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Transactive response DNA-binding protein 43 kDa (TDP-43) proteinopathy is the hallmark of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). LATE-NC is a common copathology with Alzheimer disease neuropathologic change (ADNC). Data from the National Alzheimer’s Coordinating Center were analyzed to compare clinical features and copathologies of autopsy-confirmed ADNC with versus without comorbid LATE-NC. A total of 735 participants with ADNC alone and 365 with ADNC with LATE-NC were included. Consistent with prior work, brains with LATE-NC had more severe ADNC, more hippocampal sclerosis, and more brain arteriolosclerosis copathologies. Behavioral symptoms and cognitive performance on neuropsychological tests were compared, stratified by ADNC severity (low/intermediate vs high). Participants with ADNC and LATE-NC were older, had higher ADNC burden, and had worse cognitive performance than participants with ADNC alone. In the low/intermediate ADNC strata, participants with comorbid LATE-NC had higher prevalence of behavioral symptoms (apathy, disinhibition, agitation, personality change). They also had worsened performance in episodic memory and language/semantic memory. Differences narrowed in the high ADNC strata, with worsened performance in only episodic memory in the comorbid LATE-NC group. The co-occurrence of LATE-NC with ADNC is associated with a different pattern of behavioral and cognitive performance than ADNC alone, particularly in people with low/intermediate ADNC burden.

Transactive response DNA-binding protein 43 kDa (TDP-43) is aberrantly aggregated and phosphorylated in frontotemporal lobar degeneration of the TDP-43 type (FTLD-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). We examined data from the National Alzheimer's Coordinating Center to compare clinical features of autopsy-confirmed LATE-NC and FTLD-TDP. A total of 265 LATE-NC and 92 FTLD-TDP participants were included. Cognitive and behavioral symptoms were compared, stratified by level of impairment based on global clinical dementia rating (CDR) score. LATE-NC participants were older at death, more likely to carry APOEε4, more likely to have Alzheimer disease neuropathology, and had lower (i.e. less severe) final CDR global scores than those with FTLD-TDP. Participants with FTLD-TDP were more likely to present with primary progressive aphasia, or behavior problems such as apathy, disinhibition, and personality changes. Among participants with final CDR score of 2–3, those with LATE-NC were more likely to have visuospatial impairment, delusions, and/or visual hallucinations. These differences were robust after sensitivity analyses excluding older (≥80 years at death), LATE-NC stage 3, or severe Alzheimer cases. Overall, FTLD-TDP was more globally severe, and affected younger participants, whereas psychoses were more common in LATE-NC.

It remains unclear what clinical features inform the accuracy of a clinical diagnosis of Alzheimer disease (AD). Data were obtained from the National Alzheimer's Coordinating Center to compare clinical and neuropathologic features among participants who did or did not have Alzheimer disease neuropathologic changes (ADNC) at autopsy. Participants (1854) had a clinical Alzheimer dementia diagnosis and ADNC at autopsy (Confirmed-AD), 204 participants had an AD diagnosis and no ADNC (AD-Mimics), and 253 participants had no AD diagnosis and ADNC (Unidentified-AD). Compared to Confirmed-AD participants, AD-Mimics had less severe cognitive impairment, while Unidentified-AD participants displayed more parkinsonian signs, depression, and behavioral problems. This study highlights the importance of developing a complete panel of biomarkers as a tool to inform clinical diagnoses, as clinical phenotypes that are typically associated with diseases other than AD may result in inaccurate diagnoses.

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.

Recently, a consensus working group provided new terminology for a common disease entity, limbic predominant age-related TDP-43 encephalopathy (LATE), and its neuropathological substrate (LATE-NC). LATE-NC not only often co-occurs with Alzheimer disease neuropathological change (ADNC), but also may present in isolation. The present study aimed to investigate potential risk factors and neuropathological characteristics associated with LATE-NC. A sample of 616 autopsied participants (>75 years at death), with TDP-43 immunohistochemical studies performed, was obtained from the National Alzheimer's Coordinating Center. Logistic regression analyses examined associations between demographic, clinical and neuropathological characteristics and LATE-NC (TDP-43 in amygdala, hippocampus, or entorhinal/inferior temporal cortex) (alpha = 0.05). Adjusted models indicated that ADNC, hippocampal sclerosis (HS), arteriolosclerosis, and limbic or amygdala-predominant Lewy body disease (LBD), but not other LBD subtypes, were associated with higher odds of LATE-NC, whereas congestive heart failure (CHF) and motor problems as first predominant symptom were associated with lower odds of LATE-NC. Our findings corroborate previous studies indicating associations between LATE-NC and ADNC, HS, and arteriolosclerosis. Novel findings suggest the association with LATE-NC is restricted to amygdala/limbic-predominant subtype of LBD, and a possible protective (or competing risk) association with CHF. This study may inform future hypothesis-driven research on LATE-NC, a common brain disease of aging.

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.

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 APOEε4 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.

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 APOEε4 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.

Context/Objective:Individuals with chronic spinal cord injury (SCI) have an increased risk of morbidity and mortality attributable to respiratory diseases. Previous studies in non-SCI populations suggest that vitamin D may be a determinant of respiratory health. Therefore, we sought to assess if lower vitamin D levels were associated with decreased pulmonary function in persons with chronic SCI.Design:Cross-sectional study.Setting:Veterans Affairs Medical Center.Participants:312 participants (260 men and 52 women) with chronic SCI recruited from VA Boston and the community participating in an epidemiologic study to assess factors influencing respiratory health.Methods:Participants provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma 25-hydroxyviatmin D and spirometric measures of pulmonary function.Outcome Measures:Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC.Results:Adjusted and unadjusted for a number of confounders, there was no significant association between plasma vitamin D levels and FEV1, FVC, or FEV1/FVC. For example, in fully adjusted models, each 10 ng/ml increase in vitamin D was associated with a 4.4 ml (95%CI −64.4, 73.2, P = 0.90) ml change in FEV1.Conclusion:There was no significant cross-sectional association between plasma vitamin D and FEV1, FVC, or FEV1/FVC in this cohort of individuals with chronic SCI.

This study examined differences in neuropsychological test scores between individuals with primary age-related tauopathy (PART) and Alzheimer disease (AD) using cross-sectional data from the National Alzheimer's Coordinating Center. Linear regression tested for differences in 4 cognitive domains stratified by cognitive status (global Clinical Dementia Rating [CDR]). The sample included 240 participants with no neuritic plaques (NP) (definite PART), 186 with sparse NP (possible PART), and 510 with moderate/frequent NP (AD). Four cognitive domain z-score outcome variables (memory, attention, executive function, and semantic memory/language) were calculated using 12 neuropsychological tests. Definite PART participants had a sparing of semantic memory/language compared to those with AD, with a mean adjusted z-score difference of 0.37 (95% confidence interval [CI]: 0.16-0.58) for those with CDR = 0.5 or 1 and of 0.92 (CI: 0.22-1.63) for those with CDR = 2 or 3. Compared to participants with AD, definite PART participants with CDR = 0.5 or 1 had sparing of memory (adjusted z-score difference: 0.61; CI: 0.39-0.84) and definite PART participants with CDR = 2 or 3 had sparing of attention (adjusted z-score difference: 0.76: CI: 0.09-1.43). Patterns of cognitive impairment differed between definite PART and AD, suggesting significant differences in clinical presentation between individuals from these 2 groups.

Context/ObjectivePersons with chronic spinal cord injury (SCI) have an increased risk of respiratory-related morbidity and mortality and chronic respiratory symptoms are clinical markers of future respiratory disease. Therefore, we sought to assess potentially modifiable factors associated with respiratory symptoms, with a focus on circulating vitamin D and measures of body fat.DesignCross-sectional study.SettingVeterans Affairs Medical Center.ParticipantsThree hundred forty-three participants (282 men and 61 women) with chronic SCI participating in an epidemiologic study to assess factors influencing respiratory health recruited from VA Boston and the community.MethodsParticipants provided a blood sample, completed a respiratory health questionnaire, and underwent dual x-ray absorptiometry (DXA) to assess % body fat. Logistic regression was used to assess cross-sectional associations between respiratory symptoms and plasma vitamin D and measures of body fat with adjustment for a number of potential confounders.Outcome MeasuresChronic cough, chronic phlegm, any wheeze, persistent wheeze.ResultsAfter adjustment for a number of confounders (including smoking), participants with greater %-android, gynoid, trunk, or total body fat had increased odds ratios for any wheeze and suggestive associations with persistent wheeze, but not with chronic cough or phlegm. Vitamin D levels were not associated with any of the respiratory symptoms.ConclusionIncreased body fat, but not vitamin D, was associated with wheeze in chronic SCI independent of a number of covariates.

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer's Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer's Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

Physical activity is an important clinical marker of disease status in COPD. COPD is also characterized by low-grade systemic inflammation. However, the relationship between physical activity and systemic inflammation in COPD is unclear.

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

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