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Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.

Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI.A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs).Three SNVs were significantly associated (P5 × 10The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.

Background: Current practice guidelines recommend against Apolipoprotein E (APOE) testing. However, advances in Alzheimer’s disease (AD) research and care may soon change this. Objective: To examine longitudinally the experience of learning an APOE result and, if an ɛ4 carrier, taking a disease-specific treatment to reduce one’s risk of AD. Methods: Fifty ɛ4 carriers and 20 non-carriers completed semi-structured interviews 3 months and 15 months after APOE disclosure. Results: Individuals generally understand their APOE results. While non-carriers felt relief, ɛ4 carriers often described themselves as disappointed by their result but nevertheless glad to know. Carriers expressed concerns about stigma and discrimination, including in the workplace. Carriers adopted new health behaviors at higher rates than non-carriers and revised their future plans to account for their increased risk of AD. Individuals participating in research were hopeful that their participation would help them or others; individuals who learned they were at increased risk for AD but who could not participate in research were disappointed. Conclusion: Providers disclosing APOE results should be sensitive to how APOE results shape emotions, self-perceptions, and attitudes about memory; raise concerns about stigma and discrimination in personal and professional relationships; influence health behaviors and decision-making; and can have follow-on effects on family members.

INTRODUCTION Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration. METHODS We examined the effect of intensive (

To generate robust, demographically-adjusted regression-based norms for the Montreal Cognitive Assessment (MoCA) using a large sample of diverse older US adults. Baseline MoCA scores were examined for participants in the Systolic Blood Pressure Intervention Trial (SPRINT). A robust, cognitively-normal sample was drawn from individuals not subsequently adjudicated with cognitive impairment through 4 years of follow-up. Multivariable Beta-Binomial regression was used to model the association of demographic variables with MoCA performance and to create demographically-stratified normative tables. Participants' (N = 5,338) mean age was 66.9 ± 8.8 years, with 35.7% female, 63.1% White, 27.4% Black, 9.5% Hispanic, and 44.5% with a college or graduate education. A large proportion scored below published MoCA cutoffs: 61.4% scored below 26 and 29.2% scored below 23. A disproportionate number falling below these cutoffs were Black, Hispanic, did not graduate from college, or were ≥75 years of age. Multivariable modeling identified education, race/ethnicity, age, and sex as significant predictors of MoCA scores (p

BACKGROUND Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost. e-Cube is a new vision-based, computerized cognitive assessment tool that integrates computational measures of play complexity and item generators to enable automated and adaptive testing. The e-Cube games use a set of cubes, and the system tracks the movements and locations of these cubes as manipulated by the player. OBJECTIVE The primary objectives of the study were to validate the play complexity measures that form the basis of developing the adaptive assessment system and evaluate the preliminary utility and usability of the e-Cube system as an automated cognitive assessment tool. METHODS This study used 6 e-Cube games, namely, Assembly, Shape-Matching, Sequence-Memory, Spatial-Memory, Path-Tracking, and Maze, each targeting different cognitive domains. In total, 2 versions of the games, the fixed version with predetermined sets of items and the adaptive version using the autonomous item generators, were prepared for comparative evaluation. Enrolled participants (N=80; aged 18-60 years) were divided into 2 groups: 48% (38/80) of the participants in the fixed group and 52% (42/80) in the adaptive group. Each was administered the 6 e-Cube games; 3 subtests of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Block Design, Digit Span, and Matrix Reasoning); and the System Usability Scale (SUS). Statistical analyses at the 95% significance level were applied. RESULTS The play complexity values were correlated with the performance indicators (ie, correctness and completion time). The adaptive e-Cube games were correlated with the WAIS-IV subtests (r=0.49, 95% CI 0.21-0.70; Pr=0.34, 95% CI 0.03-0.59; P=.03 for Shape-Matching and Matrix Reasoning; r=0.51, 95% CI 0.24-0.72; Pr=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Block Design; and r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Matrix Reasoning). The fixed version showed weaker correlations with the WAIS-IV subtests. The e-Cube system showed a low false detection rate (6/5990, 0.1%) and was determined to be usable, with an average SUS score of 86.01 (SD 8.75). CONCLUSIONS The correlations between the play complexity values and performance indicators supported the validity of the play complexity measures. Correlations between the adaptive e-Cube games and the WAIS-IV subtests demonstrated the potential utility of the e-Cube games for cognitive assessment, but a further validation study is needed to confirm this. The low false detection rate and high SUS scores indicated that e-Cube is technically reliable and usable.

Background Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost. e-Cube is a new vision-based, computerized cognitive assessment tool that integrates computational measures of play complexity and item generators to enable automated and adaptive testing. The e-Cube games use a set of cubes, and the system tracks the movements and locations of these cubes as manipulated by the player. Objective The primary objectives of the study were to validate the play complexity measures that form the basis of developing the adaptive assessment system and evaluate the preliminary utility and usability of the e-Cube system as an automated cognitive assessment tool. Methods This study used 6 e-Cube games, namely, Assembly, Shape-Matching, Sequence-Memory, Spatial-Memory, Path-Tracking, and Maze, each targeting different cognitive domains. In total, 2 versions of the games, the fixed version with predetermined sets of items and the adaptive version using the autonomous item generators, were prepared for comparative evaluation. Enrolled participants (N=80; aged 18-60 years) were divided into 2 groups: 48% (38/80) of the participants in the fixed group and 52% (42/80) in the adaptive group. Each was administered the 6 e-Cube games; 3 subtests of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Block Design, Digit Span, and Matrix Reasoning); and the System Usability Scale (SUS). Statistical analyses at the 95% significance level were applied. Results The play complexity values were correlated with the performance indicators (ie, correctness and completion time). The adaptive e-Cube games were correlated with the WAIS-IV subtests (r=0.49, 95% CI 0.21-0.70; P Conclusions The correlations between the play complexity values and performance indicators supported the validity of the play complexity measures. Correlations between the adaptive e-Cube games and the WAIS-IV subtests demonstrated the potential utility of the e-Cube games for cognitive assessment, but a further validation study is needed to confirm this. The low false detection rate and high SUS scores indicated that e-Cube is technically reliable and usable.

In the SPRINT (Systolic Blood Pressure Intervention Trial), the number of strokes did not differ significantly by treatment group. However, stroke subtypes have heterogeneous causes that could respond differently to intensive blood pressure control. SPRINT participants (N=9361) were randomized to target systolic blood pressures of P =0.09). The interaction between baseline cardiovascular risk factor status and treatment arm on stroke risk did not reach significance ( P =0.05). Similar numbers of stroke subtypes occurred in the intensive BP control and standard control arms of SPRINT.

After years of anticipation, non-invasive tests for detecting cerebral amyloidosis and Alzheimer’s disease (AD) are entering clinical care. The PrecivityADtrademark test from C2N is a plasma-based test yielding an Amyloid Probability score with high sensitivity and specificity for brain amyloid accumulation, but some samples may have inconclusive results. The AGREEDementia consortium raised concerns that the field needs study of how best to use and communicate results of PrecivityADtrademark. Continued attention and mindfulness should be applied to the whole class of dementia biomarker tests and directed in light of FDA biomarker context of use framework. Unintended uses of biomarkers tests may have unintended consequences, such as mislabeling patients. AD biomarker tests may efficiently stratify AD risk but will inevitably be included in electronic medical records and be subject to interpretation by medical personnel lacking proper knowledge or context to interpret results appropriately. Another way forward is mindful discussion and consensus among all stakeholders about the uses and limits of each specific test.

Summary Background Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. Methods SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov , NCT01206062 . Findings From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7–5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of −0·005 (95% CI −0·010 to 0·001) in the intensive treatment group and −0·001 (–0·006 to 0·005) in the standard treatment group (between-group difference −0·004, 95% CI −0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference −0·010, 95% CI −0·017 to −0·002; p=0·02), with an annual decline of −0·025 (–0·030 to −0·019) for the intensive treatment group and −0·015 (–0·021 to 0·009) for the standard treatment group. Interpretation Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. Funding National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

Background: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods: This pilot study enrolled 5 subjects with mild cognitive impairment due to AD. Participants were randomized to placebo (n=1) or two daily efavirenz doses (50 mg and 200 mg, n=2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.Results: In all subjects receiving efavirenz, there was a statistically significant increase (P £ 0.001) in the levels of plasma 24HC. The levels of 24HC in the CSF of subjects on the 200 mg-dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions: Our findings provide evidence of efavirenz target engagement in human subjects with AD. This supports pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug effects on AD biomarkers and clinical symptomatology.Trial registration: ClinicalTrials.gov NCT03706885.

Background. Psoriasis and cutaneous T-cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown. Objective. This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health-related quality of life (HR-QOL) status. Methods. A cross-sectional study was performed in an outpatient dermatology clinic of a university teaching hospital. Thirty-nine subjects with CTCL ( N = 20 ) or psoriasis ( N = 19 ) who met eligibility criteria were included. The cognitive domains of memory, attention and processing speed, and executive function were assessed with standard neuropsychological tests. Subjects were assessed for depression, anxiety, and HR-QOL (using the SKINDEX-29 questionnaire). Results. Study participants were CTCL and psoriasis subjects; cognitive impairment was found in the domain of memory in 17.9% subjects with CTCL or psoriasis. Lower scores on executive function tests were predicted by higher (worse HR-QOL) SKINDEX-29 functioning scores ( p = 0.01 ). A higher estimated baseline intellectual functioning predicted lower scores (better HR-QOL) on the symptoms and functioning domains of SKINDEX-29 ( p = 0.01 and 0.02, respectively) and a statistical trend ( p = 0.07 ) for the emotion domain. Memory and acute anxiety were adversely impacted by shorter disease duration ( p = 0.01 for both). Conclusions. Memory impairment may be associated comorbidity in CTCL and psoriasis. Subjects with stronger cognitive resources appear to cope better with health-related quality of life (HR-QOL) challenges.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Though APOE remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance of APOE and differing genetic architecture of the Amish compared to a general European ancestry population.

BACKGROUND: To examine the effect of intensive blood pressure control on the occurrence of subtypes of mild cognitive impairment (MCI) and determine the risk of progression to dementia or death. METHODS: Secondary analysis of a randomized trial of community-dwelling adults (≥50 years) with hypertension. Participants were randomized to a systolic blood pressure (SBP) goal of

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

BackgroundWhile studying cognition in the Old Order Amish (OOA), we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuospatial memory in this population. Here, we investigate this by comparing the CPDR to the word list delayed recall (WLDR) within the OOA, as well as by comparing these results to a non-Amish cohort.Method420 OOA individuals in Indiana/Ohio age 66-95 who had complete data for the CPDR and WLDR were included. From the non-Amish CERAD cohort, 401 individuals age 60-96 with the same tests were included. For both cohorts, education-adjusted Z-scores were calculated for the CPDR and WLDR. The difference between the CPDR Z-score and the WLDR Z-score was calculated as a measure of the preservation of visuospatial memory over verbal memory. T-tests were first used to compare the tests within both cohorts and then stratified by case/control status. Linear regression was then used to investigate the effects of age, sex, cognitive status, and cohort on the Z-scores and difference between Z-scores. Additional t-tests and regressions were then performed to further investigate the effect of sex and its interaction with cohort.ResultWe found a significantly better performance on CPDR over WLDR in every cognitive status group in the OOA, but not in all groups of the CERAD cohort. After controlling for age, sex, and cognitive status, this preferential preservation remains significantly higher in the Amish, with being in the Amish cohort increasing the difference between Z-scores by an average of 0.615 units when compared to being in the CERAD cohort. When adjusting for age, sex, cognitive status, and cohort, the interaction between cohort and sex is significant, with the Amish males exhibiting a greater difference between Z-scores compared to other groups, with a significant interaction value of 0.676.DiscussionOverall, these findings suggest that the OOA preferentially preserve visuospatial memory over verbal memory, regardless of cognitive status. This effect is particularly strong in OOA males. In summary, this study gives additional evidence that the Amish exhibit unique patterns of memory loss and aging, with a preferential preservation of visuospatial memory over verbal memory. Additional studies are needed to further explain this phenomenon.

BackgroundStudies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively unimpaired (CU; unaffected after age 75) individuals. We hypothesize that these CU individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genetic risk. As well, the genetic and cultural isolation in the Amish since the early 1800s may have reduced the complexity of the genetic architecture of CI, increasing the power to detect protective alleles in this population. With this in mind we conducted a genome-wide study (GWAS) to identify loci associated with AAO of CI in a sample of Amish adults over age 75.Methods1,522 individuals aged 43-99 (mean age 73.1, 42% men) screened at least once for CI using the Modified Mini-Mental State exam (3MS) were genotyped using Illumina chipsets. Genotypes were imputed for 7,815,951 single nucleotide variants (SNV) with minor allele frequency (MAF) > 1%. The outcome studied was age, defined as 1) age at the first 3MS result indicating impairment (AAO; 3MS =87, 1,160 CU individuals). Cox mixed-effects models examined association between age and each SNV, adjusting for sex and familial relationships. To replicate genome-wide significant findings, SNVs in a 1 Megabase region centered on the peak SNV were examined for association with age using these same methods in the NIA-LOAD family study dataset (1,785 AD cases, 1,565 unaffected controls, mean age 73.5.ResultsThree SNV were significantly associated (pConclusionsThe replicated genome-wide significant association with AAO on chromosome 17 suggest this may be novel locus associated with delayed onset of AD. The associated SNP is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for AD.

Definitive diagnosis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSynD) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSynD aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSynD across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSynD in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSynD aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSynD in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSynD in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSynD in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSynD as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.

Hypertension and dementia are both common disorders whose prevalence increases with age. There are multiple mechanisms by which hypertension affects the brain and alters cognition. These include blood flow dynamics, development of large and small vessel pathology and diverse molecular mechanisms including formation of reactive oxygen species and transcriptional cascades. Blood pressure interacts with Alzheimer disease pathology in numerous and unpredictable ways, affecting both β-amyloid and tau deposition, while also interacting with AD genetic risk factors and other metabolic processes. Treatment of hypertension may prevent cognitive decline and dementia, but methodological issues have limited the ability of randomized clinical trials to show this conclusively. Recent studies have raised hope that hypertension treatment may protect the function and structure of the aging brain from advancing to mild cognitive impairment and dementia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00747-y) contains supplementary material, which is available to authorized users.

Objective To examine the association of global cognitive function assessed via the Montreal Cognitive Assessment (MoCA) and deficiencies in instrumental activities of daily living (IADL) on the Functional Activity Questionnaire (FAQ) in hypertensive older adults in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods In cross-sectional analysis, 9,296 SPRINT participants completed the MoCA at baseline. The FAQ was obtained from 2,705 informants for SPRINT participants scoring Results Participants who triggered FAQ administration were older, less educated, and more likely to be Black or Hispanic (p < 0.001). Sixty-one percent (n = 1,661) of participants’ informants reported no functional difficulties in IADLs. An informant report, however, of any difficulty on the FAQ was associated with lower MoCA scores after controlling for age, sex, race/ethnicity, and education (p < 0.05). Partial proportional odds regression indicates that participants scoring lower on the MoCA (in the 10th to Conclusions While lower global cognitive function was strongly associated with IADL deficits on FAQ, informants indicated no functional difficulties for the majority of SPRINT participants, despite low MoCA scores. These findings can help with designing future studies which aim to detect mild cognitive impairment and/or dementia in large, community-dwelling populations.

Introduction Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. Methods The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

PURPOSE: Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. METHODS: Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. RESULTS: Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN’s left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. CONCLUSION: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. TRIAL REGISTRATION: NCT01206062

Category fluency test (CFT) performance is sensitive to cognitive processes of executive control and memory storage and access, and widely used to measure cognitive performance especially in early Alzheimer’s Disease. Analytical variables have included the number of items named, and various methods to identify and quantify clusters of semantically related words and cluster switches. Also encoded in the response sequence are temporal patterns as shown by “bursts” of responses and pauses between items, that have not been received attention in determining cluster characteristics.We studied a group of 51 adult Russian-English bilinguals and compared CFT responses based on two clustering methodologies: the semantic-based method (SEM) and a novel method based on the time interval between words (TEMP) with 8 different intercall time thresholds from 0.25 sec-15 sec. Each participant performed the task in both languages. Total number of words and cluster count was greater in Russian than English for both scoring methods, but cluster size did not differ between languages. We also studied stochastic modeling characteristics based on detrending of the “exponential exhaustion” effect seen with CFT, with most notable that total recall capacity (N∞) was greater in Russian than English (P

Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment. Objective: The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for cognitive impairment. Methods: Data of 2,426 individuals from the OOA aged 54–99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified into three education categories: 8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Results: Our results showed that individuals who attained lowest levels of education (8 years (OR = 2.96 and 1.85). Conclusion: Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds.