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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. [ABSTRACT FROM AUTHOR]

Background: Presence of multiple pathologies associated with neurodegenerative disease at autopsy is common. We investigated whether unsupervised cluster analysis of neuropathologic features resulted in distinct neuropathologic profiles, and compared demographic and clinical features between clusters. Method: We included autopsied participants from the National Alzheimer's Coordinating Center Uniform Data Set whose last visit was within two years of death. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathology variable used for clustering. We applied a hierarchical clustering algorithm using amyloid plaques (Thal phase, neuritic plaque density), tau neurofibrillary tangles (Braak stage, frontotemporal lobar degeneration (FTLD) tau presence), vascular pathology (infarcts, microinfarcts, arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy), Lewy bodies (LB), and transactive response DNA‐binding protein 43 (TDP‐43) inclusions. We compared neuropathologic, demographic, and clinical features of the resulting clusters. Result: The algorithm identified seven distinct clusters (Figure 1) of the 1,156 participants that met inclusion criteria. Four clusters included high levels of Alzheimer's disease neuropathologic change (ADNC), characterized as ADNC+TDP, ADNC+LB, ADNC+FTLD‐tau, and ADNC alone. Two clusters were characterized by high levels of TDP‐43 or FTLD‐tau, but mild burden of other pathologies, and the remaining cluster had mild burden of all pathologies. Vascular pathologies were prevalent across all clusters. In general, primary etiologic diagnosis among those who were cognitively impaired at their last visit corresponded well with the defining neuropathologies of each cluster (Figure 2). In the ADNC+LB cluster, primary clinical diagnosis was rarely Lewy body dementia (LBD). Even in clusters with mild ADNC, Alzheimer's disease was commonly the primary diagnosis. Overall, ADNC+TDP and ADNC+LB clusters had the most impairment at their last visit, with the highest prevalence of cognitive symptoms and lowest scores on cognitive tests. The cluster with mild pathologic burden, while having the highest proportion of participants with normal cognition, also had the highest proportions with mild cognitive impairment. Conclusion: Despite the diverse combinations of pathologies present at autopsy, unsupervised cluster analysis revealed distinct pathologic profiles of neurodegenerative disease. Clusters with mixed pathologies had higher cognitive impairment. Primary clinical diagnoses largely reflected neuropathologic burden, although Alzheimer's disease was commonly diagnosed in clusters with low ADNC burden. [ABSTRACT FROM AUTHOR]

Background: Transactive response DNA‐binding protein 43 (TDP‐43) proteinopathy is the key biomarker in limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC). LATE‐NC is a common co‐pathology with Alzheimer's Disease neuropathologic change (ADNC; plaques and tangles). We examined the symptomatic presentation and cognitive performance of autopsy‐confirmed ADNC, comparing cases with, versus without, comorbid LATE‐NC. Method: Participants with ADNC and ADNC + LATE‐NC were identified from the National Alzheimer's Coordinating Center Neuropathology Data Set. Participants were excluded if <65 years at death, had rare neuropathologic diseases (e.g., FTLD‐tau, FTLD‐TDP), or had their last clinic visit >36 months before their date of death. Presence of cognitive, behavioral, and motor symptoms at last visit were compared between those with ADNC and ADNC + LATE‐NC. Linear regression analyses with generalized estimating equations were run to test for mean differences between the two groups on five cognitive domain z‐scores (episodic memory, attention/working memory, executive function, semantic memory, global composite score) calculated from neuropsychological test scores at last visit. Models were stratified by ADNC severity score (low/intermediate vs high) and adjusted for covariates. Result: Included were 516 ADNC and 273 ADNC + LATE‐NC participants. ADNC + LATE‐NC participants were older at death and more likely to have hippocampal sclerosis. Among those with low or intermediate ADNC, ADNC + LATE‐NC participants were more likely to have impairments to memory, executive function, language, and attention, and demonstrate apathy, irritability and agitation compared to those with ADNC alone. These differences were not seen in those with high ADNC. Examining differences in cognitive domain z‐scores, participants with low/intermediate ADNC alone performed significantly better in episodic memory compared to those with low/intermediate ADNC + LATE‐NC. Participants with high ADNC alone performed significantly better in the episodic memory and executive functioning as compared to those with co‐occurring LATE‐NC. Conclusion: In this sample, LATE‐NC was a very common comorbidity with ADNC, affecting over 1/3rd of subjects. The co‐occurrence of LATE‐NC with ADNC may be distinguishable from ADNC alone through changes in behavior and cognitive performance. Although the specific features changed across the ADNC spectrum, the presence of LATE‐NC was highly impactful clinically at all stages of ADNC severity. [ABSTRACT FROM AUTHOR]

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. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0459-6) contains supplementary material, which is available to authorized users.

Study Design Cross-sectional study. Objectives: Determine clinical factors associated with plasma C-reactive protein (CRP) in persons with chronic spinal cord injury (SCI). Setting: Veterans Affairs Medical Center in Boston, MA. Methods: Participants provided a blood sample, completed a respiratory health questionnaire, and underwent dual x-ray absorptiometry (DXA) to assess total and regional body fat. Linear regression models were used to assess cross-sectional associations with plasma CRP. Results: In multivariable models, factors associated with a higher CRP included a greater BMI, urinary catheter use, a respiratory illness in the past week, and non-white race. Mean CRP also increased with decreasing mobility (motorized wheel chair >hand propelled wheel chair > walk with an assistive device > walk independently). Results were similar when adjusting for % android, gynoid, trunk, or total fat mass in place of BMI. Level and completeness of SCI was not associated with CRP in multivariable models. Conclusions: Clinical characteristics common in chronic SCI are associated with plasma CRP. These factors are more important than level and completeness of SCI and some are potentially modifiable.

Background: National Institute on Aging (NIA)‐funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS was implemented in 2015 and included several changes to its neuropsychological battery, replacing the previous version [Version 2 (V2)]. The current study compares the V3 and V2 neuropsychological batteries with respect to their ability to distinguish among categories of cognitive impairment captured by the Clinical Dementia Rating (CDR) global scores representing either no cognitive impairment (CDR=0), questionable or mild cognitive impairment (CDR=0.5) or mild stage of dementia (CDR=1.0). Method: Data from the NACC UDS V2 and V3 neuropsychological batteries were examined. There were 16,935 unique subjects from V2 and 5022 unique subjects from V3 aged 60 years and older with CDR global score ≤ 1. To reduce the influence of practice effects, only data from their first assessment was used. To control for inequalities in sample sizes between V2 and V3, we identified an approximately equal number of subjects from V2 within each CDR group. Receiver Operating Characteristics Area under Curve (ROC‐AUC) in differentiating stages of cognitive impairment were compared and optimal cut‐points based on Youden's J scores were calculated. Result: ROC‐AUCs from all of the V3 neuropsychological tests were comparable in their ability to differentiate CDR global scores with the corresponding tests in V2, despite the fact that V3 participants included more subjects at earlier stage of CDR 0.5. UDS V3 composite scores yielded similar ROC‐AUCs to the best performing individual test within each domain, while the Montreal Cognitive Assessment (MoCA) total score yielded higher ROC‐AUCs than any individual MoCA index scores. Racial differences in differentiating between CDR=0 and CDR=0.5 were also found. Conclusion: A nonproprietary suite of neuropsychological tests in UDS V3 provided similar discriminative ability to tests in UDS V2 to distinguish categories of cognitive impairment. Optimal cut‐points calculated in this study will be useful for clinical diagnosis. [ABSTRACT FROM AUTHOR]

Methyiphenidate is the psychostimulant medication most commonly prescribed to treat attention deficit hyperactivity disorder (ADHD). Recent trends in the high usage of methylphenidate for both therapeutic and nontherapeutic purposes prompted us to investigate the long-term effects of exposure to the drug on neuronal adaptation. We compared the effects of chronic methyl-phenidate or cocaine (15 mg/kg, 14 days for both) exposure in mice on dendritic spine morphology and ΔFosB expression in medium-sized spiny neurons (MSN) from ventral and dorsal striatum. Chronic methylphenidate increased the density of dendritic spines in MSN-D1 (MSN-expressing dopamine D1 receptors) from the core and shell of nucleus accumbens (NAcc) as well as MSN-D2 (MSN- expressing dopamine D2 receptors) from the shell of NAcc. In contrast, cocaine increased the density of spines in both populations of MSN from all regions of striatum. In general, the effect of methylphenidate on the increase of shorter spines (class 2) was less than that of cocaine. Interestingly, the methylphenidate-induced increase in the density of relatively longer spines (class 3) in the shell of NAcc was bigger than that induced by cocaine. Furthermore, methylphenidate exposure increased expression of ΔFosB only in MSN-D1 from all areas of striatum, and surprisingly, the increase was greater than that induced by cocaine. Thus, our results show differential effects of methylphenidate and cocaine on neuronal adaptation in specific types of MSN in reward-related brain regions. [ABSTRACT FROM AUTHOR]

Background: TAR‐DNA binding protein 43 kDa (TDP‐43) proteinopathy is a neurodegenerative pathology present in up to 50% of aged persons with dementia. Recently, a classification system for limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic changes (LATE‐NC) was proposed. In previous work, we reported that brains with TDP‐43 proteinopathy comprise four distinct clusters, based on clinical features and comorbid neuropathologies (PMID 32797255). All included participants (N=495) had autopsy‐confirmed TDP‐43 proteinopathy. Cluster 1 (n=103) contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD‐TDP). Cluster 2 (n=71) was distinguished by relatively "pure" LATE‐NC (i.e., no/low ADNC). Both Clusters 3 (n=114) and 4 (n=207) had high levels of ADNC + LATE‐NC; however, Cluster 4 featured earlier disease onset and swift disease progression without FTLD clinical features. Here, we investigate differences in genetic features between ADNC and LATE‐NC subclusters. Method: Participant data were drawn from the previously analyzed sample (N=495), which comprised of autopsied research volunteers who were followed at Alzheimer's Disease Research Centers and appear in the National Alzheimer's Coordinating Center database. Alzheimer's Disease Genetics Consortium (ADGC) data were linked to the initial sample, and we examined the association of single‐nucleotide polymorphisms (SNPs) identified as a late‐onset AD associated SNP by the International Genomics of Alzheimer's Disease Project genome wide‐association study in LATE‐NC clusters. Result: ADGC data were available for 124/495 participants. Of these, 89 were in Cluster 3 and 4 (ADNC+LATE‐NC) and 20 in Cluster 2 (pure LATE‐NC). The SNPs rs190982 located in MEF2C on Chromosome 5 and rs11218343 located in SORL1 on Chromosome 11 were significantly associated with cluster membership. The G allele of rs190982 and the C allele of rs11218343 were risk SNPs for Cluster 2. Conclusion: Two SNPs may be differentially associated with ADNC+LATE‐NC vs. pure LATE‐NC. Given that TDP‐43 proteinopathy is common in aged brains, identifying genetic factors is a crucial step toward developing disease‐modifying therapies. Although our final sample size was small, these results might help point to unsuspected pathways that influence ADNC and LATE‐NC phenotypes. [ABSTRACT FROM AUTHOR]

Mitochondrial fission and trafficking to dendritic protrusions have been implicated in dendritic spine development. Here, we show that Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1) controls depolarization-induced mitochondrial movement into dendritic spines and filopodia and regulates spine morphogenesis. Depolarization-induced degradation of the p35 regulatory subunit of cyclin-dependent kinase 5 (Cdk5), with the resultant decreased inhibitory phosphorylation on WAVE1, depend on NMDA receptor activation. Thus, WAVE1 dephosphorylation and activation are likely associated with mitochondrial redistribution and spine morphogenesis. [ABSTRACT FROM AUTHOR]

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. • Psychosis in AD is prevalent and associates with worse prognosis. • Psychosis in AD associates with neuropathological heterogeneity. • Psychosis in AD has differential cognitive symptoms and brain atrophy. [ABSTRACT FROM AUTHOR]

Background: Brain vascular pathology is an important comorbidity in Alzheimer’s disease (AD), with white matter damage independently predicting cognitive impairment. However, it is still unknown how vascular pathology differentially impacts primary age-related tauopathy (PART) compared to AD. Therefore, our objectives were to compare the brain microangiopathic burden in patients with PART and AD, evaluated by MRI, while assessing its relation with neuropathological findings, patterns of brain atrophy and degree of clinical impairment.Clinical information, brain MRI (T1 and T2-FLAIR) and neuropathological data were obtained from the National Alzheimer’s Coordinating Centre ongoing study, with a total sample of 167 patients identified, that were divided according to the presence of neuritic plaques in Consortium to Establish a Registry for Alzheimer’s disease (CERAD) 0 to 3. Microangiopathic burden and brain atrophy were evaluated by two certified neuroradiologists, using, respectively, the Fazekas score and previously validated visual rating scales to assess brain regional atrophy.Significant correlations were found between the Fazekas score and atrophy in the fronto-insular and medial temporal regions on both groups, with PART showing overall stronger positive correlations than in AD, especially in the fronto-insular region. For this specific cohort, no significant correlations were found between the Fazekas score and the degree of clinical impairment.Our results show that PART presents different pathological consequences at the brain microvascular level compared with AD and further supports PART as an independent pathological entity from AD.Methods: Brain vascular pathology is an important comorbidity in Alzheimer’s disease (AD), with white matter damage independently predicting cognitive impairment. However, it is still unknown how vascular pathology differentially impacts primary age-related tauopathy (PART) compared to AD. Therefore, our objectives were to compare the brain microangiopathic burden in patients with PART and AD, evaluated by MRI, while assessing its relation with neuropathological findings, patterns of brain atrophy and degree of clinical impairment.Clinical information, brain MRI (T1 and T2-FLAIR) and neuropathological data were obtained from the National Alzheimer’s Coordinating Centre ongoing study, with a total sample of 167 patients identified, that were divided according to the presence of neuritic plaques in Consortium to Establish a Registry for Alzheimer’s disease (CERAD) 0 to 3. Microangiopathic burden and brain atrophy were evaluated by two certified neuroradiologists, using, respectively, the Fazekas score and previously validated visual rating scales to assess brain regional atrophy.Significant correlations were found between the Fazekas score and atrophy in the fronto-insular and medial temporal regions on both groups, with PART showing overall stronger positive correlations than in AD, especially in the fronto-insular region. For this specific cohort, no significant correlations were found between the Fazekas score and the degree of clinical impairment.Our results show that PART presents different pathological consequences at the brain microvascular level compared with AD and further supports PART as an independent pathological entity from AD.Results: Brain vascular pathology is an important comorbidity in Alzheimer’s disease (AD), with white matter damage independently predicting cognitive impairment. However, it is still unknown how vascular pathology differentially impacts primary age-related tauopathy (PART) compared to AD. Therefore, our objectives were to compare the brain microangiopathic burden in patients with PART and AD, evaluated by MRI, while assessing its relation with neuropathological findings, patterns of brain atrophy and degree of clinical impairment.Clinical information, brain MRI (T1 and T2-FLAIR) and neuropathological data were obtained from the National Alzheimer’s Coordinating Centre ongoing study, with a total sample of 167 patients identified, that were divided according to the presence of neuritic plaques in Consortium to Establish a Registry for Alzheimer’s disease (CERAD) 0 to 3. Microangiopathic burden and brain atrophy were evaluated by two certified neuroradiologists, using, respectively, the Fazekas score and previously validated visual rating scales to assess brain regional atrophy.Significant correlations were found between the Fazekas score and atrophy in the fronto-insular and medial temporal regions on both groups, with PART showing overall stronger positive correlations than in AD, especially in the fronto-insular region. For this specific cohort, no significant correlations were found between the Fazekas score and the degree of clinical impairment.Our results show that PART presents different pathological consequences at the brain microvascular level compared with AD and further supports PART as an independent pathological entity from AD.Conclusion: Brain vascular pathology is an important comorbidity in Alzheimer’s disease (AD), with white matter damage independently predicting cognitive impairment. However, it is still unknown how vascular pathology differentially impacts primary age-related tauopathy (PART) compared to AD. Therefore, our objectives were to compare the brain microangiopathic burden in patients with PART and AD, evaluated by MRI, while assessing its relation with neuropathological findings, patterns of brain atrophy and degree of clinical impairment.Clinical information, brain MRI (T1 and T2-FLAIR) and neuropathological data were obtained from the National Alzheimer’s Coordinating Centre ongoing study, with a total sample of 167 patients identified, that were divided according to the presence of neuritic plaques in Consortium to Establish a Registry for Alzheimer’s disease (CERAD) 0 to 3. Microangiopathic burden and brain atrophy were evaluated by two certified neuroradiologists, using, respectively, the Fazekas score and previously validated visual rating scales to assess brain regional atrophy.Significant correlations were found between the Fazekas score and atrophy in the fronto-insular and medial temporal regions on both groups, with PART showing overall stronger positive correlations than in AD, especially in the fronto-insular region. For this specific cohort, no significant correlations were found between the Fazekas score and the degree of clinical impairment.Our results show that PART presents different pathological consequences at the brain microvascular level compared with AD and further supports PART as an independent pathological entity from AD. [ABSTRACT FROM AUTHOR]

• The WWOX/MAF locus has been identified as a potentially harboring AD risk variants • The present study failed to find associations with AD-related endophenotypes • However, several other non-AD endophenotypes were associated with WWOX/MAF variants • The novel associations were unchanged by adjustment for AD-related endophenotypes The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Studies use different instruments to measure cognitirating cognitive tests permit direct comparisons of individuals across studies and pooling data for joint analyses., Method: We began our legacy item bank with data from the Adult Changes in Thought study ( n = 5,546), the Alzheimer's Disease Neuroimaging Initiative ( n = 3,016), the Rush Memory and Aging Project ( n = 2,163), and the Religious on such as the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Wechsler Memory Scale, and the Boston Naming Test. CocalibOrders Study ( n = 1,456). Our workflow begins with categorizing items administered in each study as indicators of memory, executive functioning, language, visuospatial functioning, or none of these domains. We use confirmatory factor analysis models with data from the most recent visit on the pooled sample across these four studies for cocalibration and derive item parameters for all items. Using these item parameters, we then estimate factor scores along with corresponding standard errors for each domain for each study. We added additional studies to our pipeline as available and focused on thorough consideration of candidate anchor items with identical content and administration methods across studies., Results: Prestatistical harmonization steps such qualitative and quantitative assessment of granular cognitive items and evaluating factor structure are important steps when trying to cocalibrate cognitive scores across studies. We have cocalibrated cognitive data and derived scores for four domains for 76,723 individuals across 10 studies., Conclusions: We have implemented a large-scale effort to harmonize and cocalibrate cognitive domain scores across multiple studies of cognitive aging. Scores on the same metric facilitate meta-analyses of cognitive outcomes across studies or the joint analysis of individual data across studies. Our systematic approach allows for cocalibration of additional studies as they become available and our growing item bank enables robust investigation of cognition in the context of aging and dementia. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Our study compared brain MRI with neuropathological findings in patients with primary age-related tauopathy (PART) and Alzheimer's disease (AD), while assessing the relationship between brain atrophy and clinical impairment. We analyzed 233 participants: 32 with no plaques ("definite" PART-BRAAK stage higher than 0 and CERAD 0), and 201 cases within the AD spectrum, with 25 with sparse (CERAD 1), 76 with moderate (CERAD 2), and 100 with severe (CERAD 3) degrees of neuritic plaques. Upon correcting for age, sex, and age difference at MRI and death, there were significantly higher levels of atrophy in CERAD 3 compared to CERAD 1-2 and a trend compared to PART (p = 0.06). In the anterior temporal region, there was a trend for higher levels of atrophy in PART compared to Alzheimer's disease spectrum cases with CERAD 1 (p = 0.08). We then assessed the correlation between regional brain atrophy and CDR sum of boxes score for PART and AD, and found that overall cognition deficits are directly correlated with regional atrophy in the AD continuum, but not in definite PART. We further observed correlations between regional brain atrophy with multiple neuropsychological metrics in AD, with PART showing specific correlations between language deficits and anterior temporal atrophy. Overall, these findings support PART as an independent pathologic process from AD., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring., Methods: Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data., Results: Among PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change., Discussion: The FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring., Competing Interests: BB has served as an investigator for clinical trials sponsored by Axovant and Biogen. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation. HJR has a consulting agreement Ionis Pharmaceuticals. JHK has provided consultation for Biogen. He helped develop the Delis–Kaplan Executive Function System and receives royalties from Pearson Education, Inc., for helping to develop the California Verbal Learning Test. ALB receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeton, Abbvie, Alector, Amgen, Arkuda, Ionis, Iperian, Janssen, Merck, Novartis, Samumed, Toyama, and UCB; and has received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche, and TauRx., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Federally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1., Methods: First, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests., Results: Some V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants., Discussion: Further efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required., Competing Interests: Hiroko H Dodge, Felicia C. Goldstein, Nicole I Wakim, Tamar Gefen, Merilee Teylan, Kwun CG Chan, Walter A. Kukull, Lisa L. Barnes, Bruno Giordani, Timothy M. Hughes, Joel H. Kramer, David A. Loewenstein, Daniel C Marson, Dan M Mungas, Bonnie C. Sachs, Monica Willis‐Parker, Katherine V Wild, John C. Morris, and Sandra Weintraub have no conflicts of interest to declare. David Salmon is a paid consultant for Aptinyx, Inc. and Biogen, Inc. Kathleen Welsh‐Bohmer received funding from Verasci as a contract through Duke University and funding from Takeda over the last 5 years (until May 2019) as part of a contract with Duke., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

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.

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.

One possible approach to prevention of suicide attempts is to encourage help-seeking among individuals at risk. We assessed whether different forms of treatment were associated with lower odds of a suicide attempt in a diverse group of 388 lesbian, gay, and bisexual (LGB) adults aged 18-59, sampled from New York City venues. Of individuals who attempted suicide, 23% sought mental health or medical treatment and 14% sought religious or spiritual treatment prior to the suicide attempt. Black and Latino LGBs were underrepresented in mental health or medical treatment and Black LGBs were overrepresented in religious or spiritual treatment. Seeking mental health or medical treatment was not associated with lower odds of a suicide attempt; seeking religious or spiritual treatment was associated with higher odds of a suicide attempt. We discuss these results and posit hypotheses for further research of this understudied topic., (© 2014 The American Association of Suicidology.)

Dendritic spines play an essential role in the central nervous system. Recent experiments have revealed that neuron functional properties are highly correlated with the statistical and morphological changes of the dendritic spines. In this paper, we propose a new multi scale approach for detecting dendritic spines in a 2D Maximum Intensity Projection (MIP) image of the 3D neuron data stacks collected from a 2-photon laser scanning confocal microscope. The proposed method utilizes the curvilinear structure detector in conjunction with the multi scale spine detection algorithm which automatically and accurately extracts and segments the spines with variational sizes along the dendrite. In addition, a slice-based spine detection algorithm is also proposed to detect spines which are hidden from the MIP image within the dendrite area. Experimental results show that our proposed method is effective for automatic spine detection and is able to accurately segment dendrite.

Determining the relationship between the dendritic spine morphology and its functional properties is a fundamental while challenging problem in neurobiology research. In particular, how to accurately and automatically analyze meaningful structural information from a large microscopy image dataset is far away from being resolved. In this paper, we propose a novel method for the automated neuron reconstruction and spine detection from fluorescence microscopy images. After image processing, backbone of the neuron is obtained and the neuron is represented as a 3D surface. Based on the analysis of geometric features on the surface, spines are detected by a novel hybrid of two segmentation methods. Besides the automated detection of spines, our algorithm is able to extract accurate 3D structures of spines. Comparison results between our approach and the state of the art shows that our algorithm is more accurate and robust, especially for detecting and separating touching spines.

Recent studies on neuron imaging show that there is a strong relationship between the functional properties of a neuron and its morphology, especially its dendritic spine structures. However, most of the current methods for morphological spine classification only concern features in two-dimensional (2D) space, which consequently decreases the accuracy of dendritic spine analysis. In this paper, we propose a semi-supervised learning (SSL) framework, in which spine phenotypes in three-dimensional (3D) space are considered. With training only on a few pre-classified inputs, the rest of the spines can be identified effectively. We also derived a new scheme using an affinity matrix between features to further improve the accuracy. Our experimental results indicate that a small training dataset is sufficient to classify detected dendritic spines.