Christopher B. Brady

Distinguishing Between Neurodegenerative Disease and Disease-Free Aging: Correlating Neuropsychological Evaluations and Neuropathological Studies in Centenarians

Objective In an examination of disease-free aging and neurodegenerative disease in 100-year-olds, the New England Centenarian Study compared data from neuropsychological evaluations with postmortem brain studies of fourteen 100-year-olds to ascertain if the presence or absence of Alzheimer disease changes correlated with measured cognitive abilities. Methods Fourteen of 74 centenarians who underwent annual extensive neuropsychological evaluation proceeded to postmortem neuropathological examination. CERAD criteria, emphasizing neuritic amyloid plaques and Braak and Braak staging of neurofibrillary tangles were used to assess the 14 brains. Results Neuropsychological and neuropathological findings correlated well for four subjects with no dementia on testing (CDR = 0) and for six subjects with CDR scores in the dementia range (CDR = 1–5). In the latter group, Alzheimer’s disease was diagnosed in four brains; Pick’s disease was an etiological factor in the fifth and hippocampal sclerosis in the sixth. Correlation was low for four subjects: two subjects with no dementia on neuropsychological testing met CERAD neuropathological criteria for possible AD; two subjects with dementia on testing did not meet CERAD criteria for definite Alzheimer’s disease and had otherwise minimal changes to correlate with the cognitive findings. Conclusions Lack of correlation between level of cognitive functioning and brain pathology in two subjects with no dementia raised the question of whether a functional reserve delayed the functional expression of pathological changes. For two subjects with dementia on testing, there appeared to be no sufficient pathological explanation for the extent of the cognitive changes; depression and such factors as environment, sensory impairment, and medical illness may all have played a role. There may also have been neuropathologic changes not detected by current methods.

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.

Original InvestigationPathogenesis and Treatment of Kidney DiseaseHomocysteine 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.

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.

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

Abstract 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 Alzheimers 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.

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.

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.

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.

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

Abstract 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..