Utility of the ALSFRS-R for predicting ALS and comorbid disease neuropathology: The Veterans Affairs Biorepository Brain Bank.

INTRODUCTION/AIMS: The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) is commonly used to track ALS disease progression; however, there are gaps in the literature regarding the extent to which the ALSFRS-R relates to underlying central nervous system (CNS) pathology. The current study explored the association between ALSFRS-R (total and subdomain) scores and postmortem neuropathology (both ALS-specific and comorbid disease). METHODS: Within our sample of 93 military veterans with autopsy-confirmed ALS, we utilized hierarchical cluster analysis (HCA) to identify discrete profiles of motor dysfunction based on ALSFRS-R subdomain scores. We examined whether emergent clusters were associated with neuropathology. Separate analyses of variance and covariance with post-hoc comparisons were performed to examine relevant cluster differences. RESULTS: Analyses revealed significant correlations between ALSFRS-R total and subdomain scores with some, but not all, neuropathological variables. The HCA illustrated three groups: Cluster 1-predominantly diffuse functional impairment; Cluster 2-spared respiratory/bulbar and impaired motor function; and Cluster 3-spared bulbar and impaired respiratory, and fine and gross motor function. Individuals in Cluster 1 (and to a lesser degree, Cluster 3) exhibited greater accumulation of ALS-specific neuropathology and less comorbid neuropathology than those in Cluster 2. DISCUSSION: These results suggest that discrete patterns of motor dysfunction based on ALSFRS-R subdomain scores are related to postmortem neuropathology. Findings support use of ALSFRS-R subdomain scores to capture the heterogeneity of clinical presentation and disease progression in ALS, and may assist researchers in identifying endophenotypes for separate assessment in clinical trials.

Late-onset stress symptomatology (LOSS) scale - short form: development and validation.

Objectives: Late-onset stress symptomatology (LOSS) is a phenomenon observed in older combat veterans who experience increased combat-related thoughts, feelings, and reminiscences corresponding with the changes and challenges of aging. Previously, we developed the LOSS Scale to assess LOSS. This paper describes the development and validation of a LOSS Scale short form (LOSS-SF) to screen veterans in various settings who may be actively re-examining their past wartime experiences. Method: Three studies examined the reliability and validity of the LOSS-SF in separate samples of male combat veterans age 55 and older (total N = 346). Veterans were administered measures via telephone and mail survey. Correlation and regression analyses examined the reliability and validity of the LOSS-SF. Results: The LOSS-SF exhibited strong internal consistency (alpha = .93), test-retest reliability (2 week interval on average; r = .88), and good concurrent validity with the LOSS Scale (r = .81). Convergent and divergent validity were supported by the pattern of correlations between the LOSS-SF and other construct measures. Conclusion: The LOSS-SF is a reliable and valid measure to quickly assess thoughts, feelings, and reminiscences about past combat experiences in older veterans and identify those veterans in distress who may benefit from psychological interventions..

VA's National PTSD Brain Bank: a National Resource for Research.

The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function.

Do appraisals of military service indicate current distress in aging Vietnam War combat veterans?

OBJECTIVE: Appraisals of military service, both desirable and undesirable, assessed via Elder and Clipp's (1989) scale, are associated with psychological distress in veterans. Aging combat veterans (CV) are at increased risk for posttraumatic stress disorder and other psychological disorders yet may underreport symptoms and not seek treatment that could be beneficial. It is unknown whether desirable and undesirable appraisals of military service are associated with mental health outcomes above and beyond typical risk and protective factors, such as age, education, and combat exposure. Therefore, we examined associations between appraisals of military service and assessments of psychological distress in Vietnam War CV, currently the largest cohort of aging veterans. METHOD: Male Vietnam War CV aged 60 and older (n = 134) were selected from a larger study. Regression analyses examined the associations between appraisals of military service and measures of physical and psychological well-being and distress. RESULTS: Both desirable and undesirable appraisals of military service exhibited associations with measures of psychological distress, with undesirable appraisals being more strongly associated with distress than desirable appraisals. In regression analyses, appraisals were related to mental health outcomes over and above covariates. In addition, appraisals were more strongly related to psychological versus physical well-being measures, with undesirable appraisals more strongly related to mental health and well-being measures than desirable appraisals. CONCLUSION: Assessing appraisals of military service may identify veterans experiencing psychological distress who may benefit from referral for psychological interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Distinguishing late-onset stress symptomatology from posttraumatic stress disorder in older combat veterans.

OBJECTIVE: To assess the discriminant validity of late-onset stress symptomatology (LOSS) in terms of its distinction from posttraumatic stress disorder (PTSD). METHOD: The LOSS Scale, PTSD Checklist - Civilian Version, and related psychological measures were administered to 562 older male combat veterans via a mailed questionnaire. Analyses focused on: (a) comparing associations of LOSS and PTSD with other psychological variables and (b) examining a hypothesized curvilinear relationship between LOSS and PTSD scores. RESULTS: Compared to PTSD, LOSS was more strongly associated with concerns about retirement and less strongly associated with depression, anxiety, sense of mastery, and satisfaction with life. LOSS also demonstrated a curvilinear relationship with PTSD, such that the positive association between LOSS and PTSD diminished at higher levels of PTSD. CONCLUSION: LOSS is conceptually and statistically more strongly associated with a normative late-life stressor than is PTSD, but is less strongly related to mental health symptoms and emotional well-being. Additionally, LOSS seems more related to subthreshold PTSD than it is to clinically significant PTSD. The present findings support the discriminant validity of LOSS.

MicroRNA Alterations in Chronic Traumatic Encephalopathy and Amyotrophic Lateral Sclerosis.

Repetitive head impacts (RHI) and traumatic brain injuries are risk factors for the neurodegenerative diseases chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). ALS and CTE are distinct disorders, yet in some instances, share pathology, affect similar brain regions, and occur together. The pathways involved and biomarkers for diagnosis of both diseases are largely unknown. MicroRNAs (miRNAs) involved in gene regulation may be altered in neurodegeneration and be useful as stable biomarkers. Thus, we set out to determine associations between miRNA levels and disease state within the prefrontal cortex in a group of brain donors with CTE, ALS, CTE + ALS and controls. Of 47 miRNAs previously implicated in neurological disease and tested here, 28 (60%) were significantly different between pathology groups. Of these, 21 (75%) were upregulated in both ALS and CTE, including miRNAs involved in inflammatory, apoptotic, and cell growth/differentiation pathways. The most significant change occurred in miR-10b, which was significantly increased in ALS, but not CTE or CTE + ALS. Overall, we found patterns of miRNA expression that are common and unique to CTE and ALS and that suggest shared and distinct mechanisms of pathogenesis.

The Department of Veterans Affairs Gulf War Veterans' Illnesses Biorepository: Supporting Research on Gulf War Veterans' Illnesses.

AIMS: To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans' Illnesses Biorepository (GWVIB). METHODS: Gulf War era veterans (GWVs) are recruited nationally and enrolled via telephone and email/postal mail. Enrolled veterans receive annual telephone and mail follow-up to collect health data until their passing. A postmortem neuropathological examination is performed, and fixed and frozen brain and spinal cord samples are banked to support research. Investigators studying GWI and related disorders may request tissue and data from the GWVIB. RESULTS: As of September 2021, 127 GWVs from 39 states were enrolled; 60 met the criteria for GWI, and 14 met the criteria for chronic multisymptom illness (CMI). Enrollees have been followed up to six years. Postmortem tissue recoveries were performed on 14 GWVs. The most commonly found neuropathologies included amyotrophic lateral sclerosis, chronic traumatic encephalopathy, and Lewy body disease. Tissue was of good quality with an average RNA integrity number of 5.8 (SD = 1.0) and ≥4.8 in all of the cases. DISCUSSION: The availability of health data and high-quality CNS tissue from this well-characterized GWV cohort will support research on GWI and related disorders affecting GWVs. Enrollment is ongoing.

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Neuropathological profile of long-duration amyotrophic lateral sclerosis in military Veterans.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long-duration (≥10 years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long-duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.

Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study.

BACKGROUND: Individuals with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) have high plasma total homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: A substudy of 659 patients (mean age, 67.3 +/- 11.7 years) who participated in a randomized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level. 236 (35.8%) were treated by using dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less (advanced CKD). All had high tHcy levels (> or =15 micromol/L) at baseline. Cognitive assessments began during the follow-up period of the main trial 3 years after treatment began; participants subsequently were retested 1 year later to assess cognitive change. INTERVENTION: Daily high-dose B vitamin capsule (40 mg of folic acid, 100 mg of vitamin B(6), and 2 mg of vitamin B(12)) or placebo. OUTCOMES: Cognitive function at initial assessment and 1 year later. MEASUREMENTS: Telephone Interview of Cognitive Status-modified, supplemented with attention, working memory, and executive function tests. RESULTS: Initial cognitive function was impaired in approximately 19% of patients regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment decreased tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later. LIMITATIONS: Cognitive assessments began after treatment was initiated; cognitive assessment was limited. CONCLUSION: Treatment with high daily doses of B vitamins, which decreased tHcy levels, did not affect cognitive outcomes in patients with advanced CKD and ESRD.

Chronic Traumatic Encephalopathy Within an Amyotrophic Lateral Sclerosis Brain Bank Cohort.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive head impacts and has been associated with amyotrophic lateral sclerosis (ALS), a fatal, degenerative neuromuscular disorder. The Department of Veterans Affairs Biorepository Brain Bank (VABBB) is a tissue repository that collects antemortem disease progression data and postmortem central nervous system tissue from veterans with ALS. We set out to determine the frequency of co-morbid ALS and CTE in the VABBB cohort and to characterize the clinical, genetic, and pathological distinctions between participants with ALS only and those with both ALS and CTE (ALS+CTE). Of 155 participants, 9 (5.8%) had neuropathologically confirmed ALS+CTE. Participants with ALS+CTE were more likely to have a history of traumatic brain injury (p < 0.001), served during the first Persian Gulf War (p < 0.05), and to have more severe tau pathology within the frontal cortex and spinal cord (p < 0.05). The most common exposures to head impacts included contact sports (n = 5) and military service (n = 2). Clinically, participants with ALS+CTE were more likely to have bulbar onset ALS (p = 0.006), behavioral changes (p = 0.002), and/or mood changes (p < 0.001). Overall, compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation.

Effects of age and hypertension status on cognition: the Veterans Affairs Normative Aging Study.

The authors examined the influence of age and hypertensive status (normotensive, controlled, untreated, or uncontrolled) on several cognitive tests via multiple regression in 357 nondemented, community-dwelling older men (mean age=67 years) whose hypertensive status was stable over 3 years and who had no medical comorbidities. Age was negatively associated with performance on all but 1 test. Age interacted with hypertensive status on verbal fluency and word list immediate recall; older uncontrolled hypertensives exhibited significantly larger age decrements on these tests compared with normotensives. These findings suggest that uncontrolled hypertension produces specific cognitive deficits beyond those attributable to age alone. These and previous findings illustrate that health conditions such as hypertension should be regularly considered in studies of "normal" cognitive aging.

The Department of Veterans Affairs Biorepository Brain Bank: a national resource for amyotrophic lateral sclerosis research.

Our objective was to describe a unique national resource to facilitate amyotrophic lateral sclerosis (ALS) research, the Department of Veterans Affairs Biorepository Brain Bank. Enrolled veterans receive biannual telephone follow-up to collect clinical data until death including the ALS Functional Rating Scale-Revised (ALSFRS-R). A comprehensive post mortem examination is performed and a wide range of fixed and frozen brain and spinal cord samples are banked. As of December 2012, 240 veterans were enrolled from 47 states and post mortem tissue recoveries were performed on 100 veterans from 37 states. Average disease duration was 13.5 (range 3-45) years. Average follow-up for living subjects was 3.1 years and average ALSFRS-R score was 23.5 compared to 25.9 (12-24 months earlier), indicating slow disease progression. ALS was confirmed by post mortem examination in 97% of cases. Eighty-six percent of cases were TDP-43-positive. Additional neuropathological diagnoses include Lewy body disease (13%), frontotemporal lobar degeneration (6.3%), chronic traumatic encephalopathy with motor neuron disease (3.2%), and Alzheimer's disease (2.1%). Tissue RIN values were ≥ 4.0 in 88% of cases. In conclusion, the availability of high quality fixed and frozen CNS tissue from this well characterized cohort is an important resource to facilitate research into genetic and environmental risk factors and clinical pathological relationships in ALS.

Integrating health into cognitive aging: toward a preventive cognitive neuroscience of aging.

OBJECTIVES: We argue that age is a descriptive, and not explanatory, variable and consequently cannot account for the cognitive changes that often occur with aging. Once age is removed from consideration, other truly causal explanations for "cognitive aging" must be identified. We argue that health and disease represent an important class of explanatory variables for age-related cognitive changes. METHODS/RESULTS: We make this argument first by reviewing the prevalence of risk factors, disability, and subclinical and frank disease in the elderly population. We emphasize that the complexity of health effects rivals that of age on cognition while noting that most studies of cognitive aging rarely consider this complexity fully. We then consider in more detail the "vascular hypothesis," which proposes that vascular diseases (e.g., stroke, heart disease) and their risk factors (e.g., hypertension) can explain aspects of cognitive decline in aging through their impact on circulatory and brain functions. Clinical implications of this hypothesis suggest that treatment of vascular risk factors might well reduce the incidence or severity of dementia syndromes. DISCUSSION: We conclude with a brief summary of approaches to further integrate aspects of health and disease into the study of "cognitive aging."

Effects of health status on word finding in aging.

OBJECTIVES: To evaluate effects of health status on word-finding difficulty in aging, adjusting for the known contributors of education, sex, and ethnicity. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Two hundred eighty-four adults aged 55 to 85 (48.6% female) participating in an ongoing longitudinal study of language in aging. MEASUREMENTS: Medical, neurological, and laboratory evaluations to determine health status and presence or absence of hypertension and diabetes mellitus. Lexical retrieval evaluated with the Boston Naming Test (BNT) and Action Naming Test. RESULTS: Unadjusted regression models showed that presence of diabetes mellitus was not related to naming. Presence of hypertension was associated with significantly lower accuracy on both tasks (P<.02). Adjustment for demographics attenuated the effect of hypertension (P<.08). For the BNT, a variable combining presence, treatment, and control of hypertension was marginally significant (P<.10), with subjects with uncontrolled hypertension being least accurate (91.4%). Previously observed findings regarding the effects of age, education, sex, and ethnicity were confirmed. CONCLUSION: In this sample of older adults, hypertension contributed to the word-finding difficulty of normal aging, but diabetes mellitus did not.