Veronica Witte

Prevalence of DSM-5 Mild Neurocognitive Disorder in Dementia-Free Older Adults: Results of the Population-Based LIFE-Adult-Study

OBJECTIVEnThe DSM-5 introduces mild neurocognitive disorder (miNCD) as a syndrome that recognizes the potential clinical importance of acquired cognitive deficits being too mild to qualify for diagnosis of dementia. We provide new empirical data on miNCD including total, age-, and sex-specific prevalence rates; number and types of neurocognitive domains being impaired; and diagnostic overlap with the well-established mild cognitive impairment (MCI) concept.nnnDESIGNnCross-sectional results of an observational cohort study (LIFE-Adult-Study).nnnSETTINGnGeneral population.nnnPARTICIPANTSnA total of 1,080 dementia-free individuals, aged 60-79 years.nnnMEASUREMENTSnWe calculated weighted point prevalence rates with confidence intervals (95% CI) for miNCD and analyzed diagnostic overlap between miNCD and MCI by calculating overall percentage agreement and Cohens kappa coefficient.nnnRESULTSnWeighted total prevalence of miNCD was 20.3% (95% CI: 17.8-23.0). Prevalence was similar in both sexes, but significantly higher in older age. Two-thirds (66.2%) of the individuals with miNCD showed impairment restricted to only one out of six possible neurocognitive domains. Learning and memory was the most frequently (38.3%) impaired domain in all miNCD-cases, followed by social cognition (26.1%). Analysis of diagnostic overlap with MCI yielded an overall agreement of 98.6% and a kappa of 0.959.nnnCONCLUSIONSnBy considering all six predefined neurocognitive domains, our study observed a substantial proportion of dementia-free older adults having miNCD. Provision of information on the underlying etiology/ies may be of prime importance in future studies aiming at evaluating the clinical relevance of the miNCD syndrome.

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex1. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 19,171 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (“global”) component was associated mainly with loci on chromosome 17 (8.8×10 -26 ≤ p ≤ 2.3×10-14), including those detected previously as linked with intracranial volume2,3. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=3.0×10-32). DAAM1 is a key component in the planar-cell-polarity signaling pathway4,5. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that - in concert with thalamocortical input to cortical subplate - DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Age-, sex-, and education-specific norms for an extended CERAD Neuropsychological Assessment Battery—Results from the population-based LIFE-Adult-Study.

Objective: To provide new age-, sex-, and education-specific reference values for an extended version of the well-established Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery (CERAD-NAB) that additionally includes the Trail Making Test and the Verbal Fluency Test—S-Words. Method: Norms were calculated based on the cognitive performances of n = 1,888 dementia-free participants (60–79 years) from the population-based German LIFE-Adult-Study. Multiple regressions were used to examine the association of the CERAD-NAB scores with age, sex, and education. In order to calculate the norms, quantile and censored quantile regression analyses were performed estimating marginal means of the test scores at 2.28, 6.68, 10, 15.87, 25, 50, 75, and 90 percentiles for age-, sex-, and education-specific subgroups. Results: Multiple regression analyses revealed that younger age was significantly associated with better cognitive performance in 15 CERAD-NAB measures and higher education with better cognitive performance in all 17 measures. Women performed significantly better than men in 12 measures and men than women in four measures. The determined norms indicate ceiling effects for the cognitive performances in the Boston Naming, Word List Recognition, Constructional Praxis Copying, and Constructional Praxis Recall tests. Conclusions: The new norms for the extended CERAD-NAB will be useful for evaluating dementia-free German-speaking adults in a broad variety of relevant cognitive domains. The extended CERAD-NAB follows more closely the criteria for the new DSM–5 Mild and Major Neurocognitive Disorder. Additionally, it could be further developed to include a test for social cognition.

FTO IS NOT RELATED TO IMAGING PARAMETERS OF THE HIPPOCAMPUS: A VOLUMETRIC AND DIFFUSION TENSOR IMAGING STUDY

collected and aggregated together from GAAIN, and APOE genotype frequencies were calculated for different age, cognitive status, and race subject groups. Hippocampal radial profiles were computed from structural MRI scans of 383 e2 and 1616 e4 carriers and grouped by cognitive status. Results:Although the APOE e2 allele was found to be associated with a smaller risk of developing Alzheimer’s disease, it did not significantly protect the hippocampi of subjects from atrophy. Conclusions: GAAIN provides a useful foundation for discovering and aggregating data from over 20 research studies of Alzheimer’s disease around the world. This has the potential to reveal trends and correlations in data that are not apparent from small sample sizes.

Impact of caloric restriction and caloric restriction-mimetics on brain structure and function in older adults and patients with mild cognitive impairment

overview of these findings. Animals in this study were part of the longitudinal “Dietary Restriction and Aging Study” at theWisconsin National Primate Research Center (WNPRC). Animals were either fed a normal diet or maintained on a moderately restricted diet (approximately 30% reduced intake from baseline), with both groups receiving comparable diet supplements. Results: Using volumetric imaging we demonstrated that CR preserves gray matter cortex in limbic and heteromodal association areas, indicating a positive effect of CR against age-related brain atrophy. Diffusion tensor imaging showed preservation of white matter integrity in the corpus callosum and fronto-occipital fasciculus, superior longitudinal fasciculus, external capsule, and brainstem. CR also attenuated age-related iron accumulation in the basal ganglia, red nucleus, and parietal, temporal, and perirhinal cortex. Decreased iron accumulation was in turn associated with faster performance on fine motor function tests, signifying a protective effect against motor slowness that results during aging. CR moderated the effect of important plasma-based inflammatory markers (e.g. IL-6) on gray and white matter changes in several brain areas, including the parietal and temporal graymatter regions that are sensitive to aging. CR improved glucoregulatory profiles and positively influenced gray matter volume in the hippocampus. Histopathology studies reveal that CR monkeys express significantly lower (w30%) levels ofmicroglial activation in the hippocampus. Energy metabolism in the hippocampus as indexed by PGC1alpha and GSK3B was preserved in CR. Number of MTL amyloid plaques was however equivalent between groups. Conclusions: Overall, these results recapitulate the neuroprotective effects of CR from lower animal models. Taken together, these findings point to an overall beneficial effect of CR on the brain in this non-human primate model of aging.

Impact of vitamin b12 on memory performance, hippocampus structure, and function in patients with mild cognitive impairment

(early-or late-onset; n:21, n:53,respectively), MCI (n:30) and PD (n:40) in this study to investigate the effect of vitamin D on the serum levels of IL-1b, IL-6, TNFa and BDNF, to see the vitamin D regulation of inflammatory response and neurotrophin synthesis in neurodegenerative disorders with different molecular backgrounds. Results:Our results indicated that the serum 25OHD levels of EOAD, LOAD and PD patients were significantly lower than their age-matched controls or MCI patients (p<0.05). Serum 25OHD levels and MMSE scores showed a significant correlation in healthy controls, EOAD and MCI patients. In addition lower 25OHD levels were correlated with younger age or younger age of onset in EOAD patients. Although 25OHD levels were inversely correlated with serum TNFa, IL-1b, IL-6 levels in healthy controls andMCI patients, 25OHDwere positively correlated with same cytokines in LOAD patients. Serum 25OHD levels were not correlated with age, age of onset, MMSE scores, UPDRS-ADL, Schwab-England-ADL scale and LEDD of PD patients. 25OHD were not correlated with IL-1b or IL-6 in that group. Finally, BDNF level was correlated with serum 25OHD only in healthy controls. Conclusions:Our results demonstrate that patients with neurodegenerative disorders have quite low levels of vitamin D in Turkish population. Given the results of three independent groups of individuals (healthy control, MCI, EOAD), vitamin D may regulate three important and related cytokines TNFa, IL-1b, IL-6. The power of vitamin D on regulation of systemic immune response and BDNF are compromised in EOAD, LOAD and PD due to low levels of vitamin D but not entirely in MCI.