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Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI., (© 2024. The Author(s).)

Introduction: Current estimates indicate that up to 50-75% of dementia cases are undiagnosed at an early stage when treatments are most effective. Conducting robust accurate cognitive assessments can be time-consuming for providers and difficult to incorporate into a time-limited Primary Care Provider (PCP) visit. We wanted to compare PCP visits with and without using the self-administered SAGE to determine differences in identification rates of new cognitive disorders., Methods: Three hundred patients aged 65-89 without diagnosed cognitive disorders completing a non-acute office visit were enrolled (ClinicalTrials.gov identifier: NCT04063371). Two PCP offices conducted routine visits for 100 consecutive eligible patients each. One office used the SAGE in an additional 100 subjects and asked available informants about cognitive changes over the previous year. Chart reviews were conducted 60 days later. One-way analysis of variance and Fisher exact tests were used to compare the groups and outcomes., Results: When SAGE was utilized, the PCP documented the detection of new cognitive conditions/concerns six times (9% versus 1.5%) as often ( p  = 0.003). The detection rate was nearly 4-fold for those with cognitively impaired SAGE scores ( p  = 0.034). Patients having impaired SAGE score and informant concerns were 15-fold as likely to have new cognitive conditions/concerns documented ( p  = 0.0007). Among providers using SAGE, 86% would recommend SAGE to colleagues., Discussion: SAGE was easily incorporated into PCP visits and significantly increased identification of new cognitive conditions/concerns leading to new diagnoses, treatment, or management changes. The detection rate increased 15-fold for those with impaired SAGE scores combined with informant reports., Competing Interests: Ohio State University holds the copyright for the SAGE test. SAGE was developed by DWS at Ohio State University and is freely available. This research only evaluated SAGE in its paper form. The digital version of SAGE made for tablet use is commercially available at: BrainTest.com through a license agreement with Ohio State University. DS is a member of the Scientific Advisory Board of BrainTest Inc. SEZC., (Copyright © 2024 Scharre, Vrettos, Nagaraja, Wexler, Clark and Nguyen.)

Objective: Using the metadata collected in the digital version of the Self-Administered Gerocognitive Examination (eSAGE), we aim to improve the prediction of mild cognitive impairment (MCI) and dementia (DM) by applying machine learning methods., Patients and Methods: A total of 66 patients had a diagnosis of normal cognition (NC), MCI, or DM, and eSAGE scores and metadata were used. eSAGE scores and metadata were obtained. Each eSAGE question was scored and behavioral features (metadata) such as the time spent on each test page, drawing speed, and average stroke length were extracted for each patient. Logistic regression (LR) and gradient boosting models were trained using these features to detect cognitive impairment (CI). Performance was evaluated using 10-fold cross-validation, with accuracy, precision, recall, F1 score, and receiver operating characteristic area under the curve (AUC) score as evaluation metrics., Results: LR with feature selection achieved an AUC of 89.51%, a recall of 87.56%, and an F1 of 85.07% using both behavioral and scoring. LR using scores and metadata also achieved an AUC of 84.00% in detecting MCI from NC, and an AUC of 98.12% in detecting DM from NC. Average stroke length was particularly useful for prediction and when combined with 4 other scoring features, LR achieved an even better AUC of 92.06% in detecting CI. The study shows that eSAGE scores and metadata are predictive of CI., Conclusions: eSAGE scores and metadata are predictive of CI. With machine learning methods, the metadata could be combined with scores to enable more accurate detection of CI., Competing Interests: D.W.S. is a member of the Scientific Advisory Board of BrainTest Inc. SEZC. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A large number of individual potentially modifiable factors are associated with risk for Alzheimer's disease (AD). However, less is known about the interactions between the individual factors., Methods: In order to begin to examine the relationship between a pair of factors, we performed a pilot study, surveying patients with AD and controls for stress exposure and dietary omega-3 fatty acid intake to explore their relationship for risk of AD., Results: For individuals with the greatest stress exposure, omega-3 fatty acid intake was significantly greater in healthy controls than in AD patients. There was no difference among those with low stress exposure., Conclusions: These initial results begin to suggest that omega-3 fatty acids may mitigate AD risk in the setting of greater stress exposure. This will need to be examined with larger populations and other pairs of risk factors to better understand these important relationships. Examining how individual risk factors interact will ultimately be important for learning how to optimally decrease the risk of AD.

Alzheimer's disease (AD) is the most common late-onset neurodegenerative disorder. Identifying individuals at increased risk of developing AD is important for early intervention. Using data from the Alzheimer Disease Genetics Consortium, we constructed polygenic risk scores (PRSs) for AD and age-at-onset (AAO) of AD for the UK Biobank participants. We then built machine learning (ML) models for predicting development of AD, and explored feature importance among PRSs, conventional risk factors, and ICD-10 codes from electronic health records, a total of > 11,000 features using the UK Biobank dataset. We used eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP), which provided superior ML performance as well as aided ML model explanation. For participants age 40 and older, the area under the curve for AD was 0.88. For subjects of age 65 and older (late-onset AD), PRSs were the most important predictors. This is the first observation that PRSs constructed from the AD risk and AAO play more important roles than age in predicting AD. The ML model also identified important predictors from EHR, including urinary tract infection, syncope and collapse, chest pain, disorientation and hypercholesterolemia, for developing AD. Our ML model improved the accuracy of AD risk prediction by efficiently exploring numerous predictors and identified novel feature patterns., (© 2023. The Author(s).)

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region., (© 2022. The Author(s).)

One hundred and five memory disordered (MD) patients and 57 controls were tested on item recognition memory and lexical decision tasks, and diffusion model analyses were conducted on accuracy and response time distributions for correct and error responses. The diffusion model fit the data well for the MD patients and control subjects, the results replicated earlier studies with young and older adults, and individual differences were consistent between the item recognition and lexical decision tasks. In the diffusion model analysis, MD patients had lower drift rates (with mild Alzheimer's [AD] patients lower than mild cognitive impairment [MCI] patients) as well as wider boundaries and longer nondecision times. These data and results were used in a series of studies to examine how well MD patients could be discriminated from controls using machine-learning techniques, linear discriminant analysis, logistic regression, and support vector machines (all of which produced similar results). There was about 83% accuracy in separating MD from controls, and within the MD group, AD patients had about 90% accuracy and MCI patients had about 68% accuracy (controls had about 90% accuracy). These methods might offer an adjunct to traditional clinical diagnosis. Limitations are noted including difficulties in obtaining a matched group of control subjects as well as the possibility of misdiagnosis of MD patients. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The purpose of this manuscript is to summarize research on how experimental pain is experienced by adults with Alzheimer's disease (AD) and to translate results into implications for nurses., Design: This discursive review synthesizes the results of three previous research studies exploring experimental pain in adults with AD., Methods: Using a series of fictional clinical vignettes, the authors discuss how the results from three previous papers using acute experimental pain can potentially be translated into clinical practice. The authors also introduce the reader to the concept of research-related psychophysics using introductory definitions and concepts with the impetus to encourage other nurses to consider this research methodology., Results: Pain characteristics in AD that differ from cognitively intact controls must be explored to properly address pain in this population. Nurses are well positioned to address these issues in order to provide a high quality of care to adults with AD., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed., Competing Interests: TB has conducted consultation for a peripheral synuclein assay and speakers honorarium from Roche Diagnostics. RL is employed full time by Amprion, serves on Amprion's Board, and is a shareholder. CT research is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), and JPND), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, the Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is the recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes Strijbisfonds. IV is appointed on a research grant by Alzheimer Nederland (NL 17004). CT has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, who performed contract research or received grants from AC Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. CT serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology and Neuroinflammation, and is editor of a Neuromethods book by Springer. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (all outside submitted work). CMo is an inventor of several US and International Georgetown University patents to use tyrosine kinase inhibitors (TKis) for the treatment of neurodegenerative diseases. CMo is a co-founder and shareholder and receives consulting fees from KeifeRx LLC. CMo receives consulting fees from Neumentum LLC, SUn Pharmaceuticals Research Industry, and SkyBIo. CMo received NIH NIA funding, Alzheimer's Association, and Sun Pharmaceuticals Research Industry Funding to study TKis in neurodegeneration, including LBD. KP has received consulting fees from Curasen and is funded by grants from the NIH, Michael J Fox Foundation for Parkinson's Research, LBDA, and Alzheimer's Drug Discovery Foundation, and has received funding from Sanofi US Services, Inc. to perform clinical trials. MS declares ownership interest (Stock or stock options): Brain Health Inc, NeuroTau, Optimal Cognitive Health Company, uMethod Health, Versanum, Athira, Cognoptix and consulting work for Alzheon, Biogen, Cortexyme, Roche Genentech, Stage 2 Innovations/Renew Research, Acadia, T3D, Eisai, KeifeRx. MS also declares royalties: HarperCollins, Humanix and speakers bureau: Health and Wellness Partners. LR receives grant funding from the NINDS, Michael J. Fox Foundation, Parkinson's Foundation, and National Ataxia Foundation. She has also served on advisory boards for Uniqure and other pharmaceutical companies through the Parkinson's Study Group. MJA receives research support from the NIA (R01AG068128, P30AG047266), the Florida Department of Health (Grant 20A08), and as the local PI of a Lewy Body Dementia Association Research Center of Excellence. MJA serves on the data safety monitoring boards (DSMBs) for ACTC/ATRI and ADCS. MJA receives royalties from the publication of the book Parkinson's Disease: Improving Patient Care. MJA serves on the level of evidence editorial board for Neurology and related publications (uncompensated). JGG declares grants/research—Acadia, Michael J. Fox Foundation, Parkinson's Foundation, Consultant—Worldwide Med, Honoraria—American Academy of Neurology, Davis Phinney Foundation, International Parkinson and Movement Disorders Society, Medscape, Parkinson's Foundation, Other: Lewy Body Dementia Association Research Center of Excellence. ZM received institutional grant support from NIH, MJFF, LBDA, Parkinson's Foundation, Eli Lilly, NeuroDerm, Cerevel Therapeutics and personal consulting honoraria from Global Kinetics Corporation, GB Sciences, ACADIA, PSG, Elsevier, Kyowa Kirin, AbbVie, and Supernus. IL's research is supported by the National Institutes of Health Grants: 2R01AG038791-06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911-1 and 1R21NS114764-01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio, and United Biopharma SRL—UCB. IL was a member of the Scientific Advisory Board of Lundbeck and is a Scientific Advisor for Amydis and Rossy Center for the Progressive Supranuclear Palsy University of Toronto. IL receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. JL receives grant funding from the NIH/NIA/NINDS (P30AG072959/P30AG062428/U01NS100610), LBDA, GE Healthcare and serves as a consultant for Eisai Pharmaceuticals. RW serves on the data safety monitoring boards for Alexion, Bukwang, and Sarepta Pharmaceuticals and the Scientific Platform Steering Committee for Adams Pharmaceuticals. RW serves as a consultant for Lundbeck, Acadia, Teva, Abbvie, Alexion, Adamas, Prime, Bukwang, Sarepta, Syneos, Techspert, Guidepoint and also for R01R01NS117547 with Principal Investigator, Virendra Mishra. AL has received research support from the Dutch Research Council (ZonMW), Alzheimer Netherlands, Dioraphte Foundation, AL has given lectures in symposia sponsored by GE. CG is a scientific consultant and has stock in CND Life Sciences. SG has served on Advisory Boards of Jannsen, Acadia, and Sanofi, has received consulting fees from EIP Pharma, and has received funding from the NIH, the DOD CDMRP, the Michael J. Fox Foundation, the FFFPRI, and the Lewy Body Dementia Association. BB has served as an investigator for clinical trials sponsored by Alector, EIP Pharma, and Biogen. He serves on the Scientific Advisory Board of the Tau Consortium. He receives institutional research support from the NIH, the Lewy Body Dementia Association Research Centers of Excellence Program, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, and the Ted Turner and Family Foundation. AP serves on the Scientific Advisory Board of MedRhythms, Inc. and receives research support from the Lewy Body Dementia Association (as Co-Director of the Johns Hopkins LBDA Research Center of Excellence) and NIH/NINDS/NIA (U01NS102035; K23AG059891). DG receives research support from NIA (AG062429), the State of California, and the Michael J. Fox Foundation, which is a paid consultant for Biogen, Roche, Esai, Cognition Therapeutics, Fujirebio, Amprion, Generian, and Editor of Alzheimer's Research & Therapy. DH is supported by The Michael J. Fox Foundation (MJFF-010556), NIH-NINDS 1K23NS105944-01A1, the American Parkinson's Disease Association Center for Advanced Research (Emory University), and the Lewy Body Dementia Association Research Center of Excellence (Emory University). JF is on the editorial board of the American Academy of Neurology's Brain and Life magazine (uncompensated), Lewy Body Dementia Association Scientific Affairs Committee (uncompensated), and has received honoraria from Parkinson's Foundation. JF receives grant funding from the NIH/NIA/NINDS (K23NS097615, 5P30AG064200-02), CurePSP, and Parkinson's Foundation. KD-R receives research funding from the NIH (P30 AG066509) and LBDA Research Center of Excellence; has served on a Biogen advisory board; receives speakers honoraria from MedBridge. LS receives research support from NIH/NIA U19 AG024904, ADNI3 grant; NIH/NIA P30 AG010124, UPENN ADCC grant; and the Michael J. Fox Foundation for Parkinson's Research. He is a consultant for Biogen and Roche Diagnostics and is on the speaker's bureaus for Biogen and Fujirebio. DI receives research funding from NIH (R01-NS109260, P01-AG066597, U19-AG062418, U01-NS100610), Penn Institute on Aging and is the co-PI of the Penn LBDA Research Centers of Excellence. He is a member of the scientific advisory board of Denali Therapeutics. LH is a paid consultant for Biogen, Cortexyme, Eisai, Medscape, and Prevail. LH receives grant support from NIA, NINDS, LBDA, Acumen, Alector, Avanir, Eisai, Genentech/Roche, Janssen/Johnson & Johnson, NovoNordisk, Transposon, UCB, and Vaccinex. JD receives research funding from NIH, the Department of Veterans Affairs, the Michael J. Fox Foundation and Innervace, Inc. He is also the co-PI of the Penn LBDA Research Center of Excellence. IL is the Editor in Chief of the journal but she was not involved in the process of referee selection, peer review or the acceptance decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scott, Arnold, Beach, Gibbons, Kanthasamy, Lebovitz, Lemstra, Shaw, Teunissen, Zetterberg, Taylor, Graham, Boeve, Gomperts, Graff-Radford, Moussa, Poston, Rosenthal, Sabbagh, Walsh, Weber, Armstrong, Bang, Bozoki, Domoto-Reilly, Duda, Fleisher, Galasko, Galvin, Goldman, Holden, Honig, Huddleston, Leverenz, Litvan, Manning, Marder, Pantelyat, Pelak, Scharre, Sha, Shill, Mari, Quinn and Irwin.)

Background: Significant cognitive changes as individuals' age are not being identified in a timely manner, delaying diagnosis and treatments. Use of brief, multi-domain, self-administered, objective cognitive assessment tools may remove some barriers in assessing and identifying cognitive changes. We compared longitudinal Self-Administered Gerocognitive Examination (SAGE) test scores to non-self-administered Mini-Mental State Examination (MMSE) scores in 5 different diagnostic subgroups., Methods: A cohort study evaluating annual rates of change was performed on 665 consecutive patients from Ohio State University Memory Disorders Clinic. Patients with at least two visits 6 months apart evaluated with SAGE and MMSE and classified according to standard clinical criteria as subjective cognitive decline (SCD), mild cognitive impairment (MCI), or Alzheimer's disease (AD) dementia were included. The pattern of change in SAGE scores was compared to MMSE. One way and repeated measures ANOVA and linear regression models were used., Results: Four hundred twenty-four individuals (40 SCD, 94 MCI non-converters to dementia, 70 MCI converters to dementia (49 to AD dementia and 21 to non-AD dementia), 220 AD dementia) met inclusion criteria. SAGE and MMSE scores declined respectively at annual rates of 1.91 points/year (p < 0.0001) and 1.68 points/year (p < 0.0001) for MCI converters to AD dementia, and 1.82 points/year (p < 0.0001) and 2.38 points/year (p < 0.0001) for AD dementia subjects. SAGE and MMSE scores remained stable for SCD and MCI non-converters. Statistically significant decline from baseline scores in SAGE occurred at least 6 months earlier than MMSE for MCI converters to AD dementia (14.4 vs. 20.4 months), MCI converters to non-AD dementia (14.4 vs. 32.9 months), and AD dementia individuals (8.3 vs. 14.4 months)., Conclusions: SAGE detects MCI conversion to dementia at least 6 months sooner than MMSE. Being self-administered, SAGE also addresses a critical need of removing some barriers in performing cognitive assessments. Limitations of our single-site cohort study include potential referral and sampling biases. Repetitively administering SAGE and identifying stability or decline may provide clinicians with an objective cognitive biomarker impacting evaluation and management choices., (© 2021. The Author(s).)

This brief report details a pilot analysis conducted to explore racial differences in pain sensitivity and unpleasantness between cognitively healthy Black and White adults, stratified by sex. A total of 24 cognitively healthy adults (12 Black and 12 White) from two completed studies were matched by age and sex, and divided into two groups based on race. Stratified analyses by sex demonstrated that Black females reported experiencing pain intensity ratings of all three intensity sensations at lower temperatures than White females. These findings will inform future research studies to determine if these results hold true in a fully-powered sample and should include mixed methodologies, incorporating neuroimaging data to further assess this phenomenon. Improving pain assessment and management across racial/ethnic groups will help healthcare providers such as nurses and physicians to ensure optimal quality of life for all., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moss, Wright, Tan, Rose, Scharre, Gure, Cowan, Failla and Monroe.)

Background: Clinical trials involving individuals with mild cognitive impairment (MCI) have reported mixed results for the effects of cholinesterase inhibitors on cognitive outcomes. Our previous work demonstrated that a visuospatial problem-solving task was sensitive to non-memory impairments in individuals with MCI., Objective: To determine whether the same task is also sensitive to the effects of cholinesterase inhibitors in individuals with amnestic MCI (aMCI)., Method: We gave 22 individuals with aMCI (clinical dementia rating of 0.5) and Mini-Mental State Examination (MMSE) scores of at least 24 the following measures at baseline and at follow-up 1 year later: Hopkins Verbal Learning Test, Boston Naming Test, Rey Complex Figures Test copying task, anagrams task, and visuospatial problem-solving task. The MMSE was also given at the 1-year follow-up. Twelve of the individuals were drug naïve, having never taken cholinesterase inhibitors before, and donepezil was initiated and titrated to 10 mg daily after baseline in an open-label manner. Ten of the individuals had already been taking donepezil, and there was no change in treatment. We compared the two groups for amount of performance change over 1 year., Results: Individuals for whom donepezil was initiated performed significantly better on the visuospatial problem-solving task after 1 year compared with individuals who had already been taking donepezil. No difference was observed for any of the other variables., Conclusion: The visuospatial problem-solving task appeared to be more sensitive than memory measures to the effects of cholinesterase inhibitors in individuals with aMCI, perhaps due to the high attentional demand of the task., Competing Interests: D.W.S. was on the speaker’s bureau for Ortho-McNeil, Pfizer, Eisai, Forest, and Novartis at the time of the study, and D.Q.B. was on the speaker’s bureau for Pfizer and Eisai at the time of the study. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treadmill training may improve gait disorders associated with neurodegenerative diseases. In Parkinson's disease (PD), treadmill training alters gait patterns after one session, and long-term training improves gait parameters, fall risk, and quality of life., Research Question: What is the feasibility and safety of using this intervention for people with Lewy body dementia (LBD) or Huntington's disease (HD)?, Methods: In this observational study, 10 individuals with HD, 8 individuals with LBD, and 10 control individuals walked for 20 min on a treadmill using a speed dependent protocol starting at a slow comfortable speed and increasing incrementally toward their normal overground speed. Feasibility was determined by compliance to protocol and safety by no incidents of abnormal vital signs or expressions of distress. Changes in gait measures, Timed Up and Go (TUG) scores and quantitative motor function measures (Q-Motor; precision grasp force variability, finger and foot tapping frequency) before and after treadmill walking were analyzed using linear models., Results: Treadmill training is feasible and safe in LBD and HD; although, participants could not initiate treadmill walking at their comfortable overground speeds, and only 3 participants with HD were able to achieve their overground walking speed within the 20-minute session. No changes in gait measures, TUG times, and Q-Motor measures were found among LBD and HD participants after treadmill walking, although control participants demonstrated significant increases in several gait measures, and foot tap frequency (estimated difference = 0.290; p = 0.026)., Significance: Longer and more frequent treadmill sessions may be needed to see gait and motor function effects in LBD and HD. Motor and cognitive impairments associated with these diseases may make them less amenable to the effects of treadmill training., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Hypertension increases the risk of developing Alzheimer's disease or related dementias. This pilot study's purpose was to examine the feasibility and acceptability of a novel intervention, Mindfulness in Motion (MIM) and Dietary Approaches to Stop Hypertension DASH (MIM DASH), to improve diet, mindfulness, stress, and systolic blood pressure (BP) in older African Americans with mild cognitive impairment (MCI) and hypertension., Design: Cluster randomized controlled trial., Setting: Intergenerational community center in a large metropolitan area., Participants: African Americans with MCI and hypertension. Participants were divided into six groups randomized 1:1:1 to the MIM DASH group, attention only (non-hypertensive education) group, or true control group. The MIM DASH and attention only interventions were delivered in 8-weekly 2 hour group sessions. MIM included mindful movements from chair/standing, breathing exercises, and guided meditation. The DASH component used a critical thinking approach of problem solving, goal setting, reflection, and self-efficacy. The true control group received a DASH pamphlet at the end., Measurements: Feasibility was tracked through enrollment and attendance records; acceptability was assessed through interviews. Blood pressure was measured using the Omron HEM-907XL Monitor. Dietary intake was measured by DASH-Q. Mindfulness was measured by the Cognitive and Affective Mindfulness Scale. Stress was measured by the Perceived Stress Scale. MCI was determined using the Self-Administered Gerocognitive Examination. Data were collected at baseline and 3-months., Results: Median session attendance was six for the MIM DASH group and six for the attention only group. There were no changes in diet, mindfulness, or stress. There was a clinically significant reduction in systolic BP in the MIM DASH group (-7.2 mmHg) relative to the attention only group (-.7), and no change between the MIM DASH and true control groups., Conclusion: Results indicate that the MIM DASH intervention was feasible and culturally acceptable in African Americans with hypertension and MCI., (© 2021 The American Geriatrics Society.)

Objective: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations., Methods: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center., Results: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity., Conclusions: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pre-existing cognitive impairment is associated with poor surgical outcomes, long hospital stays, and increased morbidity and mortality. This necessitates the use of screening tools to evaluate preoperative cognitive status in elderly surgical patients. Given the growing population of older adults and increased prevalence of cognitive impairment, it is necessary to investigate whether staff-administered or self-administered cognitive screening examinations provide more sensitive information about pre-existing (preoperative) cognitive status. Self-administered Gerocognitive Screening Examination (SAGE) was developed out of the need for a cognitive self-assessment scale in the clinic. At our institution, SAGE was given to 189 elderly surgical patients to evaluate baseline cognitive status, and preliminary results are promising that self-assessment scales are both feasible and acceptable in the surgical setting., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Multiple variants in SNCA, encoding alpha-synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease., Methods: We searched for cis-acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3'UTR (2,520 bp) luciferase reporter gene assay, translation in SH-SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome-wide association studies., Results: Allelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3' untranslated region (3'UTR), but not at a marker at its start, suggesting regulation of 3'UTR processing. 3'UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3'UTR isoforms. A second 3'UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3'UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome-wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the "Genome Wide Association Study of Yoruba in Nigeria," rs356165 was associated with reduced memory performance., Conclusions: Here, we identify two cis-acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3'UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer's disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

With the increasing prevalence of Alzheimer's disease (AD), significant efforts have been directed toward developing novel diagnostics and biomarkers that can enhance AD detection and management. AD affects the cognition, behavior, function, and physiology of patients through mechanisms that are still being elucidated. Current AD diagnosis is contingent on evaluating which symptoms and signs a patient does or does not display. Concerns have been raised that AD diagnosis may be affected by how those measurements are analyzed. Unbiased means of diagnosing AD using computational algorithms that integrate multidisciplinary inputs, ranging from nanoscale biomarkers to cognitive assessments, and integrating both biochemical and physical changes may provide solutions to these limitations due to lack of understanding for the dynamic progress of the disease coupled with multiple symptoms in multiscale. We show that nanoscale physical properties of protein aggregates from the cerebral spinal fluid and blood of patients are altered during AD pathogenesis and that these properties can be used as a new class of "physical biomarkers." Using a computational algorithm, developed to integrate these biomarkers and cognitive assessments, we demonstrate an approach to impartially diagnose AD and predict its progression. Real-time diagnostic updates of progression could be made on the basis of the changes in the physical biomarkers and the cognitive assessment scores of patients over time. Additionally, the Nyquist-Shannon sampling theorem was used to determine the minimum number of necessary patient checkups to effectively predict disease progression. This integrated computational approach can generate patient-specific, personalized signatures for AD diagnosis and prognosis.

Background: The original paper Self-Administered Gerocognitive Examination (SAGE) is a valid and reliable cognitive assessment tool used to identify individuals with mild cognitive impairment (MCI) or early dementia. We evaluated identical test questions in a digital format (eSAGE) made for tablet use with the goals of calibrating it against SAGE and establishing its association with other neuropsychological tests and clinical assessments of cognitive impairment., Methods: Subjects aged 50 and over who had taken SAGE were recruited from community and clinic settings. Subjects were randomly selected to participate in a clinical evaluation including neuropsychological evaluations. SAGE and eSAGE were administered using a crossover design. Subjects were identified as dementia, MCI, or normal based on standard clinical criteria. Associations were investigated using Spearman correlations, linear regression, and sensitivity and specificity measures., Results: Of the 426 subjects screened, 66 completed the evaluation. eSAGE score correlation to a battery of neuropsychological tests was 0.73 (p < 0.0001) with no significant difference between the paper and digital format. Spearman correlation of SAGE versus eSAGE was 0.88 (p < 0.0001), and they are related by the formula: eSAGE score = -1.05 + 0.99 × SAGE score. Since the slope is very close to 1 (p = 0.86) there is strong evidence that the scaling is identical between eSAGE and SAGE, with no scale bias. Overall, eSAGE scores are lower by an average of 1.21 and the decrease is statistically significant (p < 0.0001). For those subjects familiar with smartphones or tablets (one measure of digital proficiency), eSAGE scores are lower by an average of 0.83 points (p = 0.029). With a score 16 and higher being classified as normal, eSAGE had 90% specificity and 71% sensitivity in detecting those with cognitive impairment from normal subjects., Conclusions: Tablet-based eSAGE shows a strong association with the validated paper SAGE and a neuropsychological battery. It shows no scale bias compared to SAGE. Both have the advantage of self-administration, brevity, four interchangeable forms, and high sensitivity and specificity in detecting cognitive impairment from normal subjects. Their potential widespread availability will be a major factor in overcoming the many obstacles in identifying early cognitive changes., Trial Registration: ClinicalTrials.gov, NCT02544074 . Registered on 18 March 2015.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative disorder in the elderly. The development and progression of DLB remain unclear. In this study we used next generation sequencing to assess RNA expression profiles and cellular processes associated with DLB in the anterior cingulate cortex, a brain region affected by DLB pathology. The expression measurements were made in autopsy brain tissues from 8 DLB subjects and 10 age-matched controls using AmpliSeq technology with ion torrent sequencing. The analysis of RNA expression profiles revealed 490 differentially expressed genes, among which 367 genes were down-regulated and 123 were up-regulated. Functional enrichment analysis of genes differentially expressed in DLB indicated downregulation of genes associated with myelination, neurogenesis, and regulation of nervous system development. miRNA binding sites enriched in these mRNAs yielded a list of candidate miRNAs participating in DLB pathophysiology. Our study provides a comprehensive picture of gene expression landscape in DLB, identifying key cellular processes associated with DLB pathology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Introduction: Differential diagnosis of dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Parkinson's disease (PD) and Alzheimer's disease (AD) is challenging. Comparative motor profiles of these neurodegenerative disorders may aid in earlier diagnosis but have not been extensively studied., Methods: Groups were rigorously matched by age, education, and sex. DLB/PDD participants were matched by Mini-Mental State Examination Score to individuals with AD and by Unified Parkinson's Disease Rating Scale motor scores to individuals with PD. Gait, balance, dual task walking and hand dexterity measures were compared between a combined group (n=21) of individuals with Lewy body dementia (LBD) consisting of those with DLB (n=11) and PDD (n=10) to individuals with PD (n=21) or AD (n=21)., Results: Individuals at the same disease stage with LBD walked significantly slower with shorter stride lengths (p<0.05), demonstrated poorer balance on both the Tinetti and Berg Balance Scale, and poorer performance on dual-task and figure-of-eight walking compared to PD and AD (p<0.05 for all) groups. Upper extremity coordination on the 9-hole peg test differentiated LBD from both PD and AD and was the only motor test in which individuals with AD performed worse than those with PD. Tinetti balance subscores were significantly lower in PDD compared to DLB participants (10.4±2.3 versus 12.8±2.3; p=0.027)., Conclusions: Motor features distinguish individuals with LBD from those with AD and PD. Measures of gait, balance and finger dexterity provide an additional means of differentiating individuals with LBD from those with AD and PD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Importance: Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking., Objective: To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation., Design, Setting, and Participants: Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed., Interventions: In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60)., Main Outcomes and Measures: The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity])., Results: A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation., Conclusions and Relevance: In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated., Trial Registration: clinicaltrials.gov Identifier: NCT01584440.

To date, little is known regarding the etiology and disease mechanisms of Alzheimer's disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR ≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson's disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound extracellular matrix impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage, and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research.

This study investigated the functionality of the Self-Administered Gerocognitive Examination (SAGE) for cognitive screening in community settings and examined its characteristics as a cognitive screening assessment tool. From 45 community events, 1,047 individuals over age 50 were screened with SAGE. Cognitive impairment was identified in 28%. Principal-component and correlation analysis indicate that SAGE is an internally-consistent test that is very well balanced, with language, cognition, visuospatial, executive, and memory domains. Community cognitive screening using SAGE was found to be feasible and efficient in diverse settings with both small and large groups.

Background and Objective: Rivastigmine and donepezil are two cholinesterase inhibitors (ChEIs) indicated for the treatment of mild-to-moderate Alzheimer's disease. Dementia-related behavioural issues are typically managed by environmental modification and the use of psychotropics including antipsychotic medications. However, ChEIs have also been associated with reductions in behavioural symptoms in Alzheimer's disease patients. This retrospective, parallel-cohort, hypothesis-generating study investigated whether treatment with rivastigmine is associated with reduced prescription of antipsychotic medications compared with treatment with donepezil., Methods: A combined analysis of two claims databases was conducted. Patients were included if they had a diagnosis of Alzheimer's disease and were newly initiated on either rivastigmine or donepezil. Patients with prior use of memantine and/or antipsychotics were excluded. Kaplan-Meier and Cox analyses were conducted to compare the rate of antipsychotic drug use between the rivastigmine and donepezil groups., Results: A total of 956 patients receiving rivastigmine and 12 778 patients receiving donepezil formed the study population. Analysis revealed that 64 (6.7%) rivastigmine and 989 (7.7%) donepezil recipients received antipsychotic medications (log-rank test from Kaplan-Meier analysis, p = 0.2289). The Cox regression analysis showed that rivastigmine was associated with a statistically significant reduction in the prescription of antipsychotic drugs relative to donepezil (hazard ratio 0.73; p = 0.044). Older age, longer time between Alzheimer's disease diagnosis and first ChEI dispensing, lower dose of ChEI at treatment initiation and the presence of baseline depression and neuropsychiatric symptoms were associated with a significantly increased likelihood of antipsychotic drug use., Conclusions: In this retrospective analysis, Alzheimer's disease patients with no prior use of antipsychotics initiated on rivastigmine had a significantly lower rate of prescription of antipsychotic drugs than those treated with donepezil.

Polymorphisms in the gene encoding SORL1, involved in cellular trafficking of APP, have been implicated in late-onset Alzheimer's disease, by a mechanism thought to affect mRNA expression. To search for regulatory polymorphisms, we have measured allele-specific mRNA expression of SORL1 in human autopsy tissues from the prefrontal cortex of 26 Alzheimer's patients, and 51 controls, using two synonymous marker SNPs (rs3824968 in exon 34 (11 heterozygous AD subjects and 16 controls), and rs12364988 in exon 6 (8 heterozygous AD subjects)). Significant allelic expression imbalance (AEI), indicative of the presence of cis-acting regulatory factors, was detected in a single control subject, while allelic ratios were near unity for all other subjects. We genotyped 7 SNPs in two haplotype blocks that had previously been implicated in Alzheimer's disease. Since each of these SNPs was heterozygous in several subjects lacking AEI, this study fails to support a regulatory role for SORL1 polymorphisms in mRNA expression.

Background: Our purpose was to assess the safety and tolerability of extended-release galantamine (GAL-ER), using a 1-week dose titration in Alzheimer's patients., Methods: An open-label, 12-week, multicenter study was performed (n = 82). Results were compared with findings from a placebo-controlled trial using a 4-week titration of GAL-ER and immediate-release galantamine. The primary analysis compared incidences of adverse events (AEs)., Results: Although not statistically significant, more patients in the 1-week titration study experienced an AE. More patients with a 1-week titration had at least one prespecified gastrointestinal (GI) AE. These findings correlated with a higher baseline incidence of GI disturbances. Four patients experienced serious AEs; no deaths occurred. Mean Mini-Mental State Examination scores improved by 1.8 and 1.9 points at weeks 4 and 12, respectively., Conclusions: A 1-week titration of GAL-ER was generally safe and well tolerated, with a potential risk of more GI side effects. A 1-week titration may permit dosing flexibility and promote increased adherence to medication regimens.

Background and Objective: It is important to determine which patients with mild cognitive impairment (MCI) are at risk for progression to dementia. The presence of mild impairments not restricted to the domain of memory may suggest such progression. Our goal is to determine how well a visuospatial problem solving task assessing the cumulative burden of frontal and posterior damage differentiates MCI patients from matched controls., Methods: Twenty-six patients with MCI [Clinical Dementia Rating (CDR) score of 0.5] and mini-mental state examination (MMSE) scores of at least 24/30, were compared with 20 age and education level matched controls without cognitive impairment. All patients were given the MMSE, Hopkins Verbal Learning Test (HVLT), Boston Naming Test (BNT), Rey Complex Figures copying (RCF), anagrams, and visuospatial problem solving battery (VPS). The VPS is a complex problem solving task, which we predicted would better discriminate patient groups than the relatively simpler tasks., Results: Differences existed between groups on most tasks, but logistic regression revealed that the VPS discriminated the 2 groups better than the other nonmemory cognitive tests., Conclusions: The VPS, a problem solving task assessing the cumulative burden of frontal and posterior damage is more sensitive for detecting nonmemory impairments in MCI than other tasks. Future research will be needed to determine if impairment in the VPS is a sensitive predictor of progression to dementia or treatment response.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

With the rapid development of human MRI at field strengths > or = 7 T, knowledge of T(2) (*) relaxation times at such field strengths is needed to optimize acquisition parameters and understand relaxation mechanisms in many applications. However, standard T(2) (*) measurements (e.g., using conventional multiecho gradient-echo (GE) sequences) are affected by macroscopic static magnetic field (B(0)) inhomogeneities, which are particularly severe at high field strength. The multi-GE slice excitation profile imaging (mGESEPI) method was developed for T(2) (*) measurements in the presence of macroscopic B(0) inhomogeneity, but it requires excessive acquisition times at field strengths > or = 7 T. In this paper a more efficient technique, named blipped mGESEPI (bmGESEPI), is proposed. To demonstrate its advantages, T(2) (*) maps were acquired using a conventional multiecho GE method, the mGESEPI method, and the bmGESEPI method in postmortem and in vivo human brains at 8 T., (Copyright 2006 Wiley-Liss, Inc.)

To characterize the severe static (B(0)) and radiofrequency (B(1)) magnetic field inhomogeneity in ultra-high field (> or =7 T) magnetic resonance imaging, gradient echo (GE) and spin echo (SE) images of in vivo and postmortem human brains were acquired. The B(0) and B(1) inhomogeneity were experimentally mapped and/or numerically simulated, and correlated with the image artifacts. Whereas B(0) inhomogeneity affects predominantly GE images near air/tissue interfaces, B(1) inhomogeneity affects SE images more severely and shows non-intuitive patterns. Mapping of the B(0) and B(1) inhomogeneity is important in characterizing image artifacts. This will help develop better B(0) and B(1) inhomogeneity correction methods.

The purpose of this study was to evaluate the capacity of high-resolution magnetic resonance imaging (MRI) to visualize the normal anatomic features of the human hippocampus in vitro, using high field imaging equipment, parameters, and acquisition times appropriate for imaging human subjects in vivo. This research compared high field, high-resolution MRI of formalin-fixed normal human hippocampus specimens to histologic sectioning of the same hippocampus samples. Four specimens were evaluated using an 8 Tesla (T), 80 cm bore whole-body MRI scanner equipped with a 12.7 cm single strut transverse electromagnetic resonator (TEM) coil. Hahn spin echo images were acquired with a repetition time (TR) of 800 msec, echo times (TE) of 20, 50, 90, and 134 msec, and an acquisition time (TA) of 3.25 min. The image quality was superb with demonstration of most of the features of the hippocampus. High field, high-resolution MRI can be used to depict multiple layers of the formalin-fixed human hippocampus in vitro using an 8 T whole-body scanner, a TEM coil, and short acquisition times compatible with human imaging in vivo., (Copyright 2005 Wiley-Liss, Inc.)

Objective: In a prospective, open-label pilot study in probable-Alzheimer disease (AD) outpatients, the authors investigated the efficacy of citalopram to reduce restless activity and aberrant motor behaviors., Methods: Nineteen subjects were evaluated with Neuropsychiatric Inventory subscale and total scores., Results: There was a significant decline in aberrant motor behaviors and overall behavior problems at 4, 8, and 12 weeks., Conclusion: This study provides initial evidence that citalopram may be effective in reducing aberrant motor behaviors in AD. However, because of the potential biases of an open-label study, these findings need to be confirmed in a larger, controlled trial.

A retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long-term effects of combination therapy with donepezil and vitamin E on patients with Alzheimer disease. Subjects were included if they met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease, had taken at least 5 mg donepezil and at least 1000 U vitamin E daily, had at least a 1-year follow-up while continuing these medications, and had a Mini-Mental State Examination score of 10-24. The Mini-Mental State Examination was then recorded annually thereafter. These data were compared with the Consortium to Establish a Registry for Alzheimer's Disease database for patients collected prior to the availability of these treatment options. Patients declined at a significantly lower rate as compared with the Consortium to Establish a Registry for Alzheimer's Disease data. The long-term combination therapy of donepezil and vitamin E appears beneficial for patients with Alzheimer disease. Future prospective studies would be needed to compare combination treatment to vitamin E and donepezil alone.

In a prospective, open-label, 12-week pilot study in outpatients with probable Alzheimer disease (AD) with psychosis or aggressive behaviors, we used the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Neuropsychiatric Inventory (NPI) to evaluate the cognitive and behavioral effects of quetiapine. After receiving doses ranging from 50 to 150 mg, patients given quetiapine showed a significant decrease of delusions, aggression, and overall behaviors based on NPI scores at 6 and 12 weeks. ADAS-cog scores did not show a significant change over 12 weeks. This study provides initial evidence that quetiapine does not significantly worsen cognition in AD outpatients.

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study. Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250 x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of > 6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi 2 = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.

Neurofibrillary tangles and dystrophic neurites are characteristic pathological features found in the brains of Alzheimer's disease (AD) patients. A major constituent of these lesions is the cytoskeletal protein tau. This study examined whether the measurement of tau in cerebral spinal fluid (CSF) has value in the diagnosis of AD. Seventy-seven subjects were enrolled in this prospective study: These included AD (N = 24), Neurological Controls (dementing diseases/syndromes, N = 26), Normal Controls (N = 14), and Others (N = 13). CSF was obtained by lumbar puncture, and tau concentrations (pg/mL) were determined using a dual monoclonal antibody microplate immunoassay. The mean tau value for AD subjects (1,430 +/- 739) was significantly different from Neurological Control subjects (790 +/- 579) (p < 0.001) and Normal Control subjects (816 +/- 355) (p < 0.001). Tau values were elevated in two Neurological Control subjects, one with Binswanger's disease (age 75) and one with depression (age 90). Tau values were also elevated in three Normal Control subjects; two were subjects with a family history of AD. Tau concentrations did not correlate significantly with age in AD subjects (r = 0.05, p = 0.82) or in Normal Control subjects (r = -0.49, p = 0.08). Tau also did not correlate with severity of cognitive impairment in AD subjects (r = -0.03, p = 0.91) or duration of AD symptoms (r = 0.16, p = 0.52). Based on these results and others, CSF levels of tau protein may provide a useful biochemical marker to aid in the clinical diagnosis of AD.

Parkinson's disease is a progressive neurodegenerative condition of unknown cause and with no known cure. The diagnosis is based on clinical findings of rest tremor, muscle rigidity, bradykinesia, and gait instability. Over 40% of patients develop a dementia syndrome that is largely distinct from Alzheimer's disease. Depression is common, also occurring in more than 40% of patients with PD. Careful evaluation in necessary to help distinguish Parkinson's disease from secondary causes of parkinsonism. Carbidopa/levodopa, dopamine agonists, and monoamine oxidase type B inhibitors are the mainstays of treatment. Anticholinergics and other agents may also be useful. Pharmacologic treatment must be carefully titrated to control symptoms and to avoid side effects. In advanced disease, dose-related dyskinesias, end-of-dose wearing-off effect, and unpredictable sudden motor fluctuations become very disabling and difficult to manage.

A patient with left infero-medial occipital-temporal infarct suffered a visual agnosia that, by a minor change of the task, could be manipulated to optic aphasia. Tools in actual use and pantomimes of tool use were better named than stationary tools, a dissociation that suggests differences in the ability of stimuli to evoke associations over multiple modalities. Based on this case and analysis of previous reports we suggest that optic aphasia differs from visual agnosia primarily in the degree of callosal disconnection and that the preserved demonstration of tools use and semantic classification of optic aphasia reflect right hemisphere contribution to visual processing.