Brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Cognitive trajectory in mild cognitive impairment due to primary age-related tauopathy.

Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease.

Risk of mild cognitive impairment among older adults in the United States by ethnoracial group.

OBJECTIVES: To compare the risk of mild cognitive impairment (MCI) among a wide range of ethnoracial groups in the US. DESIGN: Non-probabilistic longitudinal clinical research. SETTING: Participants enrolling into the National Alzheimer's Coordinating Center Unified Data Set recruited via multiple approaches including clinician referral, self-referral by patients or family members, or active recruitment through community organizations. PARTICIPANTS: Cognitively normal individuals 55 and older at the initial visit, who reported race and ethnicity information, with at least two visits between September 2005 and November 2018. MEASUREMENTS: Ethnoracial information was self-reported and grouped into non-Latino Whites, Asian Americans, Native Americans, African Americans (AAs), and individuals simultaneously identifying as AAs and another minority race (AA+), as well as Latinos of Caribbean, Mexican, and Central/South American origin. MCI was evaluated clinically following standard criteria. Four competing risk analysis models were used to calculate MCI risk adjusting for risk of death, including an unadjusted model, and models adjusting for non-modifiable and modifiable risk factors. RESULTS: After controlling for sex and age at initial visit, subhazard ratios of MCI were statistically higher than non-Latino Whites among Native Americans (1.73), Caribbean Latinos (1.80), and Central/South American Latinos (1.55). Subhazard ratios were higher among AA+ compared to non-Latino Whites only in the model controlling for all risk factors (1.40). CONCLUSION: Compared to non-Latino Whites, MCI risk was higher among Caribbean and South/Central American Latinos as well as Native Americans and AA+. The factors explaining the differential MCI risk among ethnoracial groups are not clear and warrant future research.

Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy.

To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer's Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositive cases based on age at death and extensive neuropathologic data. Although many of the brains had mixed pathologies, four discernible clusters were identified. Key differentiating features were age at death and the severity of comorbid Alzheimer's disease neuropathologic changes (ADNC), particularly neuritic amyloid plaque densities. Cluster 1 contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD-TDP), consistent with enrichment of frontotemporal dementia clinical phenotypes including appetite/eating problems, disinhibition and primary progressive aphasia (PPA). Cluster 2 consisted of elderly limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) subjects without severe neuritic amyloid plaques. Subjects in Cluster 2 had a relatively slow cognitive decline. Subjects in both Clusters 3 and 4 had severe ADNC + LATE-NC; however, Cluster 4 was distinguished by earlier disease onset, swifter disease course, more Lewy body pathology, less neocortical TDP-43 proteinopathy, and a suggestive trend in a subgroup analysis (n = 114) for increased C9orf72 risk SNP rs3849942 T allele (Fisher's exact test p value = 0.095). Overall, clusters enriched with neocortical TDP-43 proteinopathy (Clusters 1 and 2) tended to have lower levels of neuritic amyloid plaques, and those dying older (Clusters 2 and 3) had far less PPA or disinhibition, but more apathy. Indeed, 98% of subjects dying past age 85 years lacked clinical features of the frontotemporal dementia syndrome. Our study revealed discernible subtypes of LATE-NC and underscored the importance of age of death for differentiating FTLD-TDP and LATE-NC.

The Utility of the National Alzheimer's Coordinating Center's Database for the Rapid Assessment of Evolving Neuropathologic Conditions.

The field of dementia research is rapidly evolving, especially with regards to our understanding of the diversity of neuropathologic changes that underlie cognitive decline. Definitions and criteria for known conditions are being periodically revised and refined, and new findings are being made about neuropathologic features associated with dementia status. The database maintained by the National Alzheimer's Coordinating Center (NACC) offer researchers a robust, rapid, and statistically well-powered method to evaluate the implications of newly identified neuropathologic conditions with regards to comorbidities, demographic associations, cognitive status, neuropsychologic tests, radiographic findings, and genetics. NACC data derive from dozens of excellent US Alzheimer disease research centers, which collectively follow thousands of research volunteers longitudinally. Many of the research participants are autopsied using state-of-the-art methods. In this article, we describe the NACC database and give examples of its use in evaluating recently revised neuropathologic diagnoses, including primary age-related tauopathy (PART), limbic predominant age-related TDP-43 encephalopathy (LATE), and the preclinical stage of Alzheimer disease neuropathologic change, based on the National Institute on Aging-Alzheimer's Association consensus guidelines. The dementia research community is encouraged to make use of this readily available database as new neuropathologic changes are recognized and defined in this rapidly evolving field.

Factor Consistency of Neuropsychological Test Battery Versions in the NACC Uniform Data Set.

The proprietary neuropsychological tests (Form C1) of the National Alzheimer's Coordinating Center (NACC) Uniform Data Set were replaced with nonproprietary versions (Form C2) chosen to closely model their proprietary counterparts. Correlations between analogous test pairs as measured in previous work were good (0.68-0.78), but it is unclear whether the paired tests represent the same set of common factors of cognition or if important factors specific to C1 or C2 only exist. The authors performed multiple factor analysis to analyze correlated C1 and C2 data. They included participants who completed both neuropsychological batteries within 1 year with no change in cognitive status. They found that the C1 and C2 neuropsychological test pairs are strongly related and are represented by the same principal factors. These findings support the use of the C2 test results in conjunction with C1 in longitudinal analyses of NACC data.

Correction: Plasma vitamin D, past chest illness, and risk of future chest illness in chronic spinal cord injury (SCI): a longitudinal observational study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Clinical associations with telomere length in chronic spinal cord injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Plasma vitamin D, past chest illness, and risk of future chest illness in chronic spinal cord injury (SCI): a longitudinal observational study.

STUDY DESIGN: Observational study. OBJECTIVE: Assess associations between vitamin D levels and other risk factors on future chest illness in a chronic spinal cord injury (SCI) cohort. SETTING: Veterans Affairs Boston and the Boston, MA community. METHODS: Between August 2009 and August 2017, 253 participants with chronic SCI were followed over a median of 3.2 years (up to 7.4 years) with two to four visits a median of 1.7 years apart. At each visit, plasma 25-hydroxyvitamin D level was obtained, spirometry performed, and a respiratory questionnaire assessing chest illnesses since last visit was completed. Repeated measures negative binomial regression was used to assess chest illness risk longitudinally. RESULTS: At entry, 25% had deficient vitamin D levels (<20 nanograms/milliliter (ng/ml)), 52% were insufficient (20 to <30 ng/ml), and 23% were sufficient (≥30 ng/ml). Over 545 study visits, chest illnesses (n = 106) were reported by 60 participants. In multivariable models (including previous chest illness history), deficient vitamin D levels (compared with those with sufficient levels) were associated with future chest illness though with wide confidence limits (relative risk (RR) = 1.36, 95% confidence intervals (CI) = 0.74, 2.47). The strongest association with chest illness during the follow-up period was in persons who reported pneumonia/bronchitis after injury and a chest illness in the three years before study entry (RR = 7.62; 95% CI = 3.70, 15.71). CONCLUSION: Assessed prospectively in chronic SCI, there was a suggestive association between deficient vitamin D levels and future chest illness. Past chest illness history was also strongly associated with future chest illness.

Measurement and characterization of distinctive clinical phenotypes using the Frontotemporal Lobar Degeneration Module (FTLD-MOD).

INTRODUCTION: The Frontotemporal Lobar Degeneration Module (FTLD-MOD) was designed as a research neuropsychological battery to evaluate clinical symptoms associated with FTLD. This study investigated whether the FTLD-MOD could differentiate between primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD), two distinct FTLD-related syndromes. METHODS: Retrospective analysis was conducted on data collected from the initial visit of 165 subjects with PPA, 268 with bvFTD, and 251 cognitively normal controls from the National Alzheimer's Coordinating Center. Generalized linear models were used to compare group performance patterns on FTLD-MOD tasks of language, behavior, and memory. RESULTS: PPA participants showed significantly poorer performances on all language tasks whereas bvFTD participants demonstrated poorer performances on most behavioral measures. There were no differences in memory performances. Descriptive data on participant groups are provided for reference. DISCUSSION: Findings from this multi-center sample suggest that the FTLD-MOD can differentiate between distinctive clinical phenotypes commonly associated with FTLD.

Clinical diagnoses among individuals with primary age-related tauopathy versus Alzheimer's neuropathology.

Primary age-related tauopathy (PART) is increasingly recognized as a pathologic entity distinct from Alzheimer's disease (AD). Given that the diagnosis of PART is an autopsy diagnosis, it is unclear how PART is perceived in clinical practice. Thus, we investigated the presumptive primary and contributing diagnoses in individuals who had cognitive impairment while alive and who met neuropathologic criteria for PART at autopsy. We also compared these clinical diagnoses for people with PART to those with AD neuropathology (ADNP). We used data on 1354 participants from the National Alzheimer's Coordinating Center, restricting to those with no neuritic plaques (PART) or moderate/frequent neuritic plaques (ADNP); clinical visit within two years of autopsy; and mild cognitive impairment (MCI) or dementia at last visit. To assess if PART participants were less likely to receive a clinical diagnosis of AD at their last visit prior to autopsy, we used logistic regression, controlling for age, sex, education, and APOE ε4 status. There were 161 PART individuals (n = 49 MCI; n = 112 dementia) and 1193 individuals with ADNP (n = 75 MCI; n = 1118 dementia). Primary clinical diagnosis of AD was more common in those with ADNP (MCI: 69%; demented: 86%) than PART (MCI: 57%; demented: 52%). In the adjusted analysis, primary and contributing clinical diagnoses of AD remained less likely in PART vs. ADNP participants with dementia (OR: 0.22, 95% CI: 0.13-0.38). This study suggests that clinicians recognize a distinction in the clinical presentation between PART and ADNP, diagnosing AD less frequently in those with PART. Nonetheless, clinical AD was diagnosed greater than 50% of the time in PART participants with MCI or dementia. Ante-mortem criteria for diagnosis of PART need to be established, as PART is a neuropathological entity that is distinct from AD and has its own clinical and cognitive outcomes.

Retention of Alzheimer Disease Research Participants.

INTRODUCTION: Participant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research. METHODS: We surveyed representative investigators from NIH-funded Alzheimer's Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer's Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics. RESULTS: Twenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P<0.001 for the middle compared with the lowest tertile survey scores; odds ratio=1.59, 95% confidence interval: 1.30, 1.94; P<0.001 for the highest compared with the lowest tertile survey scores) at the first follow-up visit. Participant characteristics such as normal cognition diagnosis, older age, higher education, and Caucasian race were also associated with higher retention. CONCLUSIONS: Retention in clinical research is more likely to be achieved by employing a variety of tactics.

Risk of dementia and mild cognitive impairment among older adults in same-sex relationships.

INTRODUCTION: Sexual minority discrimination might lead to a higher risk of mild cognitive impairment (MCI) and dementia. The aim of this study was to assess the risk of MCI and dementia between older adults in same-sex relationships (SSR) and opposite-sex relationships (OSR). METHODS: We analyzed longitudinal data from the National Alzheimer's Coordinating Center up to September 2017. Analyses included cognitively normal individuals 55+ at baseline who had a spouse, partner, or companion as study partner at any assessment. Associations were calculated using survival analysis adjusting for demographics and APOE-e4 carrier status. RESULTS: Hazard ratios of MCI and dementia did not differ statistically between SSR and OSR individuals in the total sample nor stratified by sex. CONCLUSION: The lack of association between SSR and MCI and dementia warrants future research into their potential resilience mechanisms and the inclusion of sexual minority status questions in research and surveillance studies. The potential recruitment bias caused by nonprobabilistic sampling of the cohort and the reporting and ascertainment bias caused by using SSR to infer sexual minority status may have influenced our findings.

Clinical associations with telomere length in chronic spinal cord injury.

STUDY DESIGN: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI). SETTING: Veterans Affairs Medical Center, Boston, MA. METHODS: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length. RESULTS: Telomere length was inversely related to age (p < 0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p = 0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p = 0.059) and persons with chronic urinary catheter use (p = 0.082) compared to persons without these characteristics. CONCLUSIONS: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.

Physical activity in COPD: Minimal clinically important difference for medical events.

Estimates of the minimal clinically important difference (MCID) for physical activity (PA) in chronic obstructive pulmonary disease (COPD) are needed. The objective is to provide an anchor-based estimate of the MCID for daily step count. PA was promoted in persons with COPD using a pedometer (Omron HJ-720ITC) alone or a pedometer plus interactive website for 3 months. Participants wore the pedometer daily and received phone calls monthly to ascertain medical events. Medical events were counted when a participant self-reported that he/she had (1) worsening of breathing, (2) change to breathing medications, (3) medical care from an emergency room for any reason, or (4) hospitalization for any reason. Generalized linear regression models assessed daily step count as change at the end of study and averaged over the 15, 31, or 61 days centered on the event, in those with an event compared to those without one. All categories of events carried equal weight in the analyses. We studied 93 persons, 46 of whom had an event. Participants who experienced an event had a decrease of 1086 (95% confidence interval (CI): -2124 to -48) or 887 (95% CI: -2030 to 257) steps/day in the pedometer plus website or pedometer alone groups, respectively, compared to those without one. In the days centered on an event, participants who had an event experienced a decrease of 882-983 steps/day (pedometer plus website) or a decrease of 351-495 steps/day (pedometer alone), compared to those without one. The MCID for PA in COPD ranges from 350 steps/day to 1100 steps/day.

Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS).

INTRODUCTION: The neuropsychological battery of the Uniform Data Set (UDSNB) was implemented in 2005 by the National Institute on Aging (NIA) Alzheimer Disease Centers program to measure cognitive performance in dementia and mild cognitive impairment due to Alzheimer Disease. This paper describes a revision, the UDSNB 3.0. METHODS: The Neuropsychology Work Group of the NIA Clinical Task Force recommended revisions through a process of due diligence to address shortcomings of the original battery. The UDSNB 3.0 covers episodic memory, processing speed, executive function, language, and constructional ability. Data from 3602 cognitively normal participants in the National Alzheimer Coordinating Center database were analyzed. RESULTS: Descriptive statistics are presented. Multivariable linear regression analyses demonstrated score differences by age, sex, and education and were also used to create a normative calculator available online. DISCUSSION: The UDSNB 3.0 neuropsychological battery provides a valuable non proprietary resource for conducting research on cognitive aging and dementia.

Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set.

INTRODUCTION: In 2015, the US Alzheimer's Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers. METHODS: UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer's Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery. RESULTS: This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions. DISCUSSION: The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.

FEV1 and FVC and systemic inflammation in a spinal cord injury cohort.

BACKGROUND: Systemic inflammation has been associated with reduced pulmonary function in individuals with and without chronic medical conditions. Individuals with chronic spinal cord injury (SCI) have clinical characteristics that promote systemic inflammation and also have reduced pulmonary function. We sought to assess the associations between biomarkers of systemic inflammation with pulmonary function in a chronic SCI cohort, adjusting for other potential confounding factors. METHODS: Participants (n = 311) provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma C-reactive protein (CRP) and interleukin-6 (IL-6) with forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: There were statistically significant inverse relationships between plasma CRP and IL-6 assessed in quartiles or continuously with FEV1 and FVC. In fully adjusted models, each interquartile range (5.91 mg/L) increase in CRP was associated with a significant decrease in FEV1 (-55.85 ml; 95% CI: -89.21, -22.49) and decrease in FVC (-65.50 ml; 95% CI: -106.61, -24.60). There were similar significant findings for IL-6. There were no statistically significant associations observed with FEV1/FVC. CONCLUSION: Plasma CRP and IL-6 in individuals with chronic SCI are inversely associated with FEV1 and FVC, independent of SCI level and severity of injury, BMI, and other covariates. This finding suggests that systemic inflammation associated with chronic SCI may contribute to reduced pulmonary function.

Psychosis in Alzheimer's disease is associated with specific changes in brain MRI volume, cognition and neuropathology.

Psychosis in Alzheimer's Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy.