Exploring Social Cognition Tests to Differentiate Frontotemporal Dementia from Depression: A Two-Step Pilot Study.

Behavioral-variant frontotemporal dementia (bvFTD) is challenging to recognize, and often misdiagnosed as depression (DEP). Evidence suggests changes in social cognition (SoCog) precede general cognitive decline in bvFTD. Currently, there are no screening measures of social cognition. 17 bvFTD, 16 DEP, and 18 control participants underwent 6 SoCog tests measuring: emotion recognition; theory of mind; empathy; insight. We used χ 2 , Wilcoxon rank sum, Kruskal-Wallis tests to compare groups, with decision tree analysis to identify items that best differentiated bvFTD from DEP. bvFTD performed significantly worse on all SoCog tasks compared with other groups. Decision tree analysis yielded a 5-item test with ROC area under the curve of 0.973 (95% CI: 0.928, 1.0) for differentiating bvFTD versus depression. These results suggest that it may be feasible to develop a screening measure of social cognition.

Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

Current directions in tau research: Highlights from Tau 2020.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

INTRODUCTION: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. METHODS: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. RESULTS: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. DISCUSSION: Age- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.

Applying the Alzheimer Disease ATN Diagnostic Framework in Atypical Dementia.

Cerebrospinal fluid (CSF) biomarkers amyloid-ß and tau have been validated for the antemortem diagnosis of Alzheimer disease (AD) and are included in the AT(N) research framework for AD. Recently, an AT(N) CSF profile has been described for dementia with Lewy bodies (DLB), a disorder which is difficult to distinguish clinically from AD, particularly early in the disease course. Herein we describe a 71-year old male who presented with an atypical dementia syndrome including years of stability after an initial abrupt decline, marked visuospatial dysfunction, and relative sparing of memory. CSF biomarkers combined with the pattern of cognitive symptoms made AD unlikely and were consistent with DLB. This classification was confirmed clinically, with the emergence of classic DLB symptoms, and at postmortem pathologic examination. This case highlights the role for AD CSF biomarkers in facilitating earlier diagnosis of non-Alzheimer neurodegenerative dementias.

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. METHODS: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. RESULTS: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. DISCUSSION: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Therapeutic trial design for frontotemporal dementia and related disorders.

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BACKGROUND: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams. METHODS: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here. RESULTS: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020. CONCLUSION: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.

Évaluation complète d'une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L'évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés ¼ qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d'étape semi-annuel du CCNV soumis aux Instituts de recherche en santé du Canada (IRSC) en décembre 2017 ; ainsi que d'autres documents produits à la suite de modifications consécutives à la mise en œuvre de ce projet. Résultats: L'étude de cohorte COMPASS-ND du CCNV inclut des participants de partout au Canada dont les divers états cognitifs sont associés à des maladies neurodégénératives ou au risque d'en souffrir. Ils feront l'objet d'un large éventail d'examens expérimentaux, cliniques, génétiques et d'imagerie afin d'aborder de manière spécifique les causes, le diagnostic, le traitement et la prévention de ces états cognitifs chez les personnes âgées. Les données obtenues à la suite d'évaluations cliniques et cognitives, ainsi que celles issues d'échantillons biologiques, d'imagerie cérébrale, de tests génétiques et de dons de cerveaux, seront utilisées pour tester les hypothèses générées par les équipes de recherche du CCNV et d'autres chercheurs canadiens. Cette étude constitue donc à ce jour l'étude canadienne la plus complète et la plus ambitieuse au sujet de la démence. La présentation des données initiales ayant eu lieu en 2018, la cohorte devrait atteindre sa taille maximale d'ici à 2020.Conclusion : La disponibilité des données de l'étude COMPASS-ND stimulera considérablement la recherche sur la démence au Canada au cours des prochaines années.

A randomized clinical trial to evaluate home-based assessment of people over 75 years old.

INTRODUCTION: There is an unmet need for effective methods for conducting dementia prevention trials. METHODS: Home-based assessment study compared feasibility and efficiency, ability to capture change over time using in-home instruments, and ability to predict cognitive conversion using predefined triggers in a randomized clinical trial in (1) mail-in questionnaire/live telephone interviews, (2) automated telephone/interactive voice recognition, and (3) internet-based computer Kiosk technologies. Primary endpoint was defined as cognitive conversion. RESULTS: Analysis followed a modified intent-to-treat principle. Dropout rates were low and similar across technologies but participants in Kiosk were more likely to dropout earlier. Staff resources needed were higher in Kiosk. In-home instruments distinguished conversion and stable groups. Cognitively stable group showed improvement in cognitive measures. Triggering was associated with higher likelihood of conversion but statistically significant only in mail-in questionnaire/live telephone interviews. DISCUSSION: Relatively low efficiency of internet-based assessment compared with testing by live-assessors has implications for internet-based recruitment and assessment efforts currently proposed for diverse populations.

Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition.

There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.

16-Year Survival of the Canadian Collaborative Cohort of Related Dementias.

Background Survival estimates are integral to care for patients diagnosed with dementia. Few Canadian studies have carried out long-term follow-up of well-described cohorts, analyzing survival related to multiple risk factors. Methods Survival analysis of an inception cohort enrolled at a British Columbia (BC) tertiary dementia referral clinic between 1997 and 1999 was undertaken. Vital status was completed for 168 patients diagnosed with dementia. An evaluation of the effects of demographics, vascular risk factors, cognitive and functional ratings, apolipoprotein 4-status, and cholinesterase use on survival was performed using a log-rank test and time-dependent Cox regression. Survival of this dementia cohort was compared with the age-matched life expectancy of persons in BC. Results In all, 158/168 (94.0%) subjects died over 16.6 years, with a median survival of 7.08 years. Risk factors associated with shorter survival in dementia groups included age of onset ≥80 (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.05-2.32); greater functional disability (Disability Assessment for Dementia<55% [HR 1.47, 95% CI 1.04-2.08]); and cumulative medical illness severity (Cumulative Illness Rating Scale≥7 [HR 1.51, 95% CI 1.08-2.12)]. Compared with the BC population, years of potential life lost for dementia subjects aged <65 was 15.36 years, and for dementia subjects aged ≥80 it was 1.82 years. Conclusions Survival in dementia subjects is shorter than population life expectancies for each age strata, with greatest impact on younger patients. For people diagnosed with dementia, age ≥80 years, cumulative medical illness severity, and functional disabilities are the most significant survival predictors and can be used to guide prognosis.

Participant satisfaction with dementia prevention research: Results from Home-Based Assessment trial.

INTRODUCTION: Little is known about factors affecting motivation and satisfaction of participants in dementia prevention trials. METHODS: A Research Satisfaction Survey was administered to 422 nondemented older adults who participated in the Home-Based Assessment trial. RESULTS: Overall satisfaction was high, with means of all individual items near to above a value of 3 on a scale from 1 (worst) to 4 (best). Greater satisfaction was associated with staff-administered interviews versus automated technologies. The most liked aspects of research participation were volunteerism, opportunity to challenge and improve mental function, and positive interactions with staff. The least liked aspect was repetitiveness of the assessments. Participants requested more contact with staff and other older adults and more feedback on performance. DISCUSSION: Older adults' participation in research was primarily motivated by altruism. Methodologies that facilitate human contact, encourage feedback and novelty of tasks should be incorporated into future trial design.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

BACKGROUND: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. METHODS: We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). FINDINGS: Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. INTERPRETATION: The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. FUNDING: TauRx Therapeutics.

Effect of diesel exhaust inhalation on blood markers of inflammation and neurotoxicity: a controlled, blinded crossover study.

CONTEXT: Epidemiological studies and animal research have suggested that air pollution may negatively impact the central nervous system (CNS). Controlled human exposure studies of the effect of air pollution on the brain have potential to enhance our understanding of this relationship and to inform potential biological mechanisms. OBJECTIVES: Biomarkers of systemic and CNS inflammation may address whether air pollution exposure induces inflammation, with potential for CNS negative effects. MATERIALS AND METHODS: Twenty-seven healthy adults were exposed to two conditions: filtered air (FA) and diesel exhaust (DE) (300 µg PM2.5/m(3)) for 120 min, in a double-blinded crossover study with exposures separated by four weeks. Prior to and at 0, 3, and 24 h following each exposure, serum and plasma were collected and analyzed for inflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α), the astrocytic protein S100b, the neuronal cytoplasmic enzyme neuron-specific enolase (NSE), and serum brain-derived neurotrophic factor (BDNF). We hypothesized that IL-6, TNF-α, S100b and NSE would increase, and BDNF would decrease, following DE exposure. RESULTS: At no time-point following exposure to DE was a significant increase in concentration from baseline seen for IL-6, TNF-α, S100b, or NSE relative to FA exposure. Similarly, no significant decrease in BDNF concentration from baseline was seen following DE exposure, relative to FA. Furthermore, the repeated measures ANOVA considered for all time-points and biomarkers revealed no significant time-exposure interaction. DISCUSSION AND CONCLUSION: These results suggest that short-term exposure to DE amongst healthy adults does not acutely affect the systemic or CNS biomarkers that we measured.

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Early neuropsychological characteristics of progranulin mutation carriers.

Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature.

Developing the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia program.

INTRODUCTION: With Alzheimer's disease and related dementias (ADRD) representing an enormous public health challenge, there is a need to support individuals in learning about and addressing their modifiable risk factors (e.g., diet, sleep, and physical activity) to prevent or delay dementia onset. However, there is limited availability for evidence-informed tools that deliver both quality education and support for positive behavior change such as by increasing self-efficacy and personalizing goal setting. Tools that address the needs of Latino/a, at higher risk for ADRD, are even more scarce. METHODS: We established a multidisciplinary team to develop the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia (HALT-AD) program, a bilingual online personalized platform to educate and motivate participants to modify their risk factors for dementia. Grounded in social cognitive theory and following a cultural adaptation framework with guidance from a community advisory board, we developed HALT-AD iteratively through several cycles of rapid prototype development, user-centered evaluation through pilot testing and community feedback, and refinement. RESULTS: Using this iterative approach allowed for more than 100 improvements in the content, features, and design of HALT-AD to improve the program's usability and alignment with the interests and educational/behavior change support needs of its target audience. Illustrative examples of how pilot data and community feedback informed improvements are provided. DISCUSSION: Developing HALT-AD iteratively required learning through trial and error and flexibility in workflows, contrary to traditional program development methods that rely on rigid, pre-set requirements. In addition to efficacy trials, studies are needed to identify mechanisms for effective behavior change, which might be culturally specific. Flexible and personalized educational offerings are likely to be important in modifying risk trajectories in ADRD.