Alzheimer's Disease Plasma Biomarkers Distinguish Clinical Diagnostic Groups in Memory Clinic Patients

INTRODUCTION: Several recent research studies show high performance of blood biomarkers to identify Alzheimer's disease also in the pre-dementia mild cognitive impairment (MCI) stage, but data from the routine clinical care memory clinic setting are needed. METHODS: We examined plasma samples of 144 memory clinic patients, including dementia of Alzheimer type (DAT, n = 54), MCI (n = 57), and subjective cognitive decline (SCD, n = 33), who either presented as self-referrals or were referred by general practitioners or neurologists or psychiatrists. The plasma biomarkers, amyloid-beta42 (Aß42), amyloid-beta40 (Aß40), phospho-Tau181 (pTau181), total-tau (tTau), and neurofilament light (NFL), as well as different ratios, were measured using the ultrasensitive single molecule array (Simoa) immunoassay technology. Statistical analysis including Kruskal-Wallis test, linear regression, and receiver operating characteristics analyses was performed. RESULTS: Of the single markers, we observed statistically significant group effects of pTau181 (H(2) = 34.43, p < 0.001) and NFL (H(2) = 27.66, p < 0.001). All individual group comparisons of pTau181 were significant, while the contrast of SCD versus MCI for NFL was not significant. In addition, the ratios of Aß42/Aß40 (H(2) = 7.50, p = 0.02) and pTau181/Aß42 (H(2) = 25.26, p < 0.001) showed significant group effects with significant difference between all groups for pTau181/Aß42 and an SCD versus MCI difference for Aß42/Aß40. PTau181 showed the highest area under the curve of 0.85 for the discrimination of SCD and DAT with a sensitivity of 80% and a specificity of 79% at a cut-off of 12.2 pg/mL. Age influenced Aß42, Aß40, and NFL concentrations. CONCLUSION: Plasma pTau181 and NFL, as well as the ratios Aß42/Aß40 and pTau181/Aß42, are biomarkers, which can differentiate diagnostic groups in a memory clinic setting outside of research studies

Brain reserve contributes to distinguishing preclinical Alzheimer's stages 1 and 2

BackgroundIn preclinical Alzheimer's disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions.MethodsWe tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol.ResultsIn asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Ass42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs.ConclusionsThese data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline

The Effect of Mindfulness-based Programs on Cognitive Function in Adults: A Systematic Review and Meta-analysis.

peer reviewedMindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904]

Memory Clinics in Germany - Results of a Hospital Survey

Objective To assess the structures for early and differential diagnosis of dementia in hospitals in Germany. Methods Written questionnaire to all German hospitals. Results 14% of 1.758 hospitals responded. Of those, 52% reported to offer a special service for early dementia diagnosis, mostly on an outpatient basis. The applied methods were in agreement with the national guideline for diagnosis and treatment of dementias, including technical diagnostics, such as neuroimaging and cerebrospinal fluid examinations. 46% of the diagnostic spectrum were dementia. 41% were either diagnosed as mild cognitive impairment (MCI) or as subjective cognitive decline (SCD). Conclusion Despite mostly insufficient reimbursement, a large proportion of the responding hospitals offer a specialized service, which largely adheres to guideline-based diagnostic procedures. The concepts of at-risk and prodromal stages of dementia seem to be largely established

Anatomical Correlates of the Neuropsychiatric Symptoms in Alzheimer's Disease

The current study aimed to assess the relationship between the neuropsychiatric symptoms in Alzheimer's disease (AD) and the regional grey matter (GM) volume using voxel based morphometry (VBM). Data of 85 AD patients, 208 subjects with mild cognitive impairment (MCI), and 131 healthy controls were selected from the Alzheimer's Disease Neuroimaging Initiative. Individual VBM models across the entire sample for each items of the Neuropsychiatric Inventory Questionnaire as variables of interest were specified with four nuisance covariates, including age, sex, total intracranial volume (TIV), and Mini-Mental State Examination (MMSE) score. Agitation was related to the GM atrophy in the left inferior frontal/insula and bilateral retrosplenial cortices. Aberrant motor behavior (AMB) was related to the GM reductions in the right basal ganglia. The VBM models were recalculated by specifying three nuisance covariates (age, sex, TIV), and by excluding voxels related to AD severity by applying a MMSE mask. This procedure confirmed the first results, and additionally revealed associations between depression and GM atrophy in the left middle frontal cortex, between agitation and the GM atrophy in the left middle frontal cortex, and between AMB and GM reduction in the right inferior frontal cortex. Hierarchical multiple regression analyses using extracted mean GM value in these additional regions confirmed these associations. Finally, VBM analyses within a subgroup (85 AD patients and 41 MCI converters) largely confirmed the results. Our results suggest that specific patterns of GM atrophy within AD related neurodegeneration predispose to certain neuropsychiatric symptoms, suggesting distinct neurobiological mechanisms

A Reduction in Delay Discounting by Using Episodic Future Imagination and the Association with Episodic Memory Capacity

Delay discounting (DD) refers to the phenomenon that individuals discount future consequences. Previous studies showed that future imagination reduces DD, which was mediated by functional connectivity between medial prefrontal valuation areas and a key region for episodic memory (hippocampus). Future imagination involves an initial period of construction and a later period of elaboration, with the more elaborative latter period recruiting more cortical regions. This study examined whether elaborative future imagination modulated DD, and if so, what are the underlying neural substrates. It was assumed that cortical areas contribute to the modulation effect during the later period of imagination. Since future imagination is supported by episodic memory capacity, we additionally hypothesize that the neural network underlying the modulation effect is related to individual episodic memory capacity. Twenty-two subjects received an extensive interview on personal future events, followed by an fMRI DD experiment with and without the need to perform elaborative future imagination simultaneously. Subjects' episodic memory capacity was also assessed. Behavioral results replicate previous findings of a reduced discount rate in the DD plus imagination condition compared to the DD only condition. The behavioral effect positively correlated with: (i) subjective value signal changes in midline brain structures during the initial imagination period; and (ii) signal changes in left prefrontoparietal areas during the later imagination period. Generalized psychophysiological interaction (gPPI) analyses reveal positive correlations between the behavioral effect and functional connectivity among the following areas: right anterior cingulate cortex (ACC) and left hippocampus; left inferior parietal cortex (IPC) and left hippocampus; and left IPC and bilateral occipital cortices. These changes in functional connectivity are also associated with episodic memory capacity. A hierarchical multiple regression indicates that the model with both the valuation related signal changes in the right ACC and the imagination related signal changes in the left IPC best predicts the reduction in DD. This study illustrates interactions between the left hippocampus and multiple cortical regions underlying the modulation effect of elaborative episodic future imagination, demonstrating, for the first time, empirical support for a relation to individual episodic memory capacity

Social Cognition in Patients with Amnestic Mild Cognitive Impairment and Mild Dementia of the Alzheimer Type

Background: Social cognition (SC) is a core criterion for neurocognitive disorders. However, findings in patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (DAT) are inconsistent. Objective: We report assessments of emotion recognition (ER), affective and cognitive theory of mind (ToM) in young (YC) and older controls (OC) compared to aMCI and DAT. Methods: 28 aMCI, 30 DAT, 30 YC, and 29 OC received tests of SC and a comprehensive neuropsychological assessment. Analysis of covariance was used to determine group differences. Multiple regression models were applied to identify predictors for each SC task. Results: In controls, OC performed worse in ER and both ToM tasks compared to YC except for one subtest. No significant differences were found between OC and patients concerning ER and affective ToM. In cognitive ToM, differences between OC and patients depended on content and cognitive load with significant impairment in DAT compared to OC. A cognitive composite score predicted SC in OC, but not in patients. Associations of SC with single cognitive domains were found in all groups with language and complex attention as best predictors. Not all variance of SC performance was explained by variance in cognitive domains. Conclusion: Lower performance on SC tasks in OC versus YC was confirmed, although not all tasks were equally affected. With progressive cognitive impairment, cognitive ToM is more impaired than ER or affective ToM. SC seems to be at least partly independent of other cognitive domains, justifying its inclusion in batteries for dementia diagnostic

Cortical Thinning in Individuals with Subjective Memory Impairment

Elderly individuals with subjective memory impairment (SMI) report memory worsening, but perform within the age-, gender-, and education-adjusted normal range on neuropsychological tests. Longitudinal studies indicate SMI as a risk factor or early sign of Alzheimer's disease (AD). There is increasing evidence from neuroimaging that at the group level, subjects with SMI display evidence of AD related pathology. This study aimed to determine differences in cortical thickness between individuals with SMI and healthy control subjects (CO) using the FreeSurfer environment. 110 participants (41 SMI/69 CO) underwent structural 3D-T1 MR imaging. Cortical thickness values were compared between groups in predefined AD-related brain regions of the medial temporal lobe, namely the bilateral entorhinal cortex and bilateral parahippocampal cortex. Cortical thickness reduction was observed in the SMI group compared to controls in the left entorhinal cortex (p = 0.003). We interpret our findings as evidence of early AD-related brain changes in persons with SMI

Cortical Thinning in Individuals with Subjective Memory Impairment

Elderly individuals with subjective memory impairment (SMI) report memory worsening, but perform within the age-, gender-, and education-adjusted normal range on neuropsychological tests. Longitudinal studies indicate SMI as a risk factor or early sign of Alzheimer's disease (AD). There is increasing evidence from neuroimaging that at the group level, subjects with SMI display evidence of AD related pathology. This study aimed to determine differences in cortical thickness between individuals with SMI and healthy control subjects (CO) using the FreeSurfer environment. 110 participants (41 SMI/69 CO) underwent structural 3D-T1 MR imaging. Cortical thickness values were compared between groups in predefined AD-related brain regions of the medial temporal lobe, namely the bilateral entorhinal cortex and bilateral parahippocampal cortex. Cortical thickness reduction was observed in the SMI group compared to controls in the left entorhinal cortex (p = 0.003). We interpret our findings as evidence of early AD-related brain changes in persons with SMI

Multidomain cognitive impairment in non-hospitalized patients with the post-COVID-19 syndrome: results from a prospective monocentric cohort

Background A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients. Methods Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered. Results Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases (n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue. Conclusion Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology