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Abstract: Cognitive impairment is a prominent symptom of the post-COVID syndrome (PCS). However, the correspondence between subjective cognitive complaints (SCC) and objective results is inconsistent. Here, we investigated this discrepancy. This longitudinal study included N = 42 individuals who reported SCC as PCS after mild infection at inclusion. Data collection comprised questionnaires and neuropsychological assessment at baseline and follow-up (FU). At FU – on average 15 months after acute COVID-19 – 88 % of patients reported persisting SCC. There was an approx. 40 % discrepancy between subjective report and test results at both visits. Patients with SCC and objective impairment indicated elevated fatigue and reduced quality of life compared to patients without SCC at FU. A growing number of patients is anticipated to request neuropsychological assessments even after mild infections.

BACKGROUND: There is evidence that adherence to Mediterranean-like diet reduces cognitive decline and brain atrophy in Alzheimer's disease (AD). However, lengthy dietary assessments, such as food frequency questionnaires (FFQs), discourage more frequent use. OBJECTIVE: Here we aimed to validate a 6-items short questionnaire for a Mediterranean-like diet (6-QMD) and explore its associations with memory performance and hippocampal atrophy in healthy elders and individuals at risk for AD. METHODS: We analyzed 938 participants (N = 234 healthy controls and N = 704 participants with an increased AD risk) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). The 6-QMD was validated against the Mediterranean Diet (MeDi) score and the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) score, both derived from a detailed FFQ. Furthermore, associations between the 6-QMD and memory function as well as hippocampal atrophy were evaluated using linear regressions. RESULTS: The 6-QMD was moderately associated with the FFQ-derived MeDi adherence score (ρ = 0.25, p

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.

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer’s disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer’s disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer’s disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer’s disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer’s disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer’s disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer’s disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer’s disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer’s disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum.Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study.The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group.Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A−) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A− individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A− groups. After classifying this matched sample for phospho-tau pathology (T−/T+), individuals with A+/T+ were significantly more memory-impaired than A−/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer’s disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer’s disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

Background: Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

Objective To assess if SARS-CoV-2 causes a persistent central nervous system infection. Methods SARS-CoV-2 specific antibody index and SARS-CoV-2 RNA studied in cerebrospinal fluid following COVID-19. Results Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected. Interpretation The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. This article is protected by copyright. All rights reserved.

BACKGROUND: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers.METHODS: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO).RESULTS: On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs.DISCUSSION: Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT.

BackgroundImpaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates.MethodsWe examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z-scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog.ResultsPD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI.ConclusionsSimilar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

ObjectiveTo determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study.MethodThe sample (n = 512, mean age 69.5 ± 5.9 years) included 169 cognitively normal participants and individuals at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence according to the food frequency questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI, and cognitive performance was assessed with an extensive neuropsychological battery. AD-related biomarkers (β-amyloid42/40 [Aβ42/40] ratio, phosphorylated tau 181 [pTau181]) in CSF were assessed in n = 226 individuals. We analyzed the associations between MeDi and outcomes with linear regression models controlling for several covariates. In addition, we applied hypothesis-driven mediation and moderation analysis.ResultsHigher MeDi adherence related to larger mediotemporal gray matter volume (p < 0.05 family-wise error corrected), better memory (β ± SE = 0.03 ± 0.02; p = 0.038), and less amyloid (Aβ42/40 ratio, β ± SE = 0.003 ± 0.001; p = 0.008) and pTau181 (β ± SE = −1.96 ± 0.68; p = 0.004) pathology. Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations among Aβ42/40 ratio, pTau181, and mediotemporal atrophy. Results were consistent correcting for APOE-ε4 status.ConclusionOur findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. They suggest that these associations might be explained by a decrease of amyloidosis and tau pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.

Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson’s disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson’s disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson’s disease. Forty-two patients with mild-to-moderate stage Parkinson’s disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson’s disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson’s disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson’s disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson’s disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

BackgroundCognitive reserve (CR) explains interindividual differences in the impact of neurodegenerative burden on cognitive and daily functioning. A residual model was proposed to estimate CR more accurately compared to static measures, such as years of education. However, the functional brain correlates of residual CR markers (CRM) remain unexplored.MethodsFrom the DELCODE cohort, 318 participants with resting-state functional and structural MRI data were included and stratified using cerebrospinal fluid (CSF) biomarkers according to the A(myloid-β, Aβ)/T(au)/N(eurodegeneration) classification scheme, resulting in 112 Aβ-negative healthy controls and 206 Aβ-positive patients in the Alzheimer’s disease (AD) spectrum.. CRM was calculated utilizing residuals obtained from a multilinear regression model using global cognition as dependent variable and demographic and disease burden measures as predictors. Associations between the CRM and intrinsic network connectivity (INC) in resting-state networks associated with cognition were explored, including the default mode network (DMN), frontoparietal network (FPN), salience network (SAL) and dorsal attention network (DAN). Moreover, the association between memory performance-associated regional INC and CRM was assessed.ResultsCRM was positively associated with INC in the DMN in the entire cohort. In a subgroup analysis, the A+T+N+ group revealed an anti-correlation between SAL and DMN. Furthermore, CRM was positively associated with the anti-correlation between the memory-related regions in the FPN and the DMN in the A+ and A+T/N+ subgroups.ConclusionsCRM is associated with alterations of functional connectivity in resting-state networks of cognitive function, particularly the DMN and the FPN. Our results provide evidence on individual functional network differences associated with CRM in the AD continuum.

Background Subjective cognitive decline (SCD) may occur very early in the course of Parkinson’s disease (PD) before the onset of objective cognitive decline. Data on neural correlates and determinants of SCD in PD are rare. Objective The aim of the present study was to identify neural correlates as well as sociodemographic, clinical, and neuropsychological predictors of SCD in patients with PD. Methods We retrospectively analyzed 30 patients with PD without cognitive impairment (23% female, 66.90 ± 7.20 years, UPDRS-III: 19.83 ± 9.29), of which n = 12 patients were classified as having no SCD (control group, PD-CG) and n = 18 as having SCD (PD-SCD). Neuropsychological testing and 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were conducted. SCD was assessed using a questionnaire covering multiple cognitive domains. Results SCD subscores differed significantly between PD-CG and PD-SCD and correlated significantly with other scales measuring related concepts. FDG-PET whole-brain voxel-wise regression analysis revealed hypometabolism in middle frontal, middle temporal, and occipital areas, and the angular gyrus as neural correlates of SCD in PD. Next to this hypometabolism, depressive symptoms were an independent significant determinant of SCD in a stepwise regression analysis (adjusted R2 = 50.3%). Conclusion This study strengthens the hypothesis of SCD being an early manifestation of future cognitive decline in PD and, more generally, early pathological changes in PD. The early identification of the vulnerability for future cognitive decline constitutes the basis for successful prevention and delay of this non-motor symptom.

Deep Brain Stimulation (DBS) has been proven to alleviate motor symptoms in Parkinson's Disease (PD). Regarding non-motor symptoms, however, inconsistencies have been reported, on whether DBS causes reductions in well-being and functioning. To assess motor and non-motor impairment in DBS-patients, the Deep Brain Stimulation Impairment Scale (DBS-IS) has been developed. Yet, the extent to which the DBS-IS detects impairment in DBS-patients and thus could serve as a useful tool that complements the PDQ-39 (gold standard) in assessment of well-being and functioning in PD-patients has not been shown.By comparing DBS and non-DBS-patients we aimed to identify DBS-specific symptoms. We thereby aimed to show in how far the DBS-IS complements the PDQ-39 in assessing well-being and functioning in PD patients under DBS.In a cross-sectional study, 186 DBS-patients were matched (for age, disease duration and sex) to 186 non-DBS-patients (N = 372) and the two groups were compared regarding well-being and functioning: Impairment was assessed via DBS-IS and overall Quality of Life (QoL) was assessed via PDQ-39. Additionally, we analyzed differences in impairment between age and disease duration clusters.DBS-patients showed significantly higher total impairment (DBS-IS) and significantly higher impairment on the subscales Postural Instability and Gait difficulties and speaking difficulties than non-DBS-patients. Impairment increased with age and disease duration and, overall, differences in impairment rose by age. Overall QoL (PDQ-39) was non-significantly lower in DBS-patients.Since there is evidence that the PDQ-39 misses some DBS-specific symptoms, the DBS-IS is recommended to complement the PDQ-39 when assessing DBS-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.

The prevailing network perspective of Parkinson’s disease (PD) emerges not least from the ascending neuropathology traceable in histological studies. However, whether longitudinal in vivo correlates of network degeneration in PD can be observed remains unresolved. Here, we applied a trimodal imaging protocol combining 18F-fluorodeoxyglucose (FDG)- and 18F-fluoro-L-Dopa- (FDOPA)-PET with resting-state functional MRI to assess longitudinal changes in midbrain metabolism, striatal dopamine depletion and striatocortical dysconnectivity in 17 well-characterized PD patients. Whole-brain (un)paired-t-tests with focus on midbrain or striatum were performed between visits and in relation to 14 healthy controls (HC) in PET modalities. Resulting clusters of FDOPA-PET comparisons provided volumes for seed-based functional connectivity (FC) analyses between visits and in relation to HC. FDG metabolism in the left midbrain decreased compared to baseline along with caudatal FDOPA-uptake. This caudate cluster exhibited a longitudinal FC decrease to sensorimotor and frontal areas. Compared to healthy subjects, dopamine-depleted putamina indicated stronger decline in striatocortical FC at follow-up with respect to baseline. Increasing nigrostriatal deficits and striatocortical decoupling were associated with deterioration in motor scores between visits in repeated-measures correlations. In summary, our results demonstrate the feasibility of in-vivo tracking of progressive network degeneration using a multimodal imaging approach. Specifically, our data suggest advancing striatal and widespread striatocortical dysfunction via an anterior-posterior gradient originating from a hypometabolic midbrain cluster within a well-characterized and only mild to moderately affected PD cohort during a relatively short period.

Alzheimer's disease (AD) is associated with alterations in functional connectivity (FC) of the brain. The FC underpinnings of CR, that is, lifelong experiences, are largely unknown. Resting-state FC and structural MRI were performed in 76 CSF amyloid-β (Aβ) negative healthy controls and 152 Aβ positive individuals as an AD spectrum cohort (ADS; 55 with subjective cognitive decline, SCD; 52 with mild cognitive impairment; 45 with AD dementia). Following a region-of-interest (ROI) FC analysis, intrinsic network connectivity within the default-mode network (INC-DMN) and anti-correlation in INC between the DMN and dorsal attention network (DMN:DAN) were obtained as composite scores. CR was estimated by education and Lifetime Experiences Questionnaire (LEQ). The association between INC-DMN and MEM was attenuated by higher LEQ scores in the entire ADS group, particularly in SCD. In ROI analyses, higher LEQ scores were associated with higher FC within the DMN in ADS group. INC-DMN remains relatively intact despite memory decline in individuals with higher lifetime activity estimates, supporting a role for functional networks in maintaining cognitive function in AD.

1AbstractRegular musical activity as a highly-stimulating lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease (AD). This study investigated associations between lifelong regular musical instrument playing, late-life cognitive abilities and brain morphology in older adults. We show that musical activity over the life course is associated with better global cognition, working memory, executive functions, language, and visuospatial abilities accounting for reserve proxies. Playing music is not significantly associated with gray matter volume in regions most affected by aging and AD. Selectively in the musically active participants, multi-domain cognitive abilities were enhanced with preserved gray matter volume in frontal and temporal regions. Our correlational findings suggest that playing a musical instrument may improve the recruitment of existing brain resources to facilitate late-life cognitive capacities. We propose that engaging in regular musical activity could serve as a low-threshold multimodal enrichment strategy that may promote cognitive resilience in advanced age.

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.

Poster-Abstract Background Within a 12-week multicentre randomised controlled trial, standardised data on resource use of patients and their caregivers was collected using the Resource Utilization in Dementia (RUD) instrument. The aim of this study is to evaluate the insufficiently known influence of apathy on resource utilisation in Alzheimer's patients and their caregivers. Method 107 patients were included in the study. Costs were collected from a societal perspective over a four-week period and examined depending on the Apathy Evaluation Scale-Clinician Version (AES-C). Using the Mann-Whitney U and Kruskal-Wallis tests, potential cost drivers were identified in a univariate analysis. Afterwards potential cost drivers for total costs, patient costs and caregiver costs were analysed using a generalised linear model (GLM) with a γ-distributed dependent variable and log link function. Result The mean total costs were €3,069. The mean patient costs were €359 and were mainly related to professional services, hospitalisation and medication. The mean caregiver costs were €2,711 and were largely caused by informal care with a share of €2,509. Within the sensitivity analysis, informal care costs decreased to €1,742 and €903, respectively. The multiple regression analysis showed that Apathy, represented by the AES-C, is a cost driving factor for total costs and caregiver costs, however not for patient costs. Conclusion Previous studies have often presented costs as a function of cognitive impairment. The present data show that apathy also has a significant influence on resource utilisation. At the same time, however, it was also shown that this influence was mainly caused by the increased resource use of the caregivers and that the resource use of the patients did not show significant changes.

Background: Although convolutional neural networks (CNN) achieve high diagnostic accuracy for detecting Alzheimer's disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods: We trained a CNN for the detection of AD in N=663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including N=1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps. Results: Across three independent datasets, group separation showed high accuracy for AD dementia vs. controls (AUC$\geq$0.92) and moderate accuracy for MCI vs. controls (AUC$\approx$0.75). Relevance maps indicated that hippocampal atrophy was considered as the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson's r$\approx$-0.86, p, 24 pages, 9 figures/tables, supplementary material, source code available on GitHub

Citizenship is a contested and multifaceted concept. This article introduces a research design to explore individual perspectives on citizenship in Germany. Its emphasis is on capturing broad persp...

Graphical abstract, Highlights • Freezers exhibited a dopaminergic deficit in the left caudate. • The dopamine depleted caudate shows altered striatocortical functional connectivity. • Ventral tegmental area displays increased coupling with regions of the DMN. • Molecular connectivity revealed a specific impairment in mesocorticolimbic pathways., Freezing of gait is a common phenomenon of advanced Parkinson’s disease. Besides locomotor function per se, a role of cognitive deficits has been suggested. Limited evidence of associated dopaminergic deficits points to caudatal denervation. Further, altered functional connectivity within resting-state networks with importance for cognitive functions has been described in freezers. A potential pathophysiological link between both imaging findings has not yet been addressed. The current study sought to investigate the association between dopaminergic pathway dysintegrity and functional dysconnectivity in relation to FOG severity and cognitive performance in a well-characterized PD cohort undergoing high-resolution 6-[18F]fluoro-L-Dopa PET and functional MRI. The freezing of gait questionnaire was applied to categorize patients (n = 59) into freezers and non-freezers. A voxel-wise group comparison of 6-[18F]fluoro-L-Dopa PET scans with focus on striatum was performed between both well-matched and neuropsychologically characterized patient groups. Seed-to-voxel resting-state functional connectivity maps of the resulting dopamine depleted structures and dopaminergic midbrain regions were created and compared between both groups. For a direct between-group comparison of dopaminergic pathway integrity, a molecular connectivity approach was conducted on 6-[18F]fluoro-L-Dopa scans. With respect to striatal regions, freezers showed significant dopaminergic deficits in the left caudate nucleus, which exhibited altered functional connectivity with regions of the visual network. Regarding midbrain structures, the bilateral ventral tegmental area showed altered functional coupling to regions of the default mode network. An explorative examination of the integrity of dopaminergic pathways by molecular connectivity analysis revealed freezing-associated impairments in mesolimbic and mesocortical pathways. This study represents the first characterization of a link between dopaminergic pathway dysintegrity and altered functional connectivity in Parkinson’s disease with freezing of gait and hints at a specific involvement of striatocortical and mesocorticolimbic pathways in freezers.

Key Points Question Is bupropion an effective and safe treatment for apathy in nondepressed patients with dementia of Alzheimer type? Findings In this 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial, 54 patients received bupropion and 54 received placebo. The mean change in the Apathy Evaluation Scale–Clinician Version score was not statistically significant between the treatment groups. Meaning Bupropion did not improve apathy in patients with dementia of Alzheimer type without depressed mood., This randomized clinical trial examines the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type., Importance Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients’ and caregivers’ quality of life. Effective treatment options are needed. Objective To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures Change on the Apathy Evaluation Scale–Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, –0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, –1.66; 95% CI, –3.01 to –0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, –2.92; 95% CI, –5.89 to 0.06; P = .05) and cognition (mean change, –0.27; 95% CI, –3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration EU Clinical Trials Register Identifier: 2007-005352-17

Resting-state EEG microstates are brief (50–100 ms) periods, in which the spatial configuration of scalp global field power remains quasi-stable before rapidly shifting to another configuration. Changes in microstate parameters have been described in patients with psychotic disorders. These changes have also been observed in individuals with a clinical or genetic high risk, suggesting potential usefulness of EEG microstates as a biomarker for psychotic disorders. The present study aimed to investigate the potential of EEG microstates as biomarkers for psychotic disorders and future transition to psychosis in patients at ultra-high-risk (UHR). We used 19-channel clinical EEG recordings and orthogonal contrasts to compare temporal parameters of four normative microstate classes (A–D) between patients with first-episode psychosis (FEP; n = 29), UHR patients with (UHR-T; n = 20) and without (UHR-NT; n = 34) later transition to psychosis, and healthy controls (HC; n = 25). Microstate A was increased in patients (FEP & UHR-T & UHR-NT) compared to HC, suggesting an unspecific state biomarker of general psychopathology. Microstate B displayed a decrease in FEP compared to both UHR patient groups, and thus may represent a state biomarker specific to psychotic illness progression. Microstate D was significantly decreased in UHR-T compared to UHR-NT, suggesting its potential as a selective biomarker of future transition in UHR patients.

One of the most powerful line-narrowing techniques used to unravel the homogeneous lineshapes of inhomogeneously broadened systems is difference fluorescence line-narrowing spectroscopy. When this spectroscopy was applied to multichromophoric systems so far, the spectra were analyzed by an effective two-level system approach, composed of the electronic ground state and the lowest exciton state. An effective Huang-Rhys factor was assigned for the coupling of this state to the vibrations. Here, we extend this approach by including a multilevel line shape theory, which takes into account the excitonic coupling between pigments and thereby the effect of the delocalization of the excited states explicitly. In this way, it becomes possible to extract the spectral density of the local exciton-vibrational coupling. The theory is applied to the recombinant water-soluble chlorophyll binding protein reconstituted with chlorophyll a or b and reveals a significant decrease of the Huang-Rhys factor of the local exciton-vibrational coupling with decreasing transition energy of the chlorophylls. This decrease could be due to the increase in steric interactions reducing the flexibility of the environment and red-shifting the site energy of the pigments.

Background Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) has considerable influence on motor and non-motor symptoms in Parkinson's disease (PD). While improvements in motor functioning can be easily assessed with general quality of life questionnaires, the measurement of specific STN-DBS-associated impairments often remains insufficient. Hence, we aimed to develop a questionnaire that measures STN-DBS-related impairments. Methods The development of the (STN-)DBS Impairment Scale (DBS-IS) consisted of four steps. First, 30 semi-structured interviews before, three and twelve months after STN-DBS-surgery were performed to create 76 items that relate to motor and non-motor functioning in STN-DBS PD patients. Second, pilot-testing led to a rewording of the questions for better understanding. Third, a first multicentre survey was performed to reduce items by applying principal component analysis (PCA). Fourth, a second multicentre survey was conducted to examine factor structure, reliability (internal consistency) and validity. Results After the first survey (N = 215), the PCA lead to a reduction of 54 items. After the second survey (N = 391), exploratory factor analysis determined six factors with 22 items: 1. Postural instability and gait difficulties (5 items), 2. Cognitive impairment (5 items), 3. Speaking problems (3 items), 4. Apathy (3 items), 5. Impulsivity (3 items), and 6. Difficulties related to the DBS device (3 items). High reliability was reported for all subscales (Cronbach's alpha 0.71–0.90). Similarly, construct validity was high (r > 0.50, p Conclusions With this new questionnaire patients can be followed-up and STN-DBS-specific problems might be adequately measured. Also, comparisons between patients with and without STN-DBS might be possible.