Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer's disease.

Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.

Amyloid burden, neuronal function, and cognitive decline in middle-aged adults at risk for Alzheimer's disease.

The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer's disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 "Decliners" and 101 "Stables") enrolled in the Wisconsin Registry for Alzheimer's Prevention who underwent multimodality neuroimaging [11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional magnetic resonance imaging (fMRI)] 5.7 ± 1.4 years (range = 2.9-8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p = .027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p's<.05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82 ± .05, p < .001), the BVMT-R Delayed Recall (.73 ± .06, p = .001), and the Reading subtest from the Wide-Range Achievement Test-III (.72 ± .06, p = .002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically pivotal role in forecasting future cognitive course than is currently presumed.

External Validity of the New York University Caregiver Intervention: Key Caregiver Outcomes Across Multiple Demonstration Projects.

Purpose of the Study: The Administration on Aging funded six New York University Caregiver Intervention (NYUCI) demonstration projects, a counseling/support intervention targeting dementia caregivers and families. Three sites (Georgia, Utah, Wisconsin) pooled data to inform external validity in nonresearch settings. This study (a) assesses collective changes over time, and (b) compares outcomes across sites on caregiver burden, depressive symptoms, satisfaction with social support, family conflict, and quality of life. Design and Methods: Data included baseline/preintervention (N = 294) and follow-up visits (approximately 4, 8, 12 months). Results: Linear mixed models showed that social support satisfaction increased (p < .05) and family conflict decreased (p < .05; Cohen's d = 0.49 and 0.35, respectively). Marginally significant findings emerged for quality of life increases (p = .05) and burden decreases (p < .10). Depressive symptoms remained stable. Slopes did not differ much by site. Implications: NYUCI demonstrated external validity in nonresearch settings across diverse caregiver samples.

Connected Language in Late Middle-Aged Adults at Risk for Alzheimer's Disease.

Connected language is often impaired among people with Alzheimer's disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures. Participants were 39 pMCI and 39 cognitively healthy (CH) adults drawn from the Wisconsin Registry for Alzheimer's Prevention, who were matched for age, literacy, and sex. Participants completed a connected language task in which they described the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Language samples were analyzed across three language domains: content, syntactic complexity, and speech fluency. Paired t-tests were used to compare CH and pMCI groups on all variables, and Cohen's d effect sizes were calculated for each comparison. The CH and pMCI groups differed significantly on measures of content (e.g., CH group produced more semantic units, more unique words and had larger idea density, on average, than the pMCI group). The picture description findings are consistent with previous retrospective studies showing semantic language differences in adults with autopsy-confirmed AD. Given that these comparisons are between cognitively healthy and pMCI individuals (before a clinical MCI diagnosis), these findings may represent subtle language difficulty in spontaneous speech, and may be predictive of larger language changes over time.

Verbal Fluency and Early Memory Decline: Results from the Wisconsin Registry for Alzheimer's Prevention.

This study examined the relationship between phonemic and semantic (category) verbal fluency and cognitive status in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort enriched for family history of Alzheimer's disease. Participants were 283 WRAP subjects (age 53.1[6.5] years at baseline); who had completed three waves of assessment, over ∼6 years and met psychometric criteria either for "cognitively healthy" (CH) or for psychometric amnestic mild cognitive impairment (aMCI) using an approach that did not consider fluency scores. CH and aMCI groups differed significantly on phonemic total scores, category total scores, phonemic switching, and category mean cluster size. These results suggest that measures of both phonemic and semantic fluency yield lower scores in persons with evidence of psychometric aMCI compared with those who are CH. Differences have not previously been reported in a group this young, and provide evidence for the importance of including multiple verbal fluency tests targeting preclinical Alzheimer's disease.

Participation in cognitively-stimulating activities is associated with brain structure and cognitive function in preclinical Alzheimer's disease.

This study tested the hypothesis that frequent participation in cognitively-stimulating activities, specifically those related to playing games and puzzles, is beneficial to brain health and cognition among middle-aged adults at increased risk for Alzheimer's disease (AD). Three hundred twenty-nine cognitively normal, middle-aged adults (age range, 43.2-73.8 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP) participated in this study. They reported their current engagement in cognitive activities using a modified version of the Cognitive Activity Scale (CAS), underwent a structural MRI scan, and completed a comprehensive cognitive battery. FreeSurfer was used to derive gray matter (GM) volumes from AD-related regions of interest (ROIs), and composite measures of episodic memory and executive function were obtained from the cognitive tests. Covariate-adjusted least squares analyses were used to examine the association between the Games item on the CAS (CAS-Games) and both GM volumes and cognitive composites. Higher scores on CAS-Games were associated with greater GM volumes in several ROIs including the hippocampus, posterior cingulate, anterior cingulate, and middle frontal gyrus. Similarly, CAS-Games scores were positively associated with scores on the Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility domains. These findings were not modified by known risk factors for AD. In addition, the Total score on the CAS was not as sensitive as CAS-Games to the examined brain and cognitive measures. For some individuals, participation in cognitive activities pertinent to game playing may help prevent AD by preserving brain structures and cognitive functions vulnerable to AD pathophysiology.

Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-aged adults at risk for AD.

BACKGROUND: Subjective memory complaints (SMCs) represent an individual's perception of subtle changes in memory in the absence of objective impairment in memory. However, it is not fully known whether persons with SMCs harbor brain alterations related to Alzheimer's disease (AD) or whether they indeed demonstrate poorer cognitive performance. METHODS: Participants were 261 middle-aged adults (mean age=54.30 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention, a registry of cognitively normal adults at risk for AD. They answered a question pertaining to subjective memory, completed a comprehensive neuropsychological exam, and subsequently underwent a volumetric MRI scan. Cortical thickness measurements were derived from 10 a priori regions of interest involved in AD. Analyses of covariance were conducted to investigate group differences in cortical thickness and neuropsychological measures. RESULTS: Compared with individuals without SMCs, individuals with SMCs had significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume. Similarly, those with SMCs had significantly lower test scores on measures of Immediate Memory, Verbal Learning & Memory, and Verbal Ability. Additional adjustment for depressive symptoms (which differed between the groups) attenuated only the findings for the entorhinal cortex (p=.061) and Verbal Ability (p=.076). CONCLUSIONS: At-risk, cognitively healthy individuals with SMCs exhibit cortical thinning in brain regions affected by AD as well as poorer performance on objective memory tests. These findings suggest that, in some individuals, SMCs might represent the earliest stages of AD.

Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer's disease.

Cardiorespiratory fitness (CRF) is an objective measure of habitual physical activity (PA), and has been linked to increased brain structure and cognition. The gold standard method for measuring CRF is graded exercise testing (GXT), but GXT is not feasible in many settings. The objective of this study was to examine whether a non-exercise estimate of CRF is related to gray matter (GM) volumes, white matter hyperintensities (WMH), cognition, objective and subjective memory function, and mood in a middle-aged cohort at risk for Alzheimer's disease (AD). Three hundred and fifteen cognitively healthy adults (mean age =58.58 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent structural MRI scanning, cognitive testing, anthropometric assessment, venipuncture for laboratory tests, and completed a self-reported PA questionnaire. A subset (n = 85) underwent maximal GXT. CRF was estimated using a previously validated equation incorporating sex, age, body-mass index, resting heart rate, and self-reported PA. Results indicated that the CRF estimate was significantly associated with GXT-derived peak oxygen consumption, validating its use as a non-exercise CRF measure in our sample. Support for this finding was seen in significant associations between the CRF estimate and several cardiovascular risk factors. Higher CRF was associated with greater GM volumes in several AD-relevant brain regions including the hippocampus, amygdala, precuneus, supramarginal gyrus, and rostral middle frontal gyrus. Increased CRF was also associated with lower WMH and better cognitive performance in Verbal Learning & Memory, Speed & Flexibility, and Visuospatial Ability. Lastly, CRF was negatively correlated with self- and informant-reported memory complaints, and depressive symptoms. Together, these findings suggest that habitual participation in physical activity may provide protection for brain structure and cognitive function, thereby decreasing future risk for AD.

Amyloid burden, cortical thickness, and cognitive function in the Wisconsin Registry for Alzheimer's Prevention.

There is a growing interest in understanding how amyloid-ß (Aß) accumulation in preclinical Alzheimer's disease relates to brain morphometric measures and cognition. Existing investigations in this area have been primarily conducted in older cognitively-normal (CN) individuals. Therefore, not much is known about the associations between Aß burden, cortical thickness, and cognition in midlife. We examined this question in 109, CN, late-middle-aged adults (mean age=60.72±5.65 years) from the Wisconsin Registry for Alzheimer's Prevention. They underwent Pittsburgh Compound B (PiB) and anatomical magnetic resonance (MR) imaging, and a comprehensive cognitive exam. Blinded visual rating of the PiB scans was used to classify the participants as Aß+ or Aß-. Cortical thickness measurements were derived from the MR images. The Aß+ group exhibited significant thinning of the entorhinal cortex and accelerated age-associated thinning of the parahippocampal gyrus compared with the Aß- group. The Aß+ group also had numerically lower, but nonsignificant, test scores on all cognitive measures, and significantly faster age-associated cognitive decline on measures of Speed & Flexibility, Verbal Ability, and Visuospatial Ability. Our findings suggest that early Aß aggregation is associated with deleterious changes in brain structure and cognitive function, even in midlife, and that the temporal lag between Aß deposition and the inception of neurodegenerative/cognitive changes might be narrower than currently thought.

The APO E4 allele and cognition in New Mexico Hispanic elderly.

OBJECTIVE: To determine if the apolipoprotein E E4 (APO E4) allele is associated with cognitive performance in New Mexico Hispanic elderly. METHOD: We performed a cross-sectional survey of 105 community volunteers, aged 60 years and older, born in New Mexico, with both parents of Hispanic descent. Subjects were excluded for medical conditions that could influence cognitive performance. We also performed a longitudinal analysis on 18 participants who were re-tested over a 3-year interval. The main outcome measures for both the cross-sectional and longitudinal analysis were scores on 5 cognitive tests comparing subjects with the E4 allele to those without the E4 allele. RESULTS: The mean age was 69 years, with a range of 60 to 91. For the cross-sectional analysis, there were no significant differences between the 2 groups on the cognitive tests, although subjects with an E4 allele did not perform as well on color trails A (P=.09). In the longitudinal analysis we found that the variability of cognitive test scores tended to be higher in the E4 group on most cognitive measures. The time needed to complete color trails A (indicating slower performance) was significantly greater (P<.05) in the E4 group. For the total recall portion of the Fuld Object Memory test, the E4 group did not perform as well on follow-up (P=.08). CONCLUSION: We found no significant cross-sectional association between the APO E4 allele and cognitive performance. In our longitudinal analysis, the time needed to complete color trails A was significantly greater in the E4 group, and the E4 group did not perform as well on total recall.

Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function.

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.

Physical activity attenuates age-related biomarker alterations in preclinical AD.

OBJECTIVE: To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults. METHODS: Three hundred seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention underwent T1 MRI; a subset also underwent (11)C-Pittsburgh compound B-PET (n = 186) and (18)F-fluorodeoxyglucose-PET (n = 152) imaging. Participants' responses on a self-report measure of current physical activity were used to classify them as either physically active or physically inactive based on American Heart Association guidelines. They also completed a comprehensive neuropsychological battery. Covariate-adjusted regression analyses were used to test whether the adverse effect of age on imaging and cognitive biomarkers was modified by physical activity. RESULTS: There were significant age × physical activity interactions for ß-amyloid burden (p = 0.014), glucose metabolism (p = 0.015), and hippocampal volume (p = 0.025) such that, with advancing age, physically active individuals exhibited a lesser degree of biomarker alterations compared with the physically inactive. Similar age × physical activity interactions were also observed on cognitive domains of Immediate Memory (p = 0.042) and Visuospatial Ability (p = 0.016). In addition, the physically active group had higher scores on Speed and Flexibility (p = 0.002) compared with the inactive group. CONCLUSIONS: In a middle-aged, at-risk cohort, a physically active lifestyle is associated with an attenuation of the deleterious influence of age on key biomarkers of AD pathophysiology. However, because our observational, cross-sectional design cannot establish causality, randomized controlled trials/longitudinal studies will be necessary for determining whether midlife participation in structured physical exercise forestalls the development of AD and related disorders in later life.

Low cerebral blood flow is associated with lower memory function in metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS)--a cluster of cardiovascular risk factors--is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle-aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed. DESIGN AND METHODS: Late middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention (N = 69, mean age = 60.4 years) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on three or more factors, including abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose. RESULTS: Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF. CONCLUSIONS: The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population.

Children of persons with Alzheimer disease: what does the future hold?

Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

What does the WMS-III tell us about memory changes with normal aging?

The standardization sample from the WMS-III (N = 1250), which varied in age from 16 to 89, was used to determine whether encoding, retrieval, or storage of verbal and spatial information was most affected by normal aging. Immediate and delayed recall and recognition of Logical Memory and Visual Reproduction were examined. Immediate verbal and spatial recall significantly deteriorated with increasing age, and the age-associated deterioration in delayed recall and recognition was largely explained by poorer immediate memory. These findings, in concert with the smaller aging effects for percent retention after a delay, suggest that the aging effect is due to deterioration in encoding more than retrieval or storage of new information. While Visual Reproduction deteriorated more rapidly with age than Logical Memory, the pattern of performance decrements as a function of age were comparable across both tests. Decreases in performance were first seen in the fifth decade with gradual deterioration until the eighth decade when there was another precipitous drop. These results suggest that functions that are more dependent on the frontal lobes are more vulnerable to aging than those that are more dependent on the temporal lobes.