Predictors of Reversion from Mild Cognitive Impairment to Normal Cognition.

BACKGROUND/AIMS: Few studies have examined predictors of reversion from mild cognitive impairment (MCI) to normal cognition. We sought to identify baseline predictors of reversion, using the National Alzheimer's Coordinating Center Uniform Data Set, by comparing MCI individuals who reverted to normal cognition to those who progressed to dementia. METHODS: Participants (n = 1,208) meeting MCI criteria were evaluated at the baseline visit and 3 subsequent annual visits. Clusters of baseline predictors of MCI reversion included demographic/genetic data, global functioning, neuropsychological functioning, medical health/dementia risk score, and neuropsychiatric symptoms. Stepwise logistic regression models identified predictors of MCI reversion per cluster, which were then entered into a final comprehensive model to find overall predictor(s). RESULTS: At 2 years, 175 (14%) reverted to normal cognition, 612 (51%) remained MCI, and 421 (35%) progressed to dementia, with sustained diagnoses at 3 years. Significant variables associated with MCI reversion were younger age, being unmarried, absence of APOE ε4 allele, lower CDR-SOB score, and higher memory/language test scores. CONCLUSION: A relatively sizable proportion of MCI individuals reverted to normal cognition, which is associated with multiple factors previously noted. Findings may enhance MCI prognostic accuracy and increase precision of early intervention studies of dementia.

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline.

PURPOSE: To determine in a large multiethnic cohort the cardiovascular and genetic risk factors associated with smaller volume in the hippocampus, precuneus, and posterior cingulate, and their association with preclinical deficits in cognitive performance in patients younger and older than 50 years. MATERIALS AND METHODS: The institutional review board approved the study and all participants provided written informed consent. Eligible for this study were 1629 participants (700 men and 929 women; mean age, 50.0 years ± 10.2 [standard deviation]) drawn from the population-based Dallas Heart Study who underwent laboratory and clinical analysis in an initial baseline visit and approximately 7 years later underwent brain magnetic resonance imaging with automated volumetry and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Regression analysis showed associations between risk factors and segmental volumes, and associations between these volumes with cognitive performance in participants younger and older than 50 years. RESULTS: Lower hippocampal volume was associated with previous alcohol consumption (standardized estimate, -0.04; P = .039) and smoking (standardized estimate, -0.04; P = .048). Several risk factors correlated with lower total brain, posterior cingulate, and precuneus volumes. Higher total (standardized estimate, 0.06; P = .050), high-density lipoprotein (standardized estimate, 0.07; P = .003), and low-density lipoprotein (standardized estimate, 0.04; P = .037) cholesterol levels were associated with larger posterior cingulate volume, and higher triglyceride levels (standardized estimate, 0.06; P = .004) were associated with larger precuneus volume. Total MoCA score was associated with posterior cingulate volume (standardized estimate, 0.13; P = .001) in younger individuals and with hippocampal (standardized estimate, 0.06; P < .05) and precuneus (standardized estimate, 0.08; P < .023) volumes in older adults. CONCLUSION: Smaller volumes in specific brain regions considered to be early markers of dementia risk were associated with specific cardiovascular disease risk factors and cognitive deficits in a predominantly midlife multiethnic population-based sample. Additionally, the risk factors most associated with these brain volumes differed in participants younger and older than 50 years, as did the association between brain volume and MoCA score.

The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study.

BACKGROUND: Primary prevention of Alzheimer disease and other types of dementia (all-cause dementia) is an important public health goal. Evidence to date is insufficient to recommend any lifestyle change to prevent or delay the onset of dementia. OBJECTIVE: To assess the association between objectively measured midlife cardiorespiratory fitness ("fitness") levels and development of all-cause dementia in advanced age. DESIGN: Prospective, observational cohort study. SETTING: Preventive medicine clinic. PATIENTS: 19 458 community-dwelling, nonelderly adults who had a baseline fitness examination. MEASUREMENTS: Fitness levels, assessed using the modified Balke treadmill protocol between 1971 and 2009, and incident all-cause dementia using Medicare Parts A and B claims data from 1999 to 2009. RESULTS: 1659 cases of incident all-cause dementia occurred during 125 700 person-years of Medicare follow-up (median follow-up, 25 years [interquartile range, 19 to 30 years]). After multivariable adjustment, participants in the highest quintile of fitness level had lower hazard of all-cause dementia than those in the lowest quintile (hazard ratio, 0.64 [95% CI, 0.54 to 0.77]). Higher fitness levels were associated with lower hazard of all-cause dementia with previous stroke (hazard ratio, 0.74 [CI, 0.53 to 1.04]) or without previous stroke (hazard ratio, 0.74 [CI, 0.61 to 0.90]). LIMITATIONS: Dementia diagnoses were based on Medicare claims, and participants generally were non-Hispanic white, healthy, and well-educated and had access to preventive health care. This study evaluated fitness levels, so a specific exercise prescription cannot be generated from results and the findings may not be causal. CONCLUSION: Higher midlife fitness levels seem to be associated with lower hazards of developing all-cause dementia later in life. The magnitude and direction of the association were similar with or without previous stroke, suggesting that higher fitness levels earlier in life may lower risk for dementia later in life, independent of cerebrovascular disease. PRIMARY FUNDING SOURCE: The Cooper Institute; University of Texas Southwestern Medical Center; National Heart, Lung, and Blood Institute; and American Heart Association.

Global brain hypoperfusion and oxygenation in amnestic mild cognitive impairment.

BACKGROUND: To determine if global brain hypoperfusion and oxygen hypometabolism occur in patients with amnestic mild cognitive impairment (aMCI). METHODS: Thirty-two aMCI and 21 normal subjects participated. Total cerebral blood flow (TCBF), cerebral metabolic rate of oxygen (CMRO2), and brain tissue volume were measured using color-coded duplex ultrasonography (CDUS), near-infrared spectroscopy (NIRS), and MRI. TCBF was normalized by total brain tissue volume (TBV) for group comparisons (nTCBF). Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by TCBF. RESULTS: Reductions in nTCBF by 9%, CMRO2 by 11%, and an increase in CVR by 13% were observed in aMCI relative to normal subjects. No group differences in TBV were observed. nTCBF was correlated with CMRO2 in normal controls, but not in aMCI. CONCLUSIONS: Global brain hypoperfusion, oxygen hypometabolism, and neurovascular decoupling observed in aMCI suggest that changes in cerebral hemodynamics occur early at a prodromal stage of Alzheimer's disease, which can be assessed using low-cost and bedside-available CDUS and NIRS technology.

White matter hyperintensities: use of aortic arch pulse wave velocity to predict volume independent of other cardiovascular risk factors.

PURPOSE: To evaluate the relationship between pulse wave velocity (PWV) from the aortic arch and subsequent cerebral microvascular disease independent of other baseline cardiovascular risk factors among the participants in the multiethnic Dallas Heart Study. MATERIALS AND METHODS: Each subject gave written consent to participate in this HIPAA-compliant, institutional review board-approved prospective study. Aortic arch PWV was measured with phase-contrast magnetic resonance (MR) imaging in a population sample (n = 1270) drawn from the probability-based Dallas Heart Study. Seven years later, the volume of white matter hyperintensities (WMHs) was determined from brain MR images. Linear regression was conducted with aortic arch PWV, 15 other cardiovascular risk factors, and age, sex, and ethnicity included as predictors of WMH. The authors implemented a smoothly clipped absolute deviation-penalized variable selection method to evaluate an optimal predictive risk factor model. RESULTS: Aortic arch PWV helped predict WMH volume independent of the other demographic and cardiovascular risk factors (regression coefficient: 0.29; standard error: 0.06; 95% confidence interval: 0.17, 0.42; P < .0001). The optimal predictor variables of subsequent WMH volume adjusted for sex and ethnicity included aortic arch PWV, age, systolic blood pressure, hypertension treatment, and congestive heart failure. The authors estimated that a 1% increase in aortic arch PWV (in meters per second) is related to a 0.3% increase in subsequent WMH volume (in milliliters) when all other variables in the model are held constant. CONCLUSION: Aortic arch PWV measured with phase-contrast MR imaging is a highly significant independent predictor of subsequent WMH volume, with a higher standardized effect than any other cardiovascular risk factor assessed except for age. In an optimal predictive model of subsequent WMH burden, aortic arch PWV provides a distinct contribution along with systolic blood pressure, hypertension treatment, congestive heart failure, and age.

Leptin and cognition.

BACKGROUND: Leptin has been reported to have positive effects on cognition but has not been studied in a population-based sample or stratified by race or gender. METHODS: Leptin and fat mass were measured in 2,731 subjects, including 50% African Americans. Eight years later, subjects were administered the Montreal Cognitive Assessment (MoCA). Demographic factors and baseline measures, including a deficiency in leptin or levels in excess of what was predicted by fat, were investigated to see which predicted cognitive performance. RESULTS: There was a statistical trend for lower leptin levels to be associated with higher cognitive scores. Once stratified by race and gender, excessive leptin was associated with lower MoCA total scores and delayed recall domain score for black men, but white men demonstrated a reverse relationship. CONCLUSION: Excess leptin appears to have differential effects on delayed recall in black and white men.

The relationship of cardiovascular risk factors to Alzheimer disease in Choctaw Indians.

OBJECTIVES: To test the hypothesis that cardiovascular risk factors (CRFs) influence predisposition to and the clinical course of Alzheimer disease (AD), the authors compared Choctaw Indians, a group with known high CRF with white persons with AD. In addition to CRF history, the authors investigated the frequency of apolipoprotein E4 (apoE4) genotype andplasma homocysteine (HC) levels. METHOD: The authors compared 39 Choctaw Indians with AD and 39 Choctaw Indians without AD to 39 white persons with AD with all groups similar in age. CRF history included diabetes, hypertension, high cholesterol or hypolipidemic agent use, or myocardial infarction. The authors also compared plasma HC concentration and apoE4 allele frequency. RESULTS: Choctaw persons with AD differed significantly from white persons with AD in history of hypertension, diabetes, and in HC values but not from Indians without AD. There was a significantly lower apoE4 allele frequency in Choctaw Indian AD than white persons with AD, and both AD groups had an affected first degree relative significantly more often than Indian controls. There was no relationship between the number of CRF and age at onset among Indians or whites, whereas HC concentration was associated with significantly earlier age of onset for Choctaw Indians but not for whites. CONCLUSIONS: This small study suggests that in Choctaw Indians modifiable risk factors may play more of a role in disease pathogenesis than in whites and that nonmodifiable risk factors such as apoE4 may play less of a role.

Luria's three-step test: what is it and what does it tell us?

BACKGROUND: The purpose of this study is to determine if the three-step Luria test is useful for differentiating between cognitive disorders. METHODS: A retrospective record review of performance on the three-step Luria test was conducted on 383 participants from a university-based dementia clinic. The participants ranged in their diagnosis from frontotemporal dementia (FTD; n = 43), Alzheimer disease (AD; n = 153), mild cognitive impairment (MCI; n = 56), and normal controls (NC; n = 131). Performance of the Luria test was graded as normal or abnormal. RESULTS: An abnormal test occurred in 2.3% of NC, 21.4% of MCI, 69.8% of FTD, and 54.9% of AD subjects. The frequency of abnormal tests in all diagnostic groups increased with functional impairment as assessed by the Clinical Dementia Rating scale (CDR). When CDR = 3 (severe), 100% of the FTD and 72.2% of the AD subjects had abnormal Luria tests. CONCLUSIONS: The three-step Luria test distinguished NC and persons with MCI from FTD and AD, but did not distinguish FTD from AD subjects.

Videoconference diagnosis and management of Choctaw Indian dementia patients.

BACKGROUND: This study reports a 5-year experience using videoconference (VC) technology in diagnosing and treating adult members of the Choctaw Nation with symptoms or complaints of cognitive impairment. METHODS: Patients were given the option of a VC session or a face-to-face evaluation in the clinic. Before their VC session, patients underwent neuropsychological testing, Clinical Dementia Rating, Geriatric Depression Scale and Neuropsychiatric Inventory, brain computed tomography, and routine blood tests. Physical observations made by VC included eyesight, hearing, facial expression, gait and station, coordination, tremor, rapid alternating movements, psychomotor activity, and motor tests of executive function. Cogwheeling and rigidity were tested by our on-site nurse, who also obtained vital signs as indicated. RESULTS: Between January 2005 and March 2010, there were 47 clinics, 171 visits, and 85 unique patients. There were 52 new evaluations and 119 follow-up visits. The number of visits ranged from one to eight and the length of follow-up from 1 month to 4.5 years. The no-show rate for all VC sessions in 2009 was 3%, and only two subjects in 5 years refused further VC visits. CONCLUSION: Once cultural barriers are dealt with, VC-based diagnosis and treatment of adults with cognitive disorders who live in remote areas is feasible and well accepted by patients and families.

FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.