Baseline serum brain-derived neurotrophic factor association with future cognition in community-dwelling older adults undergoing annual memory screening.

OBJECTIVES: It has been shown that peripheral measures of brain-derived neurotrophic factor (BNDF), an important neurotrophin instrumental to the biology of learning, may contribute to predicting cognitive decline. However, the two primary forms of BDNF, mature (mBDNF) and pro (proBDNF), and how they contribute to cognition longitudinally has not been well studied. METHODS: Eighty-two older adults (average age 72.2 ± 6.4 years) provided blood samples at two time points separated on average by 4.2 years while participating in an annual memory screening that included the MoCA (Montreal Cognitive Assessment) and GDS (Geriatric Depression Scale). Both mBDNF and proBDNF from serum were quantified at each time point. Whole blood samples were genotyped for APOE and BDNF Val66Met. RESULTS: Using logistic regression analysis controlling for age, sex, baseline MoCA score, APOE, and BDNF, higher baseline mBDNF was associated with subjects whose screening score was near maximum or maximum (as defined by MoCA score of 29 or 30) at the second collection visit. APOE was a significant contributing factor; however, BDNF Val66Met was not. Using a similar logistic regression analysis, baseline proBDNF was not found to be associated with future cognition. DISCUSSION: This study further supports that mBDNF measured in the serum of older adults may reflect a protective role while proBDNF requires further investigation.

Bacopa monnieri supplementation has no effect on serum brain-derived neurotrophic factor levels but beneficially modulates nuclear factor kappa B and cyclic AMP response element-binding protein levels in healthy elderly subjects.

Background and Aim: Bacopa monnieri is an Ayurvedic herb that has been used for multiple conditions, most notably to augment cognition, particularly memory and attention. Multiple mechanisms, including raising brain-derived neurotrophic factor (BDNF), have been proposed and investigated in animal models that require translational studies in humans. Methods: Bacopa was administered in an open-labeled study to cognitively healthy controls over a 3-month period. Cognition and mood were assessed using the Montreal Cognitive Assessment (MoCA) and geriatric depression scale (GDS) at the baseline and 3-month visit. Laboratories were assessed for safety and serum levels of mature (mBDNF) and proBDNF were quantified. In a subset of subjects, intracellular signaling processes were assessed using western blot analysis. Results: Bacopa was provided to 35 subjects and was well-tolerated except for 4 (11%) subjects who early terminated due to known, reversible, and gastrointestinal side effects (i.e., nausea, diarrhea). Over the 3 months, the GDS and the total MoCA did not significantly change; however, the delayed-recall subscale significantly improved (baseline: 3.8 ± 1.2, 3-months: 4.3 ± 0.9; P = 0.032). Serum mBDNF and proBDNF levels did not significantly change. Cyclic AMP response element-binding protein (CREB) phosphorylation significantly increased (P = 0.028) and p65 nuclear factor kappa B (NF-κB) phosphorylation significantly decreased (P = 0.030). Conclusion: These results suggest that Bacopa may exert an anti-inflammatory effect through NF-κB and improve intracellular signaling processes associated with synaptogenesis (CREB). The future placebo-controlled studies are recommended. Relevance for Patients: B. monnieri will require larger, blinded trials to better understand potential mechanisms, interactions, and utilization.

Plasma cytokine IL-6 levels and subjective cognitive decline: preliminary findings.

OBJECTIVE: Detection of Alzheimer's disease (AD) prior to clinical inception will be paramount for introducing disease modifying treatments. We have begun collecting baseline characteristics of a community cohort for longitudinal assessment and testing of antecedent blood-based biomarkers. We describe the baseline visit from the first 131 subjects in relationship to a commonly described cytokine, interleukin 6 (IL-6). METHODS: Subjects from the community presented for a free memory screening with varying degrees of memory concern. We quantified the baseline plasma levels of the cytokine IL-6 and assessed cognition (Montreal Cognitive Assessment, MoCA) and mood (Geriatric Depression Scale, GDS) in relationship to their memory concern. RESULTS: Baseline MoCA scores were inversely related to age, and this association was influenced by an AD risk factor, Apolipoprotein E (APOE4) carrier status. The degree of subjective cognitive decline correlated with GDS and was inversely related to MoCA scores. Interleukin 6 levels were related to age, body mass index, and years of education. CONCLUSIONS: It will be important to assess how these baseline IL-6 levels and forthcoming novel biomarkers relate to future cognitive decline. Copyright © 2017 John Wiley & Sons, Ltd.

Screening by telephone in the Alzheimer's disease anti-inflammatory prevention trial.

Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening. Drawing on results from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples.

Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients--an open-label trial.

BACKGROUND: Evidence suggests that dihydropyridine calcium channel blockers may be useful in preventing and treating Alzheimer's disease (AD). OBJECTIVE: In an open-label trial of safety and tolerability of nilvadipine in patients with AD, we examined cognition and executive function over a short time period to determine an influence of nilvadipine on these outcomes. METHOD: We investigated change in cognition using the Mini mental state examination and in executive function using the EXIT25 in 55 patients with AD who received nilvadipine 8 mg daily for 6 weeks compared with 30 non-treated subjects with AD. Apolipoprotein E genotyping was performed, and the study team and caregivers were kept blinded to APOE ε4 status during the trial. RESULTS: Aside from differences in gender and education, both the treatment and the control groups were similar in general demographics and on baseline cognition status. After correction for potential confounders, APOE ε4 status, and use of other antihypertensive medications, a significant impact of study intervention was observed on MMSE (F = 8.67, p < 0.01) and EXIT (F = 8.77, p < 0.03) scores. An interaction between APOE ε4 carrier status and treatment (p ≤ 0.05) was observed for both outcome measures. CONCLUSION: In this open-label trial, among APOE ε4 non-carriers, we observed stabilization of cognition and improvement in executive function among treated individuals compared with non-treated individuals. Among APOE ε4 carriers, cognitive stabilization was evident for treated individuals whereas a cognitive decline was observed in non-treated individuals. These findings provide additional evidence for potential therapeutic efficacy of nilvadipine in treating AD and warrant further investigation.

Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum ß-Amyloid.

We examined the usefulness of brief neuropsychological tests and serum Aß as a predictive test for detecting MCI/AD in older adults. Serum Aß levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Aß(1-42) and the ratio of serum Aß(1-42)/Aß(1-40) were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE ε4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Aß(1-42) obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline.

Serum beta-amyloid correlates with neuropsychological impairment.

AIMS: Evidence suggests a relationship between peripheral Abeta and AD. We hypothesized that higher levels of serum Abeta(1-42) would be associated with memory impairment, thought to occur early in the disease, and rises in serum Abeta(1-40), which occur later, would be associated with impairment in non-memory measures. METHODS: Using a cross-sectional design, we examined the relationship of serum Abeta(1-40), Abeta(1-42), and the ratio of Abeta(1-42/1-40) to neuropsychological measures in 40 cognitively normal controls, 13 MCI subjects, and 25 AD patients. RESULTS: Serum Abeta(1-42) and the ratio of Abeta(1-42/1-40) were significantly higher in the MCI group compared to the controls. A significant relationship in the hypothesized direction (poorer scores associated with higher Abeta(1-40) serum levels) was found between Abeta(1-40) and measures of executive functions across the entire cohort of individuals tested and with measures of language and processing speed in the AD group. Regression analysis found that neuropsychological measures accounted for 26% of the variance in serum Abeta(1-40,) in the MCI/AD but not the controls. Furthermore that language and executive measures were significant predictors. CONCLUSIONS: Results provide preliminary data to partially support our hypotheses and suggest that changes in serum Abeta levels may be attributed to pathological changes within the brain.

Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US.

OBJECTIVE: Cross validation study of the MoCA for the detection of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) in a community-based cohort residing in the Southeastern United States. METHODS: One hundred and eighteen English-speaking older adults, who underwent diagnostic evaluation as part of an on-going prospective study, were administered the MoCA and MMSE. Twenty were diagnosed with AD, 24 met criteria for amnestic MCI and 74 were considered cognitively normal. Sensitivities and specificities were calculated using the recommended cut-off scores and ROC curve analyses were performed to determine optimal sensitivity and specificity. The influence of age, education and gender on MoCA score was also examined. RESULTS: Using a cut-off score of 24 or below, the MMSE was insensitive to cognitive impairment. Using the recommended cut-off score of 26, the MoCA detected 97% of those with cognitive impairment but specificity was fair (35%). Using a lower cut-off score of 23, the MoCA exhibited excellent sensitivity (96%) and specificity (95%). CONCLUSION: The MoCA appears to have utility as a cognitive screen for early detection of AD and for MCI and warrants further investigation regarding its applicability in primary care settings, varying ethnic groups, and younger at-risk individuals.

Diagnostic utility of APOE, soluble CD40, CD40L, and Abeta1-40 levels in plasma in Alzheimer's disease.

A continuous inflammatory state is associated with Alzheimer's disease (AD) evidenced by an increase in proinflammatory cytokines around beta-amyloid (Abeta) deposits. In addition, functional loss of CD40L is shown to result in diminished Amyloid precursor proton (APP) processing and microglial activation, supporting a prominent role of CD40-CD40L in AD etiology. We therefore hypothesize that a peripheral increase in Abeta may result in corresponding increase of sCD40 and sCD40L further contributing to AD pathogenesis. We measured plasma Abeta, sCD40 and sCD40L levels in 73 AD patients and compared to 102 controls matched on general demographics. We demonstrated that Abeta(1-40), levels of sCD40 and sCD40L are increased in AD and declining MMSE scores correlated with increasing sCD40L, which in turn, correlated positively with Abeta(1-42). We then combined sCD40, sCD40L, Abeta and APOE and found that this biomarker panel has high sensitivity and specificity (>90%) as a predictor of clinical AD diagnosis. Given the imminent availability of potentially disease modifying therapies for AD, a great need exists for peripheral diagnostic markers of AD. Thus, we present preliminary evidence for potential usefulness for combination of plasma sCD40, sCD40L along with Abeta(1-40) and APOE epsilon4 in improving the clinical diagnosis of AD.

Long-term morbidities following self-reported mild traumatic brain injury.

The objective of this study was to examine the prevalence of long-term psychiatric, neurologic, and psychosocial morbidities of self-reported mild traumatic brain injury (MTBI). A cross-sectional cohort sample of three groups was examined: those who had not been injured in a motor vehicle accident nor had a MTBI (n = 3,214); those who had been injured in an accident but did not have a MTBI (n = 539); and those who had a MTBI with altered consciousness (n = 254). Logistic regression analyses were used to model odds ratios for the association between group and outcome variables while controlling demographic characteristics, comorbid medical conditions, and early-life psychiatric problems. Compared with uninjured controls, MTBI increased the likelihood of depression and postconcussion syndrome. MTBI also was associated with peripheral visual imperceptions and impaired tandem gait. Similarly, the MTBI group had poorer psychosocial outcomes including an increased likelihood of self-reported disability, underemployment, low income, and marital problems. Results suggest that MTBI can have adverse long-term psychiatric, neurologic, and psychosocial morbidities.

Neuropsychological comparison of Alzheimer's disease and dementia with lewy bodies.

BACKGROUND/AIMS: The present study examined the patterns of memory and cognitive performance associated with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: A battery of standardized neuropsychological tests was administered to individuals with these disorders as well as to a group of cognitively intact controls. The battery included measures of memory (learning, recall and recognition), language, visuospatial ability, psychomotor speed, executive functioning and mood. All subjects (n = 115) were evaluated at a memory disorder clinic and were diagnosed based on published criteria. RESULTS: The controls outperformed both dementia groups on all cognitive measures. With respect to memory, the DLB group scored significantly higher than the AD group on measures of word list free recall and recognition (p < or = 0.001). In other cognitive domains, the AD group performed significantly better than the DLB group on constructional praxis, sustained attention, phonemic fluency, spatial judgment, psychomotor speed and working memory (all p < or = 0.01). CONCLUSION: These findings support the usefulness of memory and other cognitive test score patterns as in distinguishing AD from DLB, particularly in mild to moderately demented populations that may not present with hallmark symptomology.

Conversion to dementia among two groups with cognitive impairment. A preliminary report.

OBJECTIVE: To determine the conversion rates to dementia in patients diagnosed with mild cognitive impairment (MCI) thought to be caused by incipient Alzheimer's disease (MCI-AD) or with MCI with features of vascular disease (MCI-Vas). METHODS: On the basis of patient history, neurocognitive, neurological and MRI evaluation, 99 patients were diagnosed with MCI-AD and 35 with MCI-Vas. Conversion to dementia over an average of a 2.4 +/- 1.8-year period was determined. RESULTS: Over the follow-up period, 44% converted to dementia, 51.5% remained classified as MCI, and 4.5% were reclassified as cognitively normal. The conversion rate to dementia was significantly faster at 3 years for the MCI-AD (50.5%) than for the MCI-Vas group (25.7%). The neuropsychological test found to best differentiate converters from non-converters was the Fuld-OME, a measure of learning and recall. Age, education, gender or APOE epsilon4 allele frequency did not differentiate converters from non-converters. CONCLUSIONS: MCI-AD and MCI-Vas are clinically meaningful subtypes of MCI that may convert to dementia at different rates. Prospective studies on larger subsets of MCI patients are required to confirm these findings.

Demographic, medical, and psychiatric factors in work and marital status after mild head injury.

OBJECTIVE: To explore factors associated with long-term outcomes of work and marital status in individuals who had experienced a mild head injury (MHI), as well as those who had not. DESIGN: Population-based study using logistical regression analyses to investigate the impact of preinjury characteristics on work and marital status. PARTICIPANTS: Two groups of Vietnam-era Army veterans: 626 who had experienced a MHI an average of 8 years before examination, and 3,896 who had not. MAIN OUTCOME MEASURES: Demographic characteristics, concurrent medical conditions, early life psychiatric problems, loss of consciousness (LOC), and interactions among these variables were used to predict current work and marital status. RESULTS: Multiple variables were associated with work and marital status in the sample with MHI, accounting for approximately 23% and 17% of the variance in these two outcome variables, respectively. In contrast, the same factors accounted for significantly less variance in outcome in the sample without a head injury-13.3% and 9.4% for work and marital status, respectively. CONCLUSIONS: These findings suggest a more potent role for and increased vulnerability to the influence of demographic, medical, and psychiatric factors on outcomes after a MHI. That is, MHI itself moderates the influence of preinjury characteristics on work and marital status. In addition, in those who had a MHI, moderator relationships were found between education and LOC for both work and marital status. Similarly, complex moderator relationships among race, region of residence, and LOC were found for both work and marital status outcomes.

Predictors of postconcussion symptom complex in community dwelling male veterans.

The presence of a persistent postconcussion symptom complex (PPCSC) was examined in a non-referred sample of male veterans with a history of mild head injury and a comparison group without a history of head injury. Hierarchical logistic regression procedures were used to determine possible predictors of PPCSC using variables supported by previous research (i.e., preexisting psychiatric difficulties, demographic and social support variables, and history of an accidental injurious event). Although PPCSC was common in all groups (23% of the total sample), a significantly greater proportion of individuals in the mild head injury with loss of consciousness group (37.2%) had PPCSC compared with three other groups (head injury without loss of consciousness = 26.1%; motor vehicle accident without head injury = 23%; and control = 17.3%). However, the most salient predictors of PPCSC were early life psychiatric difficulties such as anxiety or depression, limited social support, lower intelligence, and interactions among these variables. The predictive value of loss of consciousness was significant, but low (1.4% of unique variance). The findings provide support for the premise that PPCSC is mediated in part by individual resilience, preexisting psychological status, and psychosocial support.

Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank.

Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

Mood and anxiety disorders following pediatric traumatic brain injury: a prospective study.

Studies utilizing standardized instruments for assessing mood and/or anxiety disorders following pediatric traumatic brain injury have seldom been reported in the literature. Previous reports have largely focused on cognitive impairment, behavioral dysfunction, or adaptive functioning, and have typically relied on parental informants. In this study, children hospitalized for mild (N = 42) and moderate/severe (N = 19) brain injury were assessed 6-months postinjury using the Anxiety disorders Module A and the Mood disorders Module C of the Diagnostic Interview Schedule for Children - IV Revision (DISC-IV). The data collected for the brain injury groups were compared to an orthopedic control group (N = 35). The relationship between a new onset mood and/or anxiety disorder (NOD) and injury severity indices was examined. Sequential logistical regression was also utilized to examine the impact of a brain injury, demographic variables, preinjury psychiatric disturbance, development disorders, litigation status and postinjury environmental stress on emotional outcome. Results indicated a relationship between brain injury and NOD. Multivariate analysis demonstrated that postinjury level of stress and severity of brain injury were the most robust predictors of NOD, accounting for 23% of the variance in the model. These results support the premise that the development of a mood and/or anxiety disorder following pediatric head injury is mediated by multiple determinants. The findings suggest that early psychosocial assessment and interventions aimed at increasing a child's coping may attenuate the emotional consequences of pediatric brain injury.