Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Feasibility of Telehealth Occupational Therapy for Behavioral Symptoms of Adults With Dementia: Randomized Controlled Trial.

IMPORTANCE: Supporting community residency of adults with Alzheimer's disease (AD) is a critical public health initiative. Occupational therapy can contribute to this goal. OBJECTIVE: To assess the feasibility of a novel telehealth intervention to support occupational engagement in community-residing people with AD. DESIGN: Single-blind, three-arm, parallel, randomized controlled trial. SETTING: Occupational therapy delivered through telehealth in participants' homes. PARTICIPANTS: People with AD who reside in the community with behavioral symptoms and their care partners (dyads). INTERVENTIONS: (1) HARMONY (Helping older Adults cReate & Manage OccupatioNs successfully), a telehealth intervention that applies principles of individualized guided discovery with environmental cueing for caregivers of persons with AD to promote activity participation and manage behavioral symptoms; (2) standardized training regarding the use of a sensory-based approach in dementia care; and (3) a control, including home safety education and weekly monitoring of behaviors. OUTCOMES AND MEASURES: Feasibility was assessed as the primary outcome measured by completion of at least 75% of the telehealth sessions. Secondary outcomes included change in functional activity performance and neuropsychiatric behavioral symptoms. RESULTS: Twenty-eight dyads participated. The intervention was feasible, with high adherence to weekly visits (M number of visits = 5.4 for HARMONY, 4.9 for standardized training, and 4.6 for control), with high participant retention in the intervention arms. HARMONY demonstrated promise in improving patient performance and behavioral symptoms. CONCLUSIONS AND RELEVANCE: HARMONY is feasibly delivered through telehealth service and has a positive effect on occupational performance and behavioral symptoms of AD. Additional studies are needed to explore effectiveness in a broader population. What This Article Adds: Use of HARMONY for community-residing adults with AD is feasible and has promise for improving functional activity performance and behavioral symptoms, as well as caregiver satisfaction.

Neurodegenerative pathologies associated with behavioral and psychological symptoms of dementia in a community-based autopsy cohort.

In addition to the memory disorders and global cognitive impairment that accompany neurodegenerative diseases, behavioral and psychological symptoms of dementia (BPSD) commonly impair quality of life and complicate clinical management. To investigate clinical-pathological correlations of BPSD, we analyzed data from autopsied participants from the community-based University of Kentucky Alzheimer's Disease Research Center longitudinal cohort (n = 368 research volunteers met inclusion criteria, average age at death 85.4 years). Data assessing BPSD were obtained approximately annually, including parameters for agitation, anxiety, apathy, appetite problems, delusions, depression, disinhibition, hallucinations, motor disturbance, and irritability. Each BPSD was scored on a severity scale (0-3) via the Neuropsychiatric Inventory Questionnaire (NPI-Q). Further, Clinical Dementia Rating (CDR)-Global and -Language evaluations (also scored on 0-3 scales) were used to indicate the degree of global cognitive and language impairment. The NPI-Q and CDR ratings were correlated with neuropathology findings at autopsy: Alzheimer's disease neuropathological changes (ADNC), neocortical and amygdala-only Lewy bodies (LBs), limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), primary age-related tauopathy (PART), hippocampal sclerosis, and cerebrovascular pathologies. Combinations of pathologies included the quadruple misfolding proteinopathy (QMP) phenotype with co-occurring ADNC, neocortical LBs, and LATE-NC. Statistical models were used to estimate the associations between BPSD subtypes and pathologic patterns. Individuals with severe ADNC (particularly those with Braak NFT stage VI) had more BPSD, and the QMP phenotype was associated with the highest mean number of BPSD symptoms: > 8 different BPSD subtypes per individual. Disinhibition and language problems were common in persons with severe ADNC but were not specific to any pathology. "Pure" LATE-NC was associated with global cognitive impairment, apathy, and motor disturbance, but again, these were not specific associations. In summary, Braak NFT stage VI ADNC was strongly associated with BPSD, but no tested BPSD subtype was a robust indicator of any particular "pure" or mixed pathological combination.

Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes.

BACKGROUND: Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood. OBJECTIVE: Query data from a community-based autopsy series to assess pathologies that underlie UI. METHODS: Included research subjects came to autopsy from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology. RESULTS: Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p < 0.001). More women than men had a history of UI (p < 0.04), and women with UI had had more biological children than those without UI (p < 0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p < 0.001). The presence of LATE-NC (Stage > 1) was associated with UI with or without severe Alzheimer's disease neuropathologic changes and/or Lewy body pathology. CONCLUSION: In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC.

Examining the Effects of Formal Education Level on the Montreal Cognitive Assessment.

BACKGROUND: Brief, global assessments such as the Montreal Cognitive Assessment (MoCA) are widely used in primary care for assessing cognition in older adults. Like other neuropsychological instruments, lower formal education can influence MoCA interpretation. METHODS: Data from 2 large studies of cognitive aging were used-Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC). Both use comprehensive examinations to determine cognitive status and have brain amyloid status for many participants. Mixed models were used to account for random variation due to data source. RESULTS: Cognitively intact participants with lower education (≤12 years) were more likely than those with higher education (>12 years) to be classified as potentially impaired using the MoCA cutoff of <26 (P < .01). Backwards selection revealed 4 MoCA items significantly associated with education (cube copy, serial subtraction, phonemic fluency, abstraction). Subtracting these items scores yielded an alternative MoCA score with a maximum of 24 and a cutoff of ≤19 for classifying participants with mild cognitive impairment. Using the alternative MoCA score and cutoff, among cognitively intact participants, both education groups were similarly likely to be classified as potentially impaired (P > .67). CONCLUSIONS: The alternative MoCA score neutralized the effects of formal education. Although further research is needed, this alternative score offers a simple procedure for interpreting MoCAs administered to older adults with ≤12 years education. These educational effects also highlight that the MoCA is part of the assessment process-not a singular diagnostic test-and a comprehensive workup is necessary to accurately diagnose cognitive impairments.

Examining the Effects of Formal Education Level on the Montreal Cognitive Assessment.

BACKGROUND: Brief, global assessments such as the Montreal Cognitive Assessment (MoCA) are widely used in primary care for assessing cognition in older adults. Like other neuropsychological instruments, lower formal education can influence MoCA interpretation. METHODS: Data from 2 large studies of cognitive aging were used-Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC). Both use comprehensive examinations to determine cognitive status and have brain amyloid status for many participants. Mixed models were used to account for random variation due to data source. RESULTS: Cognitively intact participants with lower education (≤12 years) were more likely than those with higher education (>12 years) to be classified as potentially impaired using the MoCA cutoff of <26 (P < .01). Backwards selection revealed 4 MoCA items significantly associated with education (cube copy, serial subtraction, phonemic fluency, abstraction). Subtracting these items scores yielded an alternative MoCA score with a maximum of 24 and a cutoff of ≤19 for classifying participants with mild cognitive impairment. Using the alternative MoCA score and cutoff, among cognitively intact participants, both education groups were similarly likely to be classified as potentially impaired (P > .67). CONCLUSIONS: The alternative MoCA score neutralized the effects of formal education. Although further research is needed, this alternative score offers a simple procedure for interpreting MoCAs administered to older adults with ≤12 years education. These educational effects also highlight that the MoCA is part of the assessment process-not a singular diagnostic test-and a comprehensive workup is necessary to accurately diagnose cognitive impairments.

Amyloid-PET Levels in the Precuneus and Posterior Cingulate Cortices Are Associated with Executive Function Scores in Preclinical Alzheimer's Disease Prior to Overt Global Amyloid Positivity.

BACKGROUND: Global amyloid-ß (Aß) deposition in the brain can be quantified by Aß-PET scans to support or refute a diagnosis of preclinical Alzheimer's disease (pAD). Yet, Aß-PET scans enable quantitative evaluation of regional Aß elevations in pAD, potentially allowing even earlier detection of pAD, long before global positivity is achieved. It remains unclear as to whether such regional changes are clinically meaningful. OBJECTIVE: Test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in pAD. METHODS: Global and regional standardized uptake value ratios (SUVr) from 18F-florbetapir PET/CT scanning were determined using the Siemens Syngo.via® Neurology software package across a sample of 99 clinically normal participants with Montreal Cognitive Assessment (MoCA) scores≥23. Relationships between regional SUVr and cognitive test scores were analyzed using linear regression models adjusted for age, sex, and education. Participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in cognitive test scores were analyzed using ANCOVA models. RESULTS: Executive function performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p < 0.05). There were no significant associations between memory and Aß-PET SUVr in any regions of the brain. CONCLUSION: These data demonstrate that increased Aß deposition in the precuneus and posterior cingulate (the earliest brain regions affected with Aß pathology) is associated with changes in executive function that may precede memory decline in pAD.

Frontotemporal neurofibrillary tangles and cerebrovascular lesions are associated with autism spectrum behaviors in late-life dementia.

BACKGROUND AND OBJECTIVES: The pathologic substrates or neuroanatomic regions responsible for similarities in behavioral features seen in autism spectrum disorder and late-life dementia remain unknown. The present study examined the neuropathologic features of late-life dementia in research volunteers with and without antemortem behaviors characteristic of autism spectrum disorders. METHODS: Antemortem cross-sectional assessment of autistic spectrum behaviors proximal to death in persons with diagnosis of mild cognitive impairment or dementia was completed using the Gilliam Autism Rating Scale, 2nd edition (GARS-2), followed by postmortem quantitative and semiquantitative neuropathologic assessment. All individuals who completed the GARS-2 prior to autopsy were included (n = 56) and we note that no participants had known diagnosis of autism spectrum disorder. The GARS-2 was used as an antemortem screening tool to stratify participants into two groups: "Autism Possible/Very Likely" or "Autism Unlikely." Data were analyzed using nonparametric statistics comparing location and scale to evaluate between-group differences in pathologic features. RESULTS: Neurofibrillary tangles (NFT; p = 0.028) density and tau burden (p = 0.032) in the frontal region, the NFT density (p = 0.048) and neuritic plaque burden (p = 0.042), and the tau burden (p = 0.032) of the temporal region, were significantly different in scale between groups. For measures with significant group differences, the medians of the Autism Possible/Very Likely group were roughly equal to the 75th percentile of the Autism Unlikely group (i.e., the distributions were shifted to the right). DISCUSSION: This study links behaviors characteristic of autism to increased pathologic tau burden in the frontal and temporal lobes in persons with late-life dementia. Additional studies are needed to determine causal factors and treatment options for behaviors characteristic of autism behaviors in late-life dementias.

Sensory Processing Abnormalities in Community-Dwelling Older Adults with Cognitive Impairment: A Mixed Methods Study.

Mild cognitive impairment (MCI) or dementia often leads to behavioral and psychiatric symptoms of dementia (BPSD). Sensory processing abnormalities may be associated with BPSD. The purpose of this study was to explore relationships among sensory processing, behavior, and environmental features within the homes of people with MCI or dementia. This project used mixed methods to assess participants' sensory processing, care partner perspectives on behaviors, and in situ observations of the home environment. Nine participants with cognitive impairment (MCI n = 8, early dementia = 1) and their care partners were included. Seven participants with cognitive impairment were reported to have abnormal sensory processing. Findings suggest that unique environmental adaptations, tailored to personal and sensory preferences for each participant, were associated with a decreased level of behavioral disruption during the observation periods. Implementing sensory-based approaches to maximize environment adaptation may be beneficial in reducing disruptive behaviors for adults with cognitive impairment.

Comparison of behaviors characteristic of autism spectrum disorder behaviors and behavioral and psychiatric symptoms of dementia.

BACKGROUND: Similarities exist in behavioral expression of autism spectrum disorder (ASD) and Alzheimer's disease and related dementias (ADRD). The purpose of this study was to assess presence of behavioral and psychiatric symptoms of dementia (BPSD) and ASD-like behaviors in adults with ADRD. METHODS: Using a cross-sectional design, data from University of Kentucky Alzheimer's Disease Center participant cohort were used. Hierarchical linear regression was used to assess (1) the relationship between ASD-like behaviors (measured by the Gilliam Autism Rating Scale-Second Edition, GARS-2) and BPSD measured by the Neuropsychiatric Inventory (NPI), and (2) the relationship between ASD-like behaviors and dementia severity (measured by the Clinical Dementia Rating [CDR] sum of boxes), when controlling for BPSD. RESULTS: Complete data were available for 142 participants. Using α of 0.05, analyses identified ASD behaviors were significantly associated with BPSD severity ratings (r = 0.47; p < 0.001) and dementia severity (r = 0.46; p < 0.001). GARS-2 explained 6.1% (p < 0.001) of variance in CDR sum of boxes when controlling for NPI and other covariates. DISCUSSION: There is significant overlap in behaviors characteristic of ASD and BPSD as assessed by the NPI and GARS-2, despite the use of these instruments in disparate developmental vs. aging settings. ASD behaviors appear to not be solely present in early childhood as a manifestation of ASD but are also present in older adults with neurodegenerative cognitive impairment. Such associations warrant additional research into causation, assessment, and behavioral interventions to further enable new therapeutic approaches targeting ASD behaviors across the lifespan.

Development of a protocol to assess within-subject, regional white matter hyperintensity changes in aging and dementia.

BACKGROUND: White matter hyperintensities (WMH), associated with both dementia risk and progression, can individually progress, remain stable, or even regress influencing cognitive decline related to specific cerebrovascular-risks. This study details the development and validation of a registration protocol to assess regional, within-subject, longitudinal WMH changes (ΔWMH) that is currently lacking in the field. NEW METHOD: 3D-FLAIR images (baseline and one-year-visit) were used for protocol development and validation. The method was validated by assessing the correlation between forward and reverse longitudinal registration, and between summated regional progression-regression volumes and Global ΔWMH. The clinical relevance of growth-regression ΔWMH were explored in relation to an executive function test. RESULTS: MRI scans for 79 participants (73.5 ± 8.8 years) were used in this study. Global ΔWMH vs. summated regional progression-regression volumes were highly associated (r2 = 0.90; p-value < 0.001). Bi-directional registration validated the registration method (r2 = 0.999; p-value < 0.001). Growth and regression, but not overall ΔWMH, were associated with one-year declines in performance on Trial-Making-Test-B. COMPARISON WITH EXISTING METHOD(S): This method presents a unique registration protocol for maximum tissue alignment, demonstrating three distinct patterns of longitudinal within-subject ΔWMH (stable, growth and regression). CONCLUSIONS: These data detail the development and validation of a registration protocol for use in assessing within-subject, voxel-level alterations in WMH volume. The methods developed for registration and intensity correction of longitudinal within-subject FLAIR images allow regional and within-lesion characterization of longitudinal ΔWMH. Assessing the impact of associated cerebrovascular-risks and longitudinal clinical changes in relation to dynamic regional ΔWMH is needed in future studies.

Associations of Future Cognitive Decline with Sexual Satisfaction among Married Older Adults.

Objectives: This study sought to explore changes in longitudinal cognitive status in relation to baseline measures of intimacy and sexuality in cognitively intact, married older adults.Methods: Baseline intimacy and sexuality survey data from 155, cognitively intact, married, older adults were collected using a novel survey instrument that explored the domains of: 1) romance with one's partner, 2) sexual satisfaction, 3) beliefs about sexuality, and 4) social support and emotional intimacy. These data were analyzed in relation to change in cognitive status over a 10-year follow-up period using binary logistic regression modeling. Exploratory factor analysis was used to assess the shared variance of survey items attributable to intimacy and sexuality without specification of an a priori hypothesis regarding the association of intimacy and sexuality with future change in cognitive status.Results: Over the 10-year study period, 33.5% (n = 52) of individuals developed cognitive impairment. Participants with greater sexual satisfaction scores at baseline were statistically less likely to convert from cognitively intact to mild cognitive impairment or dementia in the future (p = .01). The domains of romance with one's partner, beliefs about sexuality, and social support/emotional intimacy were not predictive of future longitudinal changes in cognitive status.Conclusions: Sexual satisfaction is associated with longitudinal cognitive outcomes in cognitively intact, married, older adults.Clinical implications: Clinicians should routinely assess for sexual satisfaction among older adults and refer to appropriate providers, such as couples or sex therapists, when appropriate.

Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration.

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.

The Effectiveness of Community-based Outreach Events for the Promotion of African American Research Participation.

INTRODUCTION: African Americans (AA) are disproportionately affected by Alzheimer's disease and related dementias yet are under-represented in clinical research. Outreach events for AA are offered to encourage research participation; however, this approach's effectiveness remains largely unexplored. METHODS: To explore the effectiveness of AA-focused versus general audience events, the authors examined attendance data over 5 years, encompassing 10 general audience events and 4 events focused on AA. For each individual, the authors searched center records for recruitment contacts and research enrollment. Summary scores for attendance at AA-focused events, general audience events, and total events were compared between those with and without research involvement. RESULTS: Out of 773 unique AA that attended ≥1 event, 88 became or were involved in research (11.4% engagement). AA-focused events achieved greater AA attendance than general audience events. Although research-engaged individuals were more likely to have ever attended an AA-focused event than a general audience event, attendance at AA-focused events did not statistically relate to research engagement. In contrast, attendance at events focused on the general public was related to an increased likelihood of research participation. DISCUSSION: These findings have important implications for designing and implementing community events to encourage AA research participation.

Subjective Memory Complaints Are an Important Surrogate for Objective Cognitive Performance in African Americans.

PURPOSE: Subjective memory complaints (SMCs) have been shown to be associated with lower neuropsychological test scores cross-sectionally. However, it remains unclear whether such findings hold true for African American (AA) older adults. METHODS: Baseline visit data from the National Alzheimer's Coordinating Center database collected from September 2005 to March 2018 were used. Generalized linear mixed models specifying binomial distributions were used to examine how neuropsychological test scores affect the likelihood of reporting SMCs. PATIENTS: Inclusion criteria were participants who reported AA as their primary race, 60 to 80 years of age, were cognitively unimpaired, and had a Mini-Mental Status Examination score ≥26. A total of 1021 older AA adults without missing data met the criteria. RESULTS: A total of 258 participants reported a SMC. SMCs were more likely with lower scores on measures of episodic memory and processing; however, SMCs were also more likely with higher scores on a measure of working memory. Working memory appeared to mediate reporting of SMC among participants with lower episodic memory scores. DISCUSSION: These findings demonstrate that SMCs are associated with lower scores on objective neuropsychological measures among older AAs. Additional work is needed to determine whether SMCs are further associated with a risk for clinical transition to mild cognitive impairment or dementia among AA older adults.

Behaviors Characteristic of Autism Spectrum Disorder in a Geriatric Cohort With Mild Cognitive Impairment or Early Dementia.

INTRODUCTION: Autism spectrum disorder (ASD) represents a heterogenous cluster of clinical phenotypes that are classically diagnosed by the time of adolescence. The possibility of late-life emergence of ASD has been poorly explored. METHODS: To more fully characterize the possibility of late-life emergence of behaviors characteristic of ASD in mild cognitive impairment and AD, we surveyed caregivers of 142 older persons with cognitive impairment from the University of Kentucky Alzheimer's Disease Center Longitudinal Cohort using the Gilliam Autism Rating Scale-2. RESULTS: Participants with high autism index ratings (autism "possible/very likely," n=23) reported significantly (statistically and clinically) younger age at the onset of cognitive impairment than those who scored in the autism "unlikely" range (n=119): 71.14±10.9 vs. 76.65±8.25 (P=0.034). In addition, those in the autism "possible/very likely" group demonstrated advanced severity of cognitive impairment, indicated by the Clinical Dementia Rating Scale Sum of Boxes scores. DISCUSSION: Data demonstrate that ASD behaviors may seem de novo of degenerative dementia and such behaviors are more prevalent in those with early onset dementia. Further work elucidating a connection between ASD and dementia could shed light on subclinical forms of ASD, identify areas of shared neuroanatomic involvement between ASD and dementias, and provide valuable insights that might hasten the development of therapeutic strategies.

Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-ß1-42 and Hypertension.

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aß1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. RESULTS: HTN and CSF Aß1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aß1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aß1-42 on WMH volume, but no significant HTN×CSF Aß1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aß1-42. CONCLUSION: Associations of HTN and lower CSF Aß1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

Alzheimer Disease Clinical Trial Recruitment: Does Participation in a Brief Cognitive Screen at a Community Health Fair Promote Research Engagement?

BACKGROUND: Slow participant recruitment impedes Alzheimer disease research progress. Although research suggests that direct involvement with potential participants supports enrollment, strategies for how best to engage potential participants are still unclear. PURPOSE: This study explores whether community health fair (HF) attendees who engage in a brief cognitive screen (BCS) are more likely to enroll in research than attendees who do not complete a BCS. SUBJECTS: A total of 483 HF attendees. METHODS: Attendees were tracked for a 1-year period to ascertain research involvement. RESULTS: In total, 364 attendees expressed interest in research and 126 completed a BCS. Over the follow-up period, 21 individuals prescreened as eligible and 19 enrolled in an investigational study. Among all HF attendees, BCS completers had a 2.5-fold increase in subsequently prescreening as eligible as compared with non-BCS completers. However, when limited only to participants who stated an interest in research, this difference was no longer significant. CONCLUSIONS: Completing a BCS at a community event may be an indicator of future research engagement, but for those already interested in participation, the BCS may be a poor indicator of future involvement. The BCS may also reduce anxiety and stigma around memory evaluation, which may translate into research engagement in the future.

Examining the use of tramadol hydrochloride as an antidepressant.

Tramadol (Ultram, Ultracet) is a centrally acting synthetic opioid with analgesic efficacy comparable to codeine. Antinociception is attributed to low but effective affinity for the mu-opioid receptor (µ), as well as reuptake inhibition of the monoamines norepinephrine (NE) and serotonin (5HT). Dual action antidepressants mirtazapine (Remeron), duloxetine (Cymbalta), and most notably venlafaxine (Effexor), which tramadol is closely related to in structure, also inhibit NE and 5HT reuptake. These medications are proven effective antidepressants and this shared monoaminergic action resulted in the research of tramadol as a potential treatment for depression. The present article intends to substantiate the use of tramadol in this manner by analyzing several decades of research which is presented as an illustration of neuronal theories, as well as lab work and case studies of both the supporting ideas and potential hazards. Finally, the article promotes the benefits of acute action in comparison to modern antidepressants and the documentation of low abuse rates while maintaining an object view of the risks, most notably, the risk for addiction from agonist action on µ-receptors.