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.

Cognitive domain harmonization and cocalibration in studies of older adults.

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).

Symptomatic Profile and Cognitive Performance in Autopsy-Confirmed Limbic-Predominant Age-Related TDP-43 Encephalopathy With Comorbid Alzheimer Disease.

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.

Divergent magnetic resonance imaging atrophy patterns in Alzheimer's disease and primary age-related tauopathy.

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.

Limbic-Predominant Age-Related TDP-43 Encephalopathy: Medical and Pathologic Factors Associated With Comorbid Hippocampal Sclerosis.

BACKGROUND AND OBJECTIVES: Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood. METHODS: This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study. RESULTS: A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal ß-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies. DISCUSSION: In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-ß-amyloid vessel wall pathologies.

Association between WWOX/MAF variants and dementia-related neuropathologic 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.

Differences in Symptomatic Presentation and Cognitive Performance Among Participants With LATE-NC Compared to FTLD-TDP.

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 APOE ε4, 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.

Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.

Uniform data set language measures for bvFTD and PPA diagnosis and monitoring.

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.

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.

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.

Differentiating among stages of cognitive impairment in aging: Version 3 of the Uniform Data Set (UDS) neuropsychological test battery and MoCA index scores.

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.

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.

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.

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.

Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy.

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.

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.

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.