of optimized druggable analogues.

RevDate: 2017-05-15
CmpDate: 2017-05-15

Nicolas G, Charbonnier C, D Campion (2016)

From Common to Rare Variants: The Genetic Component of Alzheimer Disease.

Human heredity, 81(3):129-141.

Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

RevDate: 2020-02-25
CmpDate: 2017-03-30

Decker M, D Muñoz-Torrero (2016)

Special Issue: "Molecules against Alzheimer".

Molecules (Basel, Switzerland), 21(12):.

This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue.

RevDate: 2020-09-30

Heo JH, Im DG, Lee SH, et al (2016)

The clinical significance of brain microbleeds in patients with Alzheimer's disease: Preliminary study.

Annals of Indian Academy of Neurology, 19(4):495-498.

BACKGROUND: Microbleeds (MBs) are observed frequently in Alzheimer's disease (AD) and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear.

MATERIALS AND METHODS: The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA), and severity of small vessel disease (SVD) according to the existence of MBs were evaluated.

RESULTS: The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+) group. The MB(+) group showed more severe MTLA and SVD than MB(-) group.

CONCLUSIONS: These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology.

RevDate: 2020-03-06

Babulal GM, Traub CM, Webb M, et al (2016)

Creating a driving profile for older adults using GPS devices and naturalistic driving methodology.

F1000Research, 5:2376.

Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. Our objective was to describe the process and associated challenges in adapting an existing, commercial, off-the-shelf (COTS), in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers. Design: The Azuga G2 Tracking Device [TM] was installed in each participant's vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven. Setting: The Knight Alzheimer's Disease Research Center at Washington University School of Medicine. Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance. Participants were aged 65+ years and had normal cognition. Measurements: Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations. Temporal components included number of trips taken during different times of the day. Behavioral components included number of hard braking, speeding and sudden acceleration events. Methods: Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS. Results: Primary locations were confirmed to be 100% accurate when compared to known addresses. Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns. Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night. Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period. Conclusions: Compared to cameras and highly instrumented vehicle in other naturalistic studies, the compact COTS device was quickly installed and transmitted high volumes of data. Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions.

RevDate: 2020-09-29

Mohammadi-Farani A, Soltani Darbandi S, A Aliabadi (2016)

Synthesis and Acetylcholinesterase Inhibitory Evaluation of 4-(1,3-Dioxoisoindolin-2-yl)-N-Phenyl Benzamide Derivatives as Potential Anti-Alzheimer Agents.

Iranian journal of pharmaceutical research : IJPR, 15(3):313-320.

Alzheimer᾽s disease is characterized by cognitive deficits, impaired long-term potentiation of learning and memory. A progressive reduction in cholinergic neurons in some areas of the brain such as cortex and hippocampus is related to the deficits in memory and cognitive function in Alzheimer's disease (AD). In the current project a new series of phthalimide derivatives were synthesized. Phthalic anhydride was reacted with 4-aminobenzoic acid in the presence of triethylamine under reflux condition. Then, the obtained acidic derivative was utilized for preparation of final compounds via an amidation reaction through a carbodiimde coupling reaction. Anti-acetylcholinesterase activity of synthesized derivatives was assessed by Ellman᾽s test. Compound 4g in this series exhibited the highest inhibitory potency (IC50 = 1.1 ± 0.25 µM) compared to donepezil (IC50 = 0.41 ± 0.12 µM) as reference drug.

RevDate: 2022-04-10
CmpDate: 2017-08-07

Iadecola C, Yaffe K, Biller J, et al (2016)

Impact of Hypertension on Cognitive Function: A Scientific Statement From the American Heart Association.

Hypertension (Dallas, Tex. : 1979), 68(6):e67-e94.

BACKGROUND: Age-related dementia, most commonly caused by Alzheimer disease or cerebrovascular factors (vascular dementia), is a major public health threat. Chronic arterial hypertension is a well-established risk factor for both types of dementia, but the link between hypertension and its treatment and cognition remains poorly understood. In this scientific statement, a multidisciplinary team of experts examines the impact of hypertension on cognition to assess the state of the knowledge, to identify gaps, and to provide future directions.

METHODS: Authors with relevant expertise were selected to contribute to this statement in accordance with the American Heart Association conflict-of-interest management policy. Panel members were assigned topics relevant to their areas of expertise, reviewed the literature, and summarized the available data.

RESULTS: Hypertension disrupts the structure and function of cerebral blood vessels, leads to ischemic damage of white matter regions critical for cognitive function, and may promote Alzheimer pathology. There is strong evidence of a deleterious influence of midlife hypertension on late-life cognitive function, but the cognitive impact of late-life hypertension is less clear. Observational studies demonstrated a cumulative effect of hypertension on cerebrovascular damage, but evidence from clinical trials that antihypertensive treatment improves cognition is not conclusive.

CONCLUSIONS: After carefully reviewing the literature, the group concluded that there were insufficient data to make evidence-based recommendations. However, judicious treatment of hypertension, taking into account goals of care and individual characteristics (eg, age and comorbidities), seems justified to safeguard vascular health and, as a consequence, brain health.

RevDate: 2022-01-29
CmpDate: 2017-12-29

Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, et al (2016)

Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury.

Science translational medicine, 8(369):369ra178.

Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred.

RevDate: 2020-09-29

Hoel DG, Berwick M, de Gruijl FR, et al (2016)

The risks and benefits of sun exposure 2016.

Dermato-endocrinology, 8(1):e1248325.

Public health authorities in the United States are recommending that men, women and children reduce their exposure to sunlight, based on concerns that this exposure will promote skin cancer. On the other hand, data show that increasing numbers of Americans suffer from vitamin D deficiencies and serious health problems caused by insufficient sun exposure. The body of science concerning the benefits of moderate sun exposure is growing rapidly, and is causing a different perception of sun/UV as it relates to human health. Melanoma and its relationship to sun exposure and sunburn is not adequately addressed in most of the scientific literature. Reports of favorable health outcomes related to adequate serum 25(OH)D concentration or vitamin D supplementation have been inappropriately merged, so that benefits of sun exposure other than production of vitamin D are not adequately described. This review of recent studies and their analyses consider the risks and benefits of sun exposure which indicate that insufficient sun exposure is an emerging public health problem. This review considers the studies that have shown a wide range health benefits from sun/UV exposure. These benefits include among others various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D.

RevDate: 2019-11-20

Leydesdorff L, Comins JA, Sorensen AA, et al (2016)

Cited references and Medical Subject Headings (MeSH) as two different knowledge representations: clustering and mappings at the paper level.

Scientometrics, 109(3):2077-2091.

For the biomedical sciences, the Medical Subject Headings (MeSH) make available a rich feature which cannot currently be merged properly with widely used citing/cited data. Here, we provide methods and routines that make MeSH terms amenable to broader usage in the study of science indicators: using Web-of-Science (WoS) data, one can generate the matrix of citing versus cited documents; using PubMed/MEDLINE data, a matrix of the citing documents versus MeSH terms can be generated analogously. The two matrices can also be reorganized into a 2-mode matrix of MeSH terms versus cited references. Using the abbreviated journal names in the references, one can, for example, address the question whether MeSH terms can be used as an alternative to WoS Subject Categories for the purpose of normalizing citation data. We explore the applicability of the routines in the case of a research program about the amyloid cascade hypothesis in Alzheimer's disease. One conclusion is that referenced journals provide archival structures, whereas MeSH terms indicate mainly variation (including novelty) at the research front. Furthermore, we explore the option of using the citing/cited matrix for main-path analysis as a by-product of the software.

RevDate: 2020-07-24

Anonymous (2016)

Tenascin-C is associated with cored amyloid-β plaques in Alzheimer disease and pathology burdened cognitively normal elderly.

Journal of neuropathology and experimental neurology, 75(12):1190.

RevDate: 2018-11-13
CmpDate: 2017-06-05

DeGrado TR, Kemp BJ, Pandey MK, et al (2016)

First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

Molecular imaging, 15:.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). [63]Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of [63]Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral [63]Zn clearances were compared with [11]C-Pittsburgh Compound B ([11]C-PiB) and [18]F-fluorodeoxyglucose ([18]F-FDG) imaging data. [63]Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in [63]Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden ([11]C-PiB) and [18]F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe [63]Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD.

RevDate: 2018-04-23
CmpDate: 2018-04-23

Nguyen PH, Sterpone F, Pouplana R, et al (2016)

Dimerization Mechanism of Alzheimer Aβ40 Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation.

The journal of physical chemistry. B, 120(47):12111-12126.

Amyloid beta (Aβ) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Aβ40 dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Aβ40 dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of-register antiparallel β-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded β-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid-forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded β-sheet or inhibiting the formation of an interpeptide β-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of Aβ species.

RevDate: 2018-11-13
CmpDate: 2017-10-25

Foveau B, Albrecht S, Bennett DA, et al (2016)

Increased Caspase-6 activity in the human anterior olfactory nuclei of the olfactory bulb is associated with cognitive impairment.

Acta neuropathologica communications, 4(1):127.

Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating. To examine this possibility, we examined the presence of Casp6 activity, neurofibrillary tangle formation and amyloid deposition by immunohistochemistry with neoepitope antisera against the p20 subunit of active Casp6 and Tau cleaved by Casp6 (Tau∆Casp6), phosphorylated Tau paired helical filament (PHF-1) antibodies and anti-β-amyloid antiserum, respectively, in brains from individuals with no or mild cognitive impairment and Alzheimer disease (AD) dementia. Co-localization of Casp6 activity, PHF-1 and β-amyloid was detected mostly in the anterior olfactory nucleus (AON) of the olfactory bulb. The levels of active Casp6 in the AON, which were the highest in the AD brains, correlated with PHF-1 levels, but not with β-amyloid levels. AON Tau∆Casp6 levels correlated with entorhinal cortex Casp6 activity and PHF-1 levels. Multiple regression analyses demonstrated that AON Casp6 activity was associated with lower global cognitive function, mini mental state exam, episodic memory and semantic memory scores. These results suggest that AON Casp6 activity could lead to Casp6-mediated degeneration in the entorhinal cortex, but cannot exclude the possibilities that entorhinal cortex degeneration signals degeneration in the AON or that the pathologies occur in both regions independently. Nevertheless, AON Casp6 activity reflects that of the entorhinal cortex.

RevDate: 2022-10-05
CmpDate: 2017-02-15

Kim J, Cho SG, Song M, et al (2016)

Usefulness of 3-dimensional stereotactic surface projection FDG PET images for the diagnosis of dementia.

Medicine, 95(49):e5622.

To compare diagnostic performance and confidence of a standard visual reading and combined 3-dimensional stereotactic surface projection (3D-SSP) results to discriminate between Alzheimer disease (AD)/mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).[F]fluorodeoxyglucose (FDG) PET brain images were obtained from 120 patients (64 AD/MCI, 38 DLB, and 18 FTD) who were clinically confirmed over 2 years follow-up. Three nuclear medicine physicians performed the diagnosis and rated diagnostic confidence twice; once by standard visual methods, and once by adding of 3D-SSP. Diagnostic performance and confidence were compared between the 2 methods.3D-SSP showed higher sensitivity, specificity, accuracy, positive, and negative predictive values to discriminate different types of dementia compared with the visual method alone, except for AD/MCI specificity and FTD sensitivity. Correction of misdiagnosis after adding 3D-SSP images was greatest for AD/MCI (56%), followed by DLB (13%) and FTD (11%). Diagnostic confidence also increased in DLB (visual: 3.2; 3D-SSP: 4.1; P < 0.001), followed by AD/MCI (visual: 3.1; 3D-SSP: 3.8; P = 0.002) and FTD (visual: 3.5; 3D-SSP: 4.2; P = 0.022). Overall, 154/360 (43%) cases had a corrected misdiagnosis or improved diagnostic confidence for the correct diagnosis.The addition of 3D-SSP images to visual analysis helped to discriminate different types of dementia in FDG PET scans, by correcting misdiagnoses and enhancing diagnostic confidence in the correct diagnosis. Improvement of diagnostic accuracy and confidence by 3D-SSP images might help to determine the cause of dementia and appropriate treatment.

RevDate: 2018-11-13
CmpDate: 2017-11-07

Clift K, Guthrie K, Klee EW, et al (2016)

Familial Creutzfeldt-Jakob Disease: Case report and role of genetic counseling in post mortem testing.

Prion, 10(6):502-506.

Here we present a case of an asymptomatic 53-year-old woman who sought genetic testing for Familial Creutzfeldt-Jakob Disease (fCJD) after learning that her mother had fCJD. The patient's mother had a sudden onset of memory problems and rapidly deteriorating mental faculties in her late 70s, which led to difficulties ambulating, progressive non-fluent aphasia, dysphagia and death within ∼1 y of symptom onset. The cause of death was reported as "rapid onset dementia." The patient's family, unhappy with the vague diagnosis, researched prion disorders online and aggressively pursued causation and submitted frozen brain tissue from the mother to the National Prion Disease Surveillance Center, where testing revealed a previously described 5-octapeptide repeat insertion (5-OPRI) in the prion protein gene (PRNP) that is known to cause fCJD. The family had additional questions about the implications of this result and thus independently sought out genetic counseling. While rare, fCJD is likely underdiagnosed due to clinical heterogeneity, rapid onset, early non-specific symptomatology, and overlap in the differential diagnosis of Alzheimer disease and Lewy body dementias. When fCJD is identified, a multidisciplinary approach to return of results that includes the affected patient's provider, genetics professionals, and mental health professionals is key to the care of the family. We present an example case which discusses the psychosocial issues encountered and the role of genetic counseling in presymptomatic testing for incurable neurodegenerative conditions. Ordering physicians should be aware of the basic issues surrounding presymptomatic genetic testing and identify local genetic counseling resources for their patients.

RevDate: 2018-11-13
CmpDate: 2017-10-26

Sanders SS, Parsons MP, Mui KK, et al (2016)

Sudden death due to paralysis and synaptic and behavioral deficits when Hip14/Zdhhc17 is deleted in adult mice.

BMC biology, 14(1):108.

BACKGROUND: Palmitoylation, the addition of palmitate to proteins by palmitoyl acyltransferases (PATs), is an important regulator of synaptic protein localization and function. Many palmitoylated proteins and PATs have been implicated in neuropsychiatric diseases, including Huntington disease, schizophrenia, amyotrophic lateral sclerosis, Alzheimer disease, and X-linked intellectual disability. HIP14/DHHC17 is the most conserved PAT that palmitoylates many synaptic proteins. Hip14 hypomorphic mice have behavioral and synaptic deficits. However, the phenotype is developmental; thus, a model of post-developmental loss of Hip14 was generated to examine the role of HIP14 in synaptic function in the adult.

RESULTS: Ten weeks after Hip14 deletion (iHip14 [Δ/Δ]), mice die suddenly from rapidly progressive paralysis. Prior to death the mice exhibit motor deficits, increased escape response during tests of anxiety, anhedonia, a symptom indicative of depressive-like behavior, and striatal synaptic deficits, including reduced probability of transmitter release and increased amplitude but decreased frequency of spontaneous post-synaptic currents. The mice also have increased brain weight due to microgliosis and astrogliosis in the cortex.

CONCLUSIONS: Behavioral changes and electrophysiological measures suggest striatal dysfunction in iHip14 [Δ/Δ] mice, and increased cortical volume due to astrogliosis and microgliosis suggests a novel role for HIP14 in glia. These data suggest that HIP14 is essential for maintenance of life and neuronal integrity in the adult mouse.

RevDate: 2018-11-13
CmpDate: 2018-01-08

Grizzanti J, Lee HG, Camins A, et al (2016)

The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer's disease.

Nutrition research (New York, N.Y.), 36(12):1305-1315.

Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non-insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease.

RevDate: 2020-09-29

Alimohammadi-Kamalabadi M, Eshraghian M, Zarindast MR, et al (2016)

Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer's disease.

Iranian journal of basic medical sciences, 19(11):1159-1165.

OBJECTIVES: Neuroprotective effect of creatine (Cr) against β-amyloid (Aβ) is reported in an in vitro study. This study investigated the effect of Cr supplementation on β-amyloid toxicity in vivo.

MATERIALS AND METHODS: Thirty two, male Wistar rats were divided into 4 groups. During ten weeks of study, control group went through no surgical or dietary intervention. At the 4th week of study Sham group had a hippocampal normal saline injection, while Aβ and AβCr groups had an β-amyloid injection in the hippocampus. AβCr group were fed by Cr diet during the study. After 10 weeks, Morris water maze (MWM) test was administered to measure learning ability and memory retrieval. Animals were sacrificed for TUNEL anti apoptotic assay and staining of amyloid plaques by Thioflavin-T.

RESULTS: There was a significant retention deficit among AβCr and Aβ group while the escape latency and the distance traveled to the platform were significantly higher in AβCr group compared to Aβ group. AβCr group had same percent of TUNEL positive neurons compared to Aβ group.

CONCLUSION: Cr supplementation before and after β-amyloid injection into the CA1 area of hippocampus deteriorates the learning and memory impairment of rats and it does not protect neuronal apoptosis caused by β-amyloid.

RevDate: 2019-12-10
CmpDate: 2017-06-22

Vandepitte S, Van Den Noortgate N, Putman K, et al (2016)

Effectiveness and cost-effectiveness of an in-home respite care program in supporting informal caregivers of people with dementia: design of a comparative study.

BMC geriatrics, 16(1):207.

BACKGROUND: Frequent hospitalization and permanent nursing home placement not only affect the well-being of persons with dementia, but also place great financial strain on society. Therefore, it is important to create effective strategies to support informal caregivers so that they can continue to perform their demanding role. Preliminary qualitative evidence suggests that community-based respite services can actually be important for caregivers, and that the level of evidence should be further established in terms of effectiveness. Therefore, a comparative study to assess the effectiveness and cost-effectiveness of an in-home respite care program will be initiated.

METHODS: This manuscript described a quasi-experimental study to assess (cost)-effectiveness of an in-home respite care program to support informal caregivers of persons with dementia.

STUDY POPULATION: 124 informal caregivers and persons with dementia will be included in the intervention group and will receive an in-home respite care program by an organization called Baluchon Alzheimer. 248 dyads will be included in the control group and will receive standard dementia care. The primary outcome is caregiver burden. Secondary outcomes are: quality of life of caregivers, frequency of behavioral problems of persons with dementia and the reactions of caregivers to those problems, intention to institutionalize the care-recipient, time to nursing home placement, resource use of the care-recipient, and willingness to pay for in-home respite care. When the trial demonstrates a difference in outcomes between both groups, within-trial and modeled cost-effectiveness analyses will be conducted in a separate economic evaluation plan to evaluate possible cost-effectiveness of the in-home respite care program compared to the control group receiving standard dementia care. Finally, the model based cost-effectiveness analyses will allow to extrapolate effects over a longer time horizon than the duration of the trial.

DISCUSSION: This study will have great added value because to date no studies measured effectiveness and cost-effectiveness of an in-home respite care program of the Baluchon type. Results of this trial can thus give much more insight in potential benefits and disadvantages of community-based respite care. Conclusions based on this trial can help policy-makers in elaborating future directions of dementia care.

TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT02630446 .

RevDate: 2018-11-13
CmpDate: 2018-05-31

Zhang W, Jiao B, Xiao T, et al (2016)

Mutational analysis of PRNP in Alzheimer's disease and frontotemporal dementia in China.

Scientific reports, 6:38435.

The prion protein (PRNP) gene is associated with prion diseases, whereas variants of the PRNP gene may also explain some cases of Alzheimer disease (AD) and frontotemporal dementia (FTD) in Caucasian populations. To determine the prevalence of the PRNP gene in patients with AD and FTD in China, we screened all exons of the PRNP gene in a cohort of 683 cases (606 AD and 77 FTD) in the Chinese Han population and we detected a novel missense mutation p.S17G in a late-onset AD (LOAD) patient. Furthermore, we analyzed the PRNP M/V polymorphism at codon 129, which was previously reported as a risk factor. However, there were no significant differences in genotype and allele frequency either in AD (OR = 0.75[0.378-1.49], P = 0.492), or FTD patients (OR = 2.046[0.265-15.783], P = 0.707). To our knowledge, this is the first study to reveal a correlation between the PRNP gene and Chinese AD and FTD patients in a large cohort. This study reports a novel p.S17G mutation in a clinically diagnosed LOAD patient, suggesting that the PRNP mutation is present in Chinese AD patients, whereas, M129V polymorphism is not a risk factor for AD or FTD in the Chinese Han population.

RevDate: 2018-11-13
CmpDate: 2018-01-19

Edmonds EC, Bangen KJ, Delano-Wood L, et al (2016)

Patterns of Cortical and Subcortical Amyloid Burden across Stages of Preclinical Alzheimer's Disease.

Journal of the International Neuropsychological Society : JINS, 22(10):978-990.

OBJECTIVES: We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer's disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods.

METHODS: A total of 312 cognitively normal Alzheimer's Disease Neuroimaging Initiative participants completed a neuropsychological assessment and florbetapir PET scan. Participants were classified into stages of preclinical AD using (1) a novel approach based on the number of abnormal biomarkers/cognitive markers each individual possessed, and (2) National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria. Preclinical AD groups were compared to one another and to a mild cognitive impairment (MCI) sample on florbetapir standardized uptake value ratios (SUVRs) in cortical and allocortical/subcortical regions of interest (ROIs).

RESULTS: Amyloid deposition increased across stages of preclinical AD in all cortical ROIs, with SUVRs in the later stages reaching levels seen in MCI. Several subcortical areas showed a pattern of results similar to the cortical regions; however, SUVRs in the hippocampus, pallidum, and thalamus largely did not differ across stages of preclinical AD.

CONCLUSIONS: Substantial amyloid accumulation in cortical areas has already occurred before one meets criteria for a clinical diagnosis. Potential explanations for the unexpected pattern of results in some allocortical/subcortical ROIs include lack of correspondence between (1) cerebrospinal fluid and florbetapir PET measures of amyloid, or between (2) subcortical florbetapir PET SUVRs and underlying neuropathology. Findings support the utility of our novel method for staging preclinical AD. By combining imaging biomarkers with detailed cognitive assessment to better characterize preclinical AD, we can advance our understanding of who is at risk for future progression. (JINS, 2016, 22, 978-990).

RevDate: 2019-06-06
CmpDate: 2017-04-24

Kaubrys G, Bukina V, Bingelytė I, et al (2016)

Perception of Fechner Illusory Colors in Alzheimer Disease Patients.

Medical science monitor : international medical journal of experimental and clinical research, 22:4670-4678.

BACKGROUND Alzheimer disease (AD) primarily affects cognition. A variety of visual disorders was established in AD. Fechner illusory colors are produced by a rotating disk with a black and white pattern. The purpose of our research was to explore the perception of illusory colors in AD. MATERIAL AND METHODS W recruited 40 AD patients (MMSE ≥14) and 40 normal controls (CG group) matched by age, education, gender in this prospective, cross-sectional, case-control study. An achromatic Benham's disk attached to a device to control the speed and direction of rotation was used to produce illusory colors. Primary, secondary, and tertiary RGB system colors were used for matching of illusory and physical colors. RESULTS Subjects in the AD group perceived less illusory colors in 5 arcs (p<0.05) of the 8 arcs assessed. The biggest difference was found between AD and CG groups for pure blue (χ[2]=26.87, p<0.001 clockwise, χ[2]=22.75, p<0.001 counter-clockwise). Groups did not differ in perception of pure yellow opponent colors (p>0.05). Mixed colors of the blue-yellow axis were perceived less often in AD, but more frequently than pure blue (#0000FF). The sequence of colors on Benham's disk followed a complex pattern, different from the order of physical spectral colors and opponent processes-based colors. CONCLUSIONS AD patients retained reduced perception of illusory colors. The perception of pure blue illusory color is almost absent in AD. The asymmetrical shift to the yellow opponent is observed in AD with red prevailing over green constituent. This may indicate cortical rather than retinal impairment.

RevDate: 2021-12-04
CmpDate: 2017-11-06

Rühlmann C, Wölk T, Blümel T, et al (2016)

Long-term caloric restriction in ApoE-deficient mice results in neuroprotection via Fgf21-induced AMPK/mTOR pathway.

Aging, 8(11):2777-2789.

Caloric restriction (CR) decelerates the aging process, extends lifespan and exerts neuroprotective effects in diverse species by so far unknown mechanisms. Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) we speculate that CR upregulates Fgf21, which phosphorylates neuronal AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of rapamycin (mTOR) signaling activity and an inhibition of tau-hyperphosphorylation. This in turn reduces the formation of neurofibrillary tangles, a neuropathological hallmark of Alzheimer´s disease. ApoE-deficient mice (ApoE-/-), serving as a model of neurodegeneration, showed upon CR vs. ad libitum feeding increased Fgf21 levels in both, plasma and brain as well as higher phosphorylation of fibroblastic growth factor receptor 1c (Fgfr1c), extracellular signal-regulated kinases 1/2 (ERK1/2) and AMPK in brain, lower activity of mTOR and decreased Tau-phosphorylation. Finally, CR in ApoE-/- mice caused neuroprotection as indicated by a higher synaptic plasticity shown by immunohistochemical analysis with increased numbers of PSD95-positive neurons and a better cognitive performance as analyzed with Morris water maze test. These data provide substantial evidence that neuroprotection upon CR seems to be Fgf21-dependent. Further experiments are necessary to evaluate Fgf21 as a therapeutic tool to treat tauopathy for improvement of cognitive performance.

RevDate: 2019-11-20

Chang A, Singh N, Boyd L, et al (2016)

Strategies to Improve Radiographic Practices for Patients With Alzheimer's Disease: A Systematic Review.

Journal of medical imaging and radiation sciences, 47(4):362-366.

BACKGROUND: Alzheimer's disease (AD) patients are one of the highest health care service users globally. In the context of radiography, there are many AD patients who undergo imaging procedures for common age-related conditions. However, there is currently no literature on how radiographers can effectively manage such patients in imaging situations.

METHODOLOGY: This review examined the literature regarding the interaction between Alzheimer's patients and other health care professionals (eg, nurses) and the strategies that have been used to improve patient compliance and accommodate functional decline.

FINDINGS: Many strategies relating to care of patients with AD are long term, and cannot be applied in a radiographic setting, where patients may only present once. Transferrable strategies for a radiographic setting include the support of carers during the examination process, a reduction in noise and use of calming music, and allowing the patient to personalize the examination room by bringing a photograph or an item of comfort.

CONCLUSION: These simple strategies can reduce the level of anxiety experienced by AD patients, reduce typical behavioral symptoms of agitation, aggression and discomfort, and increase patient cooperation and responsiveness.

RevDate: 2020-10-01

Yang HD, Kim DH, Lee SB, et al (2016)

History of Alzheimer's Disease.

Dementia and neurocognitive disorders, 15(4):115-121.

As modern society ages rapidly, the number of people with dementia is sharply increasing. Direct medical costs and indirect social costs for dementia patients are also increasing exponentially. However, the lack of social awareness about dementia results in difficulties to dementia patients and their families. So, understanding dementia is the first step to remove or reduce the stigma of dementia patients and promote the health of our community. Alzheimer's disease is the most common form of dementia. The term, 'Alzheimer's disease' has been used for over 100 years since first used in 1910. With the remarkable growth of science and medical technologies, the techniques for diagnosis and treatment of dementia have also improved. Although the effects of the current symptomatic therapy are still limited, dramatic improvement is expected in the future through the continued research on disease modifying strategies at the earlier stage of disease. It is important to look at the past to understand the present and obtain an insight into the future. In this article, we review the etymology and history of dementia and previous modes of recognizing dementia. We also review the historical developments leading to the terminology of Alzheimer's disease.

RevDate: 2020-10-01

Mesulam MM (2016)

Primary Progressive Aphasia and the Left Hemisphere Language Network.

Dementia and neurocognitive disorders, 15(4):93-102.

Primary progressive aphasia (PPA) is a clinical syndrome diagnosed when three core criteria are met. First, there should be a language impairment (i.e., aphasia) that interferes with the usage or comprehension of words. Second, the neurological work-up should determine that the disease is neurodegenerative, and therefore progressive. Third, the aphasia should arise in relative isolation, without equivalent deficits of comportment or episodic memory. The language impairment can be fluent or non-fluent and may or may not interfere with word comprehension. Memory for recent events is preserved although memory scores obtained in verbally mediated tests may be abnormal. This distinctive clinical pattern is most conspicuous in the initial stages of the disease, and reflects a relatively selective atrophy of the language network, usually located in the left hemisphere. There are different clinical variants of PPA, each with a characteristic pattern of atrophy. Clinicoanatomical correlations in patient with these variants have led to new insights on the organization of the large-scale language network in the human brain. For example, the left anterior temporal lobe, which was not part of the classic language network, has been shown to play a critical role in word comprehension and object naming. Furthermore, patients with PPA have shown that fluency can be dissociated from grammaticality. The underlying neuropathological diseases are heterogeneous and can include Alzheimer's disease as well as frontotemporal lobar degeneration. The clinician's task is to recognize PPA and differentiate it from other neurodegenerative phenotypes, use biomarkers to surmise the nature of the underlying neuropathology, and institute the most fitting multimodal interventions.

RevDate: 2021-12-04
CmpDate: 2017-11-20

Luchsinger JA, Burgio L, Mittelman M, et al (2016)

Northern Manhattan Hispanic Caregiver Intervention Effectiveness Study: protocol of a pragmatic randomised trial comparing the effectiveness of two established interventions for informal caregivers of persons with dementia.

BMJ open, 6(11):e014082.

INTRODUCTION: The prevalence of dementia is increasing without a known cure, resulting in an increasing number of informal caregivers. Caring for a person with dementia results in increased stress and depressive symptoms. There are several behavioural interventions designed to alleviate stress and depressive symptoms in caregivers of persons with dementia with evidence of efficacy. Two of the best-known interventions are the New York University Caregiver Intervention (NYUCI) and the Resources for Enhancing Alzheimer's Caregivers Health (REACH). The effectiveness of the NYUCI and REACH has never been compared. There is also a paucity of data on which interventions are more effective in Hispanics in New York City. Thus, we proposed the Northern Manhattan Hispanic Caregiver intervention Effectiveness Study (NHiCE), a pragmatic clinical trial designed to compare the effectiveness of adaptations of the NYUCI and the REACH in informal Hispanic caregivers of persons with dementia in New York City.

METHODS AND ANALYSIS: NHiCE is a 6-month randomised controlled trial comparing the effectiveness of adaptations of the NYUCI and REACH among 200 Hispanic informal adult caregivers of persons with dementia. The planned number of sessions of the NYUCI and REACH are similar. The primary outcome measures are changes from baseline to 6 months in the Zarit Caregiver Burden Scale and Geriatric Depression Scale. Our primary approach to analyses will be intent-to-treat. The primary analyses will use mixed random effects models, and a full information maximum likelihood approach, with sensitivity analyses using generalised estimating equation.

ETHICS AND DISSEMINATION: NHiCE is approved by the Institutional Review Board of Columbia University Medical Center (protocol AAAM5150). A Data Safety Monitoring Board monitors the progress of the study. Dissemination will include reports of the characteristics of the study participants, as well as a report of the results of the clinical trial.

TRIAL REGISTRATION NUMBER: NCT02092987, Pre-results.

RevDate: 2022-03-31
CmpDate: 2017-06-06

Realdon O, Rossetto F, Nalin M, et al (2016)

Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment: the Ability-TelerehABILITation study protocol for a randomized controlled trial.

BMC psychiatry, 16(1):425.

BACKGROUND: According to the World Alzheimer Report (Prince, The Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends, 2015), 46.8 million people worldwide are nowadays living with dementia. And this number is estimated to approximate 131.5 million by 2050, with an increasing burden on society and families. The lack of medical treatments able to stop or slow down the course of the disease has moved the focus of interest toward the nonpharmacological approach and psychosocial therapies for people with/at risk of dementia, as in the Mild Cognitive Impairment (MCI) condition. The purpose of the present study is to test an individualized home-based multidimensional program aimed at enhancing the continuum of care for MCI and outpatients with dementia in early stage using technology.

METHODS: The proposed study is a single blind randomized controlled trial (RCT) involving 30 subjects with MCI and Alzheimer's disease (AD) randomly assigned to the intervention group (Ability group), who will receive the "Ability Program", or to the active control group (ACG), who will receive "Treatment As Usual" (TAU). The protocol provides for three steps of assessment: at the baseline (T_0), after treatment, (T_1) and at follow-up (T_2) with a multidimensional evaluation battery including cognitive functioning, behavioral, functional, and quality of life measures. The Ability Program lasts 6 weeks, comprises tablet-delivered cognitive (5 days/week) and physical activities (7 days/week) combined with a set of devices for the measurement and monitoring from remote of vital and physical health parameters. The TAU equally lasts 6 weeks and includes paper and pencil cognitive activities (5 days/week), with clinician's prescription to perform physical exercise every day and to monitor selected vital parameters.

DISCUSSION: Results of this study will inform on the efficacy of a technology-enhanced home care service to preserve cognitive and motor levels of functioning in MCI and AD, in order to slow down their loss of autonomy in daily life. The expected outcome is to ensure the continuity of care from clinical practice to the patient's home, enabling also cost effectiveness and the empowerment of patient and caregiver in the care process, positively impacting on their quality of life.

TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02746484 (registration date: 12/apr/2016 - retrospectively registered).

RevDate: 2018-12-02
CmpDate: 2017-01-02

Liao W, Hamel RE, Olde Rikkert MG, et al (2016)

A profile of The Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment and Dementia Study (The 4C study): two complementary longitudinal, clinical cohorts in the Netherlands.

BMC neurology, 16(1):242.

BACKGROUND: Heterogeneous disease trajectories of mild cognitive impairment (MCI) and dementia are frequently encountered in clinical practice, but there is still insufficient knowledge to understand the reasons and mechanisms causing this heterogeneity. In addition to correlates of the disorder, patient characteristics such as their health status, social environment, comorbidities and frailty may contribute to variability in trajectories over time. The current paper outlines the study design and the study population of and provides an overview of the data collected in the Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment (4C-MCI cohort, n = 315) and Dementia (4C-Dementia cohort, n = 331) Study.

METHODS: The two complementary longitudinal cohorts part of the 4C study began enrolment in March 2010. Participants were prospectively recruited from three collaborating Dutch Alzheimer Centers, with three annual follow-up assessments after baseline. Extensive neuropsychological assessments, and detailed profiling of comorbidities, health and frailty at each follow up were the key features of the 4C study. As such, the 4C study was designed to study if and how patients' comorbidities and frailty are associated with the course of MCI and dementia measured with a comprehensive and multidimensional set of outcomes including cognition, daily functioning, quality of life, behavioral disturbances, caregiver burden, institutionalization and death and whether the effects of medical health and frailty differ between MCI and dementia stages of cognitive disorders.

CONCLUSION: Sampled in a clinical setting, the 4C study complements population-based studies on neurodegenerative disorders in terms of the type of assessment (e.g. comorbidity, frailty, and functional status were repeatedly assessed). The 4C study complements available clinical cohorts of MCI and dementia patients, because the exclusion criteria were kept to a minimum, to obtain a sample that is representative for the average patient visiting a memory clinic.

RevDate: 2020-09-30

Seetlani NK, Kumar N, Imran K, et al (2016)

Alzheimer and vascular dementia in the elderly patients.

Pakistan journal of medical sciences, 32(5):1286-1290.

OBJECTIVES: To find out the frequency of Alzheimer's and Vascular dementia in the elderly patients.

METHODS: This cross sectional descriptive study was conducted in Department of Medicine, Ziauddin Hospital Karachi from 1[st] October 2013 to 31[st] March 2014. Patients with symptoms of dementia for more than 6 months duration, and Mini Mental State Examination score <24 were included in this study. Patients who fell in category of dementia were assessed for duration of symptoms. Patients underwent CT scan of brain. Patients with generalized atrophy of brain on CT scanning of brain were labeled as Alzheimer's dementia, while patients with ischemic or hemorrhagic stroke on CT scan of brain were labeled as vascular dementia.

RESULTS: Four hundred twenty two patients were included in this study. There were 232 (54.98 %) male and 190 (45.02 %) were female. The mean age ± SD of the patients was 72.58±5.34 years (95% CI: 72.07 to 73.09), similarly average duration of symptoms was 10.14±2.85 months. About 18.96% of patients were illiterate, 32.23% were matric, 28.44% were intermediate and 20.33% were graduate and post graduate. Hypertension and diabetes were the commonest co-morbid i.e. 81.3% and 73.7%, hyperlipedimia and smoking were 38.2% and 45% respectively. Frequency of Alzheimer's disease and vascular dementia in the elderly was observed in 3.79% (16/422) and 2.61% (11/422) cases.

CONCLUSION: A good number of patients, 27 out of 422, in this hospital based study were suffering from Alzheimer's disease and vascular dementia. Early detection and prompt treatment can reduce the burden of the disease in our population.

RevDate: 2022-03-30
CmpDate: 2018-06-20

Bryan RN (2016)

Machine Learning Applied to Alzheimer Disease.

Radiology, 281(3):665-668.

RevDate: 2021-01-05
CmpDate: 2018-01-23

Hsu YH, Huang CF, Lo CP, et al (2016)

Frontal Assessment Battery as a Useful Tool to Differentiate Mild Cognitive Impairment due to Subcortical Ischemic Vascular Disease from Alzheimer Disease.

Dementia and geriatric cognitive disorders, 42(5-6):331-341.

BACKGROUND: Prominent executive dysfunction can differentiate vascular dementia from Alzheimer disease (AD). However, it is unclear whether the Frontal Assessment Battery (FAB) screening tool can differentiate subcortical ischemic vascular disease (SIVD) from AD at the pre-dementia stage. In addition, the neural correlates of FAB performance have yet to be clarified.

METHODS: Patients with mild cognitive impairment (MCI) due to SIVD (MCI-V), MCI due to AD (MCI-A), and demographically matched controls completed the Mini-Mental State Examination, Taiwanese FAB (TFAB), Category Fluency, and Chinese Version of the Verbal Learning Test, and underwent magnetic resonance imaging. White matter hyperintensities were rated according to the Scheltens scale.

RESULTS: TFAB total scale and its Orthographical Fluency subtest were the only measures that could differentiate MCI-V from MCI-A. Discriminative analysis showed that Orthographical Fluency scores successfully identified 73.2% of the cases with MCI-V, with 85.0% sensitivity. Orthographical Fluency scores were specifically associated with lesion load within frontal periventricular, frontal deep white matter, and basal ganglia regions.

CONCLUSION: The TFAB, and especially its 1-min Orthographical Fluency subtest, is a useful screening procedure to differentiate MCI due to SIVD from MCI due to AD. The discriminative ability is probably due to frontosubcortical white matter pathologies disproportionately involved in the two disease entities.

RevDate: 2018-03-29
CmpDate: 2018-01-31

Kang YJ, Seo DG, SY Park (2016)

Phenylpropanoids from cinnamon bark reduced β-amyloid production by the inhibition of β-secretase in Chinese hamster ovarian cells stably expressing amyloid precursor protein.

Nutrition research (New York, N.Y.), 36(11):1277-1284.

β-Amyloid (Aβ) is a substance of Alzheimer disease (AD), which is generated via the amyloidogenic pathway from amyloid precursor protein (APP) by β-secretase and γ-secretase. Inhibition of Aβ production is a potential therapeutic approach to AD. Thus, we tested the hypothesis that cinnamon bark (Cinnamomi Cortex Spissus), the dried bark of Cinnamomum cassia Blume (Lauraceae), and its constituents are beneficial to AD. The methanol extract of cinnamon bark efficiently reduced Aβ40 production in Chinese hamster ovarian (CHO) cells stably expressing APP as determined by enzyme-linked immunosorbent assay. Bioassay-guided isolation of cinnamon bark extract was carried out using open column chromatography and high-performance liquid chromatography, and the following 6 phenylpropanoids were isolated: syringaresinol (1); medioresinol (2); coumarin (3); 2-hydroxycinnamaldehyde (4); cryptamygin A (5); and 3',5,7-trimethoxy epicatechin (6). Among these, 4 μg/mL medioresinol and cryptamygin A reduced Aβ40 production by 50% and 60%, respectively, compared with dimethyl sulfoxide-treated control cells. The IC50 values of medioresinol and cryptamygin A for the inhibition of Aβ40 production were 10.8 and 8.2 μg/mL, respectively. Furthermore, treatment of APP-CHO cells with either compound decreased the amount of β-secretase and sAPPβ (the proteolytic fragment of APP catalyzed by β-secretase). These results suggest that the antiamyloidogenic activity of cinnamon bark extract was exerted by medioresinol and cryptamygin A via a reduction in the amount of β-secretase. The extract of cinnamon bark contains potentially valuable antiamyloidogenic agents for the prevention and treatment of AD.

RevDate: 2022-04-08
CmpDate: 2017-10-04

Hao W, A Friedman (2016)

Mathematical model on Alzheimer's disease.

BMC systems biology, 10(1):108.

BACKGROUND: Alzheimer disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive skills. AD is characterized by the presence of two types of neuropathological hallmarks: extracellular plaques consisting of amyloid β-peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins. The disease affects 5 million people in the United States and 44 million world-wide. Currently there is no drug that can cure, stop or even slow the progression of the disease. If no cure is found, by 2050 the number of alzheimer's patients in the U.S. will reach 15 million and the cost of caring for them will exceed $ 1 trillion annually.

RESULTS: The present paper develops a mathematical model of AD that includes neurons, astrocytes, microglias and peripheral macrophages, as well as amyloid β aggregation and hyperphosphorylated tau proteins. The model is represented by a system of partial differential equations. The model is used to simulate the effect of drugs that either failed in clinical trials, or are currently in clinical trials.

CONCLUSIONS: Based on these simulations it is suggested that combined therapy with TNF- α inhibitor and anti amyloid β could yield significant efficacy in slowing the progression of AD.

RevDate: 2018-11-13
CmpDate: 2017-06-26

Vishnu VY, Modi M, Sharma S, et al (2016)

Role of Plasma Clusterin in Alzheimer's Disease-A Pilot Study in a Tertiary Hospital in Northern India.

PloS one, 11(11):e0166369.

OBJECTIVE: To evaluate the role of plasma clusterin in Alzheimer's disease (AD).

BACKGROUND: Plasma clusterin is a promising biomarker as various studies have shown it to be associated with AD. But other studies have shown that plasma clusterin levels were not related to Alzheimer's disease or presymptomatic AD. Hence the diagnostic value of plasma clusterin is still not conclusive.

METHODS: Neuropsychological assessment, MRI brain, FDG-PET brain and CSF biomarkers of AD were used for establishing the diagnosis of MCI, AD or Vascular dementia. The CSF control group included patients who were having knee or hip surgery and plasma control group included the spouses of patients.

RESULTS: Forty-six patients who gave consent for CSF examination and FDG PET brain were included in the study along with 19 control samples. Alzheimer's group had 34 patients and Vascular group had 12 patients. Both had a significantly lower value of clusterin than the control samples (p<0.01). The median plasma clusterin level was 84.38 μg/ml in control group, 57.98μg/ml in Alzheimer's group and 49.93μg/ml in the vascular group. Alzheimer and Vascular group did not differ in plasma clusterin levels. Moreover there was no correlation of plasma clusterin with AD severity. The sensitivity and specificity of plasma clusterin was low for any significance for clinical use.

CONCLUSION: Our pilot study shows that plasma clusterin is lower in Alzheimer's disease with respect to control population. Plasma clusterin levels and severity of Alzheimer's disease had no significant correlation. There was no difference in plasma clusterin between Alzheimer's disease and Vascular Dementia. The sensitivity and specificity of plasma clusterin is low for any use in clinical practice. More studies are required to ascertain the utility of plasma clusterin as a biomarker in Alzheimer's disease.

RevDate: 2022-04-19
CmpDate: 2017-02-07

El Haj M, Gandolphe MC, Wawrziczny E, et al (2016)

Flashbulb memories of Paris attacks: Recall of these events and subjective reliving of these memories in a case with Alzheimer disease.

Medicine, 95(46):e5448.

RATIONALE: Flashbulb memories are detailed and vivid memories of attributes of the reception context of surprising and emotionally arousing public events.

This paper offers a fine-grained view of flashbulb memories in a patient with mild Alzheimer's disease (AD).

INTERVENTIONS: The patient underwent a directed interview about the 13 November 2015 attacks in Paris.

OUTCOMES: Unlike her memory about the date and month of the attacks, the patient provided accurate information about the year, time and places they occurred. The patient also provided accurate information about how she first became aware of the attacks, where she was, with whom, what she was doing, and what time it was when she learned about them. As for the affective characteristics of these memories, she tended to have high ratings of vividness and rehearsal. Negative emotional states and great surprise and novelty were also reported.

LESSONS: By assessing the impact of flashbulb memories in this patient with AD, this paper offers a unique view into how such memories may trigger a considerable recall of context as well much subjective reliving.

RevDate: 2022-04-08

Cherian I, Beltran M, Kasper EM, et al (2016)

Exploring the Virchow-Robin spaces function: A unified theory of brain diseases.

Surgical neurology international, 7(Suppl 26):S711-S714.

BACKGROUND: Cerebrospinal fluid (CSF) transport across the central nervous system (CNS) is no longer believed to be on the conventional lines. The Virchow-Robin space (VRS) that facilitates CSF transport from the basal cisterns into the brain interstitial fluid (ISF) has gained interest in a whole new array of studies. Moreover, new line of evidence suggests that VRS may be involved in different pathological mechanisms of brain diseases.

METHODS: Here, we review emerging studies proving the feasible role of VRS in sleep, Alzheimer's disease, chronic traumatic encephalopathy, and traumatic brain injury (TBI).

RESULTS: In this study, we have outlined the possible role of VRS in different pathological conditions.

CONCLUSION: The new insights into the physiology of the CSF circulation may have important clinical relevance for understanding the mechanisms underlying brain pathologies and their cure.

RevDate: 2017-02-21
CmpDate: 2017-02-21

Reece AS, GK Hulse (2016)

Elevation of the ACTH/cortisol ratio in female opioid dependent patients: A biomarker of aging and correlate of metabolic and immune activation.

Neuro endocrinology letters, 37(4):325-336.

BACKGROUND: Whilst the hypothalamic-pituitary-adrenal (HPA) Axis is a major stress axis, and is necessarily perturbed in opioid dependency, and stress is a major contributor to aging mechanisms, the HPA axis has not been studied in opioid dependency in an age-dependent manner.

OBJECTIVE: Hypothesis - Differences in age dependent levels of HPA components.

DESIGN: Cross-sectional comparison of general medical and opioid dependent patients (ODP, GMP). Setting - Primary Care. Patients - 51 GMC, 233 ODP. Ages 37.92+1.95 v. 37.12+0.62 years (P - N.S.) and 33.33% v. 71.67% male (p<0.0001). Intervention(s) - Measurement ACTH, cortisol and their ratio (ACR). Main Outcome Measure(s) - Pre-planned analysis ACR.

SECONDARY OUTCOMES: Impact of immune and metabolic markers.

RESULTS: ACTH/cortisol was a negative biomarker for age in female patients. Whilst the mean ACR were not different, the (log) ACTH/cortisol showed a positive relationship with age:sex:status (p=0.0396) and age:status (p=0.0437). The effect of addictive status was confined to hepatitis C (HCV) positive female ODP (p=0.0355), and the age:status interaction was also stronger in female HCV+ (p=0.0075) compared to HCV - (p=0.0667) patients. Multiple regression of ACR against age, status, ALT, CRP, and Globulins confirmed many significant interactions. ACTH/cortisol ratio interacted significantly from p=0.0008 in males and p=0.0079 in females, and in both sexes four terms included addictive status.

CONCLUSIONS: These data establish the ACTH/cortisol ratio as a negative biomarker of aging in females, and show that this decline is more pronounced in ODP an effect which is partly related to HCV seropositivity, immune and metabolic factors. Dementias are one of the most serious health and socioeconomic issues. Multi-infarct dementia (MID) and Alzheimer´s type dementia (AD) exhibit differences in cerebrovascular blood flow velocity profiles and in presence of microemboli, detected by transcranial Doppler sonography.

RevDate: 2022-03-17
CmpDate: 2017-05-18

Mokry LE, Ross S, Morris JA, et al (2016)

Genetically decreased vitamin D and risk of Alzheimer disease.

Neurology, 87(24):2567-2574.

OBJECTIVE: To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation.

METHODS: We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p < 5 × 10[-8]) from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) Consortium (N = 33,996) to act as instrumental variables for the MR study. We measured the effect of each of these SNPs on 25OHD levels in the Canadian Multicentre Osteoporosis Study (CaMos; N = 2,347) and obtained the corresponding effect estimates for each SNP on AD risk from the International Genomics of Alzheimer's Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate.

RESULTS: The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log-transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03-1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged.

CONCLUSIONS: Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials.

RevDate: 2019-11-20

Peter Cao, Nady Braidy, Martin Zarka, Jeffrey Welch and Wallace Bridge (2016)

Erratum: Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease.

Current Alzheimer research, 13(10):1198 pii:CAR-EPUB-78012.

Due to an oversight of the corresponding author, the list of authors was originally published incorrectly in the manuscript entitled "Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease", published in Current Alzheimer Research, volume 12, no. 4, 2015, pp. 298-313. Due to this oversight, the correct first author was omitted from the original byline. The correct list of authors, with the true first author, is provided below: Authors: Peter Cao, Nady Braidy, Martin Zarka, Jeffrey Welch and Wallace Bridge. Affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Syd-ney, Australia, NSW 2052.

RevDate: 2018-12-02
CmpDate: 2018-05-03

Tomášková H, Kühnová J, K Kuča (Summ)

[Ageing and Alzheimer disease - system dynamics model prediction].

Ceska a Slovenska farmacie : casopis Ceske farmaceuticke spolecnosti a Slovenske farmaceuticke spolecnosti, 65(3):99-103.

The aim of the paper is to describe asystem dynamics model applied on aprediction of the number of patients with Alzheimers disease in the EU in the future and related financial impacts. Dementia resulting from Alzheimers disease is the most widely spread type of dementia and is highly connected with the age of the person - the patient. Most people are diagnosed with Alzheimers disease when they are older than 64. The ageing of population will be an ongoing problem in the next few decades due to alow birth rate and increasing life expectancy. This is areason to focus on prediction models of Alzheimers disease and its impact on economy. The paper presents adynamic modelling approach of system dynamics. The created model of the EU population and patients with AD is expanded by afinancial submodel at the end. This submodel estimates the cost on patients from three available cost studies.Key words: systém dynamic Alzhimers disease population ageing.

RevDate: 2021-02-05
CmpDate: 2017-06-01

Howitt J, AF Hill (2016)

Exosomes in the Pathology of Neurodegenerative Diseases.

The Journal of biological chemistry, 291(52):26589-26597.

More than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases.

RevDate: 2020-02-25
CmpDate: 2017-07-17

Guivernau B, Bonet J, Valls-Comamala V, et al (2016)

Amyloid-β Peptide Nitrotyrosination Stabilizes Oligomers and Enhances NMDAR-Mediated Toxicity.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 36(46):11693-11703.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity.

SIGNIFICANCE STATEMENT: We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

RevDate: 2020-09-30

O'Connor CM, Clemson L, Hornberger M, et al (2016)

Longitudinal change in everyday function and behavioral symptoms in frontotemporal dementia.

Neurology. Clinical practice, 6(5):419-428.

BACKGROUND: The relationship between behavioral changes and functional decline in frontotemporal dementia (FTD) is not well understood.

METHODS: Thirty-nine patients (21 behavioral variant FTD [bvFTD], 18 semantic variant primary progressive aphasia [svPPA]) were followed up longitudinally (2-4 years follow-up). Functional (Disability Assessment for Dementia) and behavioral (Cambridge Behavioural Inventory Revised) assessments were included for between-group (pairwise comparisons, mixed model analysis) and within-group analyses (bivariate correlations).

RESULTS: Functionally, patients with bvFTD were more impaired than patients with svPPA at baseline and continued to be at follow-up, despite similar disease duration. By contrast, behavioral impairments differed between patient groups at baseline and at follow-up. At baseline, patients with bvFTD exhibited higher levels of apathy and changes in eating than patients with svPPA; disinhibited and stereotypical behaviors were similar. Over the years, patients with bvFTD showed reduction in disinhibition and stereotypical behavior while apathy and eating changes increased. By contrast, all measured behaviors increased in patients with svPPA over time. Finally, only apathy made longitudinal contributions to functional disability in patients with svPPA, whereas apathy and stereotypical behavior were associated with increased disability in patients with bvFTD.

CONCLUSIONS: Despite shared overlapping baseline behavioral symptoms, patients with bvFTD are more functionally impaired than patients with svPPA. Apathy has a strong role in disability for both bvFTD and svPPA, but stereotypical behaviors only contributed to functional deficits in patients with bvFTD. Our findings suggest that rigid/compulsive behaviors may in fact support activity engagement in patients with svPPA. Taken together, our results indicate that interventions to reduce disability in the FTD spectrum require an alternative rationale in comparison to Alzheimer disease dementia, and should carefully weigh the interaction of behavioral symptoms and functional status.

RevDate: 2019-11-20

Miller ZA, Sturm VE, Camsari GB, et al (2016)

Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture.

Neurology(R) neuroimmunology & neuroinflammation, 3(6):e301.

OBJECTIVE: To determine the prevalence of autoimmune disease in symptomatic C9ORF72 (C9) mutation carriers and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts.

METHODS: In this case-control study, we reviewed the clinical histories of 66 patients with FTD/MND and 57 symptomatic C9 carriers (24 overlapping cases), a total of 99 charts, for history of autoimmune disease. The prevalence of autoimmune disease in C9 and FTD/MND cohorts was determined by χ[2] and Fisher exact comparisons between the combined C9 and FTD/MND group with normal control, Alzheimer disease, and progressive supranuclear palsy cohorts, as well as comparisons within C9 and FTD/MND cohorts.

RESULTS: Our combined C9 and FTD/MND cohort has a 12% prevalence of nonthyroid autoimmune disease. The prevalence of nonthyroid autoimmune disease in C9 and FTD/MND is similar to the rates in previously detailed progranulin and semantic variant primary progressive aphasia cohorts and elevated in comparison to previously collected normal control and typical Alzheimer disease cohorts, as well as a newly screened progressive supranuclear palsy cohort. Furthermore, the types of autoimmune disease in this combined C9 and FTD/MND cohort cluster within the same 3 categories previously described in progranulin and semantic variant primary progressive aphasia: inflammatory arthritides, cutaneous conditions, and gastrointestinal disorders.

CONCLUSIONS: The association between selective autoimmune disease and neurodegenerative disorders unified by the underlying pathology frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) extends to C9 and FTD/MND cohorts, providing further evidence that select autoimmune inflammation may be intrinsically linked to FTLD-TDP pathophysiology.

RevDate: 2020-09-30

Schjønning Nielsen M, Simonsen AH, Siersma V, et al (2016)

Are CSF Biomarkers Useful as Prognostic Indicators in Diagnostically Unresolved Cognitively Impaired Patients in a Normal Clinical Setting.

Dementia and geriatric cognitive disorders extra, 6(3):465-476.

BACKGROUND: Despite an extensive evaluation program, patients may remain diagnostically unresolved with regard to the etiology of their cognitive dysfunction. Cerebrospinal fluid neuroinflammation and Alzheimer disease (AD) biomarkers may act as indicators of neurodegenerative disorders in diagnostically unresolved patients.

METHODS: Data on 348 patients were retrospectively evaluated. All participants had a standardized diagnostic workup and follow-up in a memory clinic.

RESULTS: Aβ42 levels and Aβ42/p-tau ratios were reduced and levels of t-tau and p-tau as well as the t-tau × p-tau/Aβ42 ratio were elevated in diagnostically unresolved patients who clinically progressed, compared to a stable group. No differences in neuroinflammatory parameters were found.

CONCLUSION: AD biomarkers - in particular the Aβ42/p-tau ratio, but not neuroinflammatory parameters - predicted clinical progression, regardless of etiology.

RevDate: 2018-11-13
CmpDate: 2017-10-24

Uchihara T, Endo K, Kondo H, et al (2016)

Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX.

Acta neuropathologica communications, 4(1):118.

Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7-36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30-34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20-25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms.

RevDate: 2020-09-30

White PJ, Z Moussavi (2016)

Neurocognitive Treatment for a Patient with Alzheimer's Disease Using a Virtual Reality Navigational Environment.

Journal of experimental neuroscience, 10:129-135.

In this case study, a man at the onset of Alzheimer's disease (AD) was enrolled in a cognitive treatment program based upon spatial navigation in a virtual reality (VR) environment. We trained him to navigate to targets in a symmetric, landmark-less virtual building. Our research goals were to determine whether an individual with AD could learn to navigate in a simple VR navigation (VRN) environment and whether that training could also bring real-life cognitive benefits. The results show that our participant learned to perfectly navigate to desired targets in the VRN environment over the course of the training program. Furthermore, subjective feedback from his primary caregiver (his wife) indicated that his skill at navigating while driving improved noticeably and that he enjoyed cognitive improvement in his daily life at home. These results suggest that VRN treatments might benefit other people with AD.

RevDate: 2020-09-30

Shojaii A, Ghods R, MA Fard (2016)

Medicinal Herbs in Iranian Traditional Medicine for Learning and Memory.

Iranian journal of medical sciences, 41(3 Suppl):S43.

BACKGROUND: A few factors such as age, stress, and emotions may lead to impaired learning, memory loss, amnesia, and dementia or threats like schizophrenia and Alzheimer's disease (AD). Iranian traditional medicine (ITM) recommends some herbs and herbal preparations for the treatment or prevention of CNS problems.

METHODS: In this study, scientific evidence related to the effectiveness of ITM herbal medicine on memory, learning and AD is reviewed. The scientific evidence of plant efficacy was searched in electronic databases including PubMed, Scopus, SID, Science Direct, and Google Scholar by keywords such as memory, Alzheimer, amnesia, learning and scientific plant names from 1969 to 2014.

RESULTS: The findings of this study confirmed the effectiveness of certain ITM medicinal plants on enhancing memory and learning or in the treatment/prevention of amnesia and AD. Some ITM plants like Melissa officinalis, Crocus sativus and Nigella sativa showed improving effects on memory and the treatment of AD in clinical trials. In some cases, active principles responsible for the efficacy of these plants on memory were also determined.

DISCUSSION: Most of the studies on ITM plants were designed in animal models and a few herbs were evaluated in clinical trials on AD. Furthermore, there are insufficient or no investigations on certain herbal medicines used in ITM to confirm their effectiveness on memory and learning. Therefore, further experimental and clinical studies are necessary to evaluate the effectiveness of these plants on memory and AD as well as determining their active components.

RevDate: 2020-09-30

Dabaghian F, Khademian S, Azadi A, et al (2016)

Fingerprints, Pharmaceutical and Radical Scavenging Activity Evaluation of an Alzheimer-Targeted Herbal Preparation.

Iranian journal of medical sciences, 41(3 Suppl):S6.

BACKGROUND: As the most common form of dementia, Alzheimer disease is characterized by progressive loss of memory and deterioration of cognitive functions. It is predicted that about 75.63 million people would suffer from dementia by 2030. Apart from conventional remedies, the application of herbal medicines is on the rise. There are numerous natural medicaments reported in the traditional manuscript of Persian medicine. Accordingly, in the present study, the intended remedy was selected and an appropriate pharmacognostical and pharmaceutical evaluations were performed.

METHODS: By searching through the traditional pharmaceutical manuscripts such as Qarabadeen-e-Salehi, Qarabadeen-e-Azam, Qarabadeen-e-Ghaderi and Canon of Medicine, a simple but proven compound remedy (frankincense and black pepper) was selected. A floating tablet was designed and formulated from those herbal components. Related pharmaceutical assessments such as weight variation, hardness, friability, and disintegration tests as well as pharmacognostical evaluations such as microscopic characterization, TLC, GC/MS, FT/IR fingerprints, and radical scavenging activity assessment (DPPH) were performed.

RESULTS: The resulting formulation, as a floating tablet, included 60% of frankincense gum and 15% of black pepper along with appropriate pharmaceutical ingredients (weight variation: 0.219±0.004 g, hardness: 6.50±0.67, friability: 0.45%, disintegration time >30 min). Microscopic characterization demonstrated stone cells, calcium oxalate crystals, sclereids of endocarp and pitted cells of mesocarp of pepper fruits as well as oil drops of frankincense gum. TLC fingerprinting showed classes of secondary metabolites related to both components. GC/MS analysis revealed Acetyl acetate and trans-Caryophyllene as the main constituent. Moderate radical scavenging activity (IC50 >100 µg/ml) was calculated for the methanol extract of tablets.

CONCLUSION: Carrying out and validating a GC method for standardization of the formulated tablet, and having the structure for the effectiveness of these medicinal herbs in Alzheimer may be the horizon for a new Alzheimer-targeted medicine.

RevDate: 2018-12-02
CmpDate: 2017-03-27

Cao G, Su P, Zhang S, et al (2016)

Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells.

European journal of pharmacology, 793:101-108.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition. Reducing the Aβ load may be a new perspective for AD treatment. Ginsenoside Re is an extract from Panax notoginseng, which is a well-known traditional Chinese medicine that has been used for the treatment of various diseases for years. Ginsenoside Re has been reported to decrease Aβ in Alzheimer's disease animal models, but the mechanism has not been fully elucidated. In the present study, we investigated the mechanism of ginsenoside Re. Our results showed that ginsenoside Re decreased the Aβ levels in N2a/APP695 cells. Aβ peptides are generated by β-secretase (β-site amyloid precursor protein cleaving enzyme 1 (BACE1)) and γ-secretase. We found that ginsenoside Re decreased the BACE1 mRNA and protein levels and inhibited BACE1 activity in the N2a/APP695 cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates the activity of the BACE1 promoter, and activating PPARγ can inhibit BACE1. The results also showed that ginsenoside Re significantly increased the PPARγ protein and mRNA levels. These effects of ginsenoside Re on BACE1 could be effectively inhibited by the PPARγ antagonist GW9662. These findings indicate that ginsenoside Re inhibits BACE1 through activation of PPARγ, which ultimately reduces the generation of Aβ1-40 and Aβ1-42. Therefore, ginsenoside Re may be a promising agent for the modulation of Aβ-related pathology in AD.

RevDate: 2018-11-13
CmpDate: 2017-11-06

Kam TI, Park H, Gwon Y, et al (2016)

FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model.

eLife, 5:.

Amyloid-β (Aβ)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aβ exerts neuropathogenic activity through tau, the mechanistic link between Aβ and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcγRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Aβ1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aβ1-42 increased PtdIns(3,4)P2 levels from PtdIns(3,4,5)P3 to mediate tau hyperphosphorylation. Further, we found that targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we concluded that the FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD.

RevDate: 2020-09-30

Li X, Wang H, Tian Y, et al (2016)

Impaired White Matter Connections of the Limbic System Networks Associated with Impaired Emotional Memory in Alzheimer's Disease.

Frontiers in aging neuroscience, 8:250.

Background: Discrepancies persist regarding retainment of emotional enhancement of memory (EEM) in mild cognitive impairment (MCI) and early Alzheimer's disease (AD) patients.In addition, the neural mechanisms are still poorly understood, little is known about emotional memory related changes in white matter (WM). Objective: To observe whether EEM is absent in amnestic MCI (aMCI) and AD patients, and to investigate if emotional memory is associated with WM connections and gray matters (GM) of the limbic system networks. Methods: Twenty-one AD patients, 20 aMCI patients and 25 normal controls participated in emotional picture recognition tests and MRI scanning. Tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) methods were used to determine white and gray matter changes of patients. Fourteen regions of interest (ROI) of WM and 20 ROIs of GM were then selected for the correlation analyses with behavioral scores. Results: The EEM effect was lost in AD patients. Both white and gray matter of the limbic system networks were impaired in AD patients. Significant correlations or tendencies between the bilateral uncinate fasciculus, corpus callosum (genu and body), left cingulum bundle, left parahippocampal WM and the recognition sensitivity of emotional valence pictures, and significant correlations or tendencies between the splenium of corpus callosum, left cingulum bundle, left crus of fornix and stria terminalis and the recognition sensitivity of EEM were found. The volume of left amygdala, bilateral insula, medial frontal lobe, anterior and middle cingulum gyrus were positively correlated with the recognition sensitivity of emotional photos, and the right precuneus was positively correlated with the negative EEM effect. However, the affected brain areas of aMCI patients were more localized, and aMCI patients benefited only from positive stimuli. Conclusion: There are impairments of the limbic system networks of AD patients. Damaged WM connections and GM volumes of those networks are associated with impaired emotional memory and EEM effect in AD patients.

RevDate: 2018-12-02
CmpDate: 2016-12-19

Deming Y, Black K, Carrell D, et al (2016)

Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40.

BMC neurology, 16(1):217.

BACKGROUND: Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.

METHODS: We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ42 ratio, Aβ42, tau, and ptau181.

RESULTS: We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau181 (r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006).

CONCLUSIONS: CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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