Rebecca J. Melrose

The neural correlates of naming and fluency deficits in Alzheimer’s disease: an FDG-PET study

To examine the neural processes associated with language deficits in Alzheimers disease (AD), and in particular to elucidate the correlates of confrontation naming and word retrieval impairments.

Neuropsychological and neuroimaging markers in early versus late-onset Alzheimer's disease.

Background: Early-onset Alzheimer’s disease (EOAD) has been overshadowed by the more common late-onset AD (LOAD). Yet, the literature indicates EOAD may have less hippocampal-memory presentations and more focal neocortical localization early in the disease. Objective: To evaluate these proposed differences between these 2 forms of AD and to explore what they inform about differences in AD pathophysiology. Methods: In all, 21 patients with EOAD and 24 patients with LOAD matched for disease progression and severity were compared on neurocognitive measures and resting state fluorodeoxy-glucose positron–emission tomography (FDG-PET). Results: Patients with EOAD had worse executive functions with greater hypometabolism in the parietal regions; whereas patients with LOAD had worse confrontation naming and verbal recognition memory with greater hypometabolism in inferior frontotemporal regions. Conclusions: In addition to highlighting significant differences between EOAD and LOAD, these results reveal dissociation between executive deficits in AD and frontal hypometabolism, suggesting early disturbances of the parietal–frontal network in EOAD.

Cerebral metabolism, cognition, and functional abilities in Alzheimer disease.

Patients with Alzheimer disease (AD) exhibit profound difficulties in completing instrumental activities of daily living (IADLs), such as managing finances, organizing medications, and food preparation. It is unclear which brain areas underlie IADL deficits in AD. To address this question, we used voxel-based analysis to correlate the performance of IADLs with resting cerebral metabolism as measured during [18F] fluorodeoxyglucose–positron emission tomography (FDG-PET) imaging in 44 patients with AD. Poorer ability to complete IADLs was associated with hypometabolism in right-sided cortical regions, including the parietal lobe, posterior temporal cortex, dorsolateral prefrontal cortex, and frontal pole. Follow-up path analyses examining anatomically defined regions of interest (ROI) demonstrated that the association between metabolism and IADLs was mediated by global cognition in frontal ROIs, and partially mediated by global cognition in the parietal ROI. Findings suggest that hypometabolism of right sided brain regions involved in executive functioning, visuospatial processing, attention, and working memory underlie functional impairments in patients with AD.

Executive deficits and regional brain metabolism in Alzheimer's disease.

Executive deficits are common in patients with Alzheimers disease (AD), contribute prominently to clinical disability, and may be associated with frontal lobe pathology. This study examined regional brain hypometabolism associated with executive dysfunction in patients with AD.

Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances

Individuals suffering from Alzheimers disease (AD) often have impaired awareness or a lack of insight into their cognitive deficits and functional abilities, especially in the later stages of the disease. Previous research has documented a relationship between depression and insight in AD, such that greater awareness of ones disease has been associated with a higher degree of depression. However, little is known about the relationship between insight, cognitive decline, and other psychiatric or behavioral problems associated with AD.

Life Experience and Demographic Influences on Cognitive Function in Older Adults

OBJECTIVE We examined the influence of a broad spectrum of life experiences on longitudinal cognitive trajectories in a demographically diverse sample of older adults. METHOD Participants were 333 educationally, ethnically, and cognitively diverse older adults enrolled in a longitudinal aging study. Mixed-effects regression was used to measure baseline status in episodic memory, executive functioning, and semantic memory and change in a global cognition factor defined by change in these 3 domain-specific measures. We examined effects of life experience variables (literacy, childhood socioeconomic status, morphometric measures of physical development, life course physical and recreational activity) on longitudinal cognitive trajectories, covarying for age, apolipoprotein E (APOE) genotype and demographics (education, ethnicity, language). RESULTS Non-Latino Whites had higher baseline cognition, but life experience variables attenuated ethnic differences in cognitive scores. Age, literacy, childhood socioeconomic status, and physical activity significantly influenced baseline cognition. Age, APOE ε4, and decline in intellectually and socially stimulating recreational activity from mid to late life were independently associated with increased late life cognitive decline. Higher literacy and late life recreational activity were associated with less decline. Literacy had similar effects for English and Spanish readers/speakers. Bilingual English and Spanish speakers did not differ from English Speakers in cognitive performance. CONCLUSIONS Life experience variables, especially literacy level, were strongly related to baseline cognition and substantially attenuated effects of race/ethnicity and education. Cognitive change was best explained by age, APOE ε4, literacy, and current recreational activities. Literacy had robust associations with baseline cognition and cognitive change in both English and Spanish speakers.

An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer’s disease

Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer’s disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics – fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter – the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia.

Early Life Development in a Multiethnic Sample and the Relation to Late Life Cognition

OBJECTIVES Poor quality of early life conditions has been associated with poorer late life cognition and increased risk of dementia. Early life physical development can be captured using adult measures of height and head circumference. Availability of resources may be reflected by socioeconomic indicators, such as parental education and family size. We sought to determine the association between early life development and experience and late life semantic memory, episodic memory, and executive functioning abilities, as well as rate of cognitive decline. METHOD This study was conducted using the UC Davis Aging Diversity cohort, an ethnically diverse sample of Caucasian, African American, and Hispanic individuals from northern California. We used latent variable modeling to measure growth and childhood socioeconomic environment (SES) and examine their associations with longitudinal cognitive outcomes using mixed effects modeling. RESULTS Growth was positively related to higher childhood SES. Higher childhood SES was associated with better semantic memory. Both low growth and low SES were associated with increased rate of cognitive decline. DISCUSSION These findings demonstrate that early life experiences influence the trajectory of cognitive aging. Early life development and experience appears to provide a distal basis upon which additional risk and protective factors interact in the development of dementia.

Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

OBJECTIVE Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This studys goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. METHODS In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. (18)F-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. RESULTS Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. CONCLUSION Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

Differences in Anxiety Among Patients With Early- Versus Late-Onset Alzheimer’s Disease

The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimers disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD.