Psychological outcomes of dementia risk estimation in MCI patients: Results from the PreDADQoL project.

INTRODUCTION: Understanding the impact of biomarker-based dementia risk estimation in people with mild cognitive impairment (MCI) and their care partners is critical for patient care. METHODS: MCI patients and study partners were counseled on Alzheimer's disease (AD) biomarker and dementia risk was disclosed. Data on mood, quality of life (QoL), and satisfaction with life (SwL) were obtained 1 week and 3 months after disclosure. RESULTS: Seventy-six dyads were enrolled, and two-thirds of the patients opted for biomarker testing. None of the participants experienced clinically relevant depression or anxiety after disclosure. All dyads reported moderate to high QoL and SwL throughout the study. Patients reported more subthreshold depressive symptoms 1 week and lower QoL and SwL 3 months after disclosure. In patients, depression (odds ratio [OR]: 0.76) and anxiety (OR: 0.81) were significant predictors for the decision against biomarker testing. DISCUSSION: No major psychological harm is to be expected in MCI patients and care partners after dementia risk disclosure. TRIAL REGISTRATION: This study is registered in the German clinical trials register (Deutsches Register Klinischer Studien, DRKS): http://www.drks.de/DRKS00011155, DRKS registration number: DRKS00011155, date of registration: 18.08.2017. HIGHLIGHTS: Patients with mild cognitive impairment (MCI) and study partners were counseled on Alzheimer's disease (AD) biomarker-based dementia risk estimation. About two-thirds of patients opted for biomarker testing and received their dementia risk based on their AD biomarker status. Patients who decided in favor or against CSF biomarker testing differed in psychological features. We did not observe major psychological harm after the dementia risk disclosure. Coping strategies were associated with better subsequent mood and well-being in all participants.

Six-month follow-up of multidomain cognitive impairment in non-hospitalized individuals with post-COVID-19 syndrome.

Some people infected with SARS-CoV-2 report persisting symptoms following acute infection. If these persist for over three months, they are classified as post-COVID-19 syndrome (PCS). Although PCS is frequently reported, detailed longitudinal neuropsychological characterization remains scarce. We aimed to describe the trajectory of cognitive and neuropsychiatric PCS symptoms. 42 individuals with persisting cognitive deficits after asymptomatic to mild/moderate acute COVID-19 at study inclusion received neuropsychological assessment at baseline (BL) and follow-up (FU; six months after BL). Assessments included comprehensive testing of five neurocognitive domains, two cognitive screening tests, and questionnaires on depression, anxiety, sleep, fatigue, and health-related quality of life. Results showed high rates of subjective cognitive complaints at BL and FU (95.2% versus 88.1%) without significant change over time. However, objectively measured neurocognitive disorder (NCD) decreased (61.9% versus 42.9%). All cognitive domains were affected, yet most deficits were found in learning and memory, followed by executive functions, complex attention, language, and perceptual motor functions. In individuals with NCD, the first three domains mentioned improved significantly over time, while the last two domains remained unchanged. Cognitive screening tests did not prove valuable in detecting impairment. Neuropsychiatric symptoms remained constant except for quality of life, which improved. This study emphasizes the importance of comprehensive neuropsychological assessment in longitudinal research and provides valuable insights into the trajectory of long-term neuropsychological impairments in PCS. While cognitive performance significantly improved in many domains, neuropsychiatric symptoms remained unchanged.

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline.

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum. METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid. RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline. DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.

Long-term environmental enrichment is associated with better fornix microstructure in older adults.

Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults. Methods: N = 201 cognitively unimpaired participants (≥ 60 years of age) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) baseline cohort were included. Two groups of participants with higher (n = 104) or lower (n = 97) long-term EE were identified, using the self-reported frequency of diverse physical, intellectual, and social leisure activities between the ages 13 to 65. White matter (WM) microstructure was measured by fractional anisotropy (FA) and mean diffusivity (MD) in the fornix, uncinate fasciculus, and parahippocampal cingulum using diffusion tensor imaging. Long-term EE groups (lower/higher) were compared with adjustment for potential confounders, such as education, crystallized intelligence, and socio-economic status. Results: Reported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized ß = 0.117, p = 0.033) and lower MD (ß = -0.147, p = 0.015). Greater fornix microstructure was indirectly associated (FA: unstandardized B = 0.619, p = 0.038; MD: B = -0.035, p = 0.026) with better memory function through higher long-term EE. No significant effects were found for the other WM tracts. Conclusion: Our findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.

Impaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction.

BACKGROUND: Impaired 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. METHODS: We 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. RESULTS: PD-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. CONCLUSIONS: Similar 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.

Why the clock ticks differently in Parkinson's disease: Insights from motor imagery and resting-state functional magnetic resonance imaging.

In Parkinson's disease (PD), an impaired perception of suprasecond time intervals has been reported. From a neurobiological perspective, dopamine is thought to be an important mediator of timing. Nevertheless, it is still unclear whether timing deficits in PD occur mainly in the motor context and are associated with corresponding striatocortical loops. This study attempted to fill this gap by investigating time reproduction in the context of a motor imagery task, and its neurobiological correlates in resting-state networks of basal ganglia substructures in PD. Nineteen PD patients and 10 healthy controls therefore underwent two time reproduction tasks. In a motor imagery task, subjects were asked to walk down a corridor for 10 s and reproduce the time spent walking during motor imagery afterwards. In an auditory task, the subjects had to reproduce an acoustically presented time interval of 10 s. Subsequently, resting-state functional magnetic resonance imaging was performed and voxel-wise regressions were conducted between striatal functional connectivity and performance in the individual task at group level and compared between groups. Patients significantly misjudged the time interval in the motor imagery task and an auditory task in comparison to controls. Seed-to-voxel functional connectivity analysis of basal ganglia substructures revealed a significant association between striatocortical connectivity and motor imagery performance. PD patients showed a different pattern of associated striatocortical connections as indicated by significantly different regression slopes for connections of the right putamen and left caudate nucleus. In accordance with previous findings, our data confirm an impaired time reproduction of suprasecond time intervals in PD patients. Our data imply that deficits in time reproduction tasks are not specific to motor context but reflect a general time reproduction deficit. According to our findings, impaired performance in context of motor imagery is accompanied by a different configuration of striatocortical resting-state networks responsible for timing.

Exploring the ATN classification system using brain morphology.

BACKGROUND: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort. METHODS: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aß42/Aß40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups. RESULTS: The ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead. CONCLUSION: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. TRIAL REGISTRATION: DRKS00007966, 04/05/2015, retrospectively registered.

Exploring impaired self-awareness of motor symptoms in Parkinson's disease: Resting-state fMRI correlates and the connection to mindfulness.

OBJECTIVE: To further explore the phenomenon of impaired self-awareness of motor symptoms in patients with Parkinson's Disease by using an evaluated measurement approach applied in previous studies, while also examining its connection with dispositional mindfulness and possible correlates of functional connectivity. BACKGROUND: Recently, the phenomenon of impaired self-awareness has been studied more intensively by applying different measurement and imaging methods. Existing literature also points towards a possible connection with mindfulness, which has not been examined in a cross-sectional study. There is no data available concerning correlates of functional connectivity. METHODS: Non-demented patients with idiopathic Parkinson's Disease without severe depression were tested for impaired self-awareness for motor symptoms following a psychometrically evaluated approach. Mindfulness was measured by applying the German version of the Five Facet Mindfulness Questionnaire. A subset of eligible patients underwent functional MRI scanning. Spearman correlation analyses were performed to examine clinical data. Whole-brain voxelwise regressions between seed-based connectivity and behavioral measures were calculated to identify functional connectivity correlates of impaired self-awareness scores. RESULTS: A total of 41 patients with Parkinson's Disease were included. 15 patients successfully underwent resting-state fMRI scanning. Up to 88% of patients showed signs of impaired self-awareness. Awareness for hypokinetic movements correlated with total mindfulness values and three facets, while awareness for dyskinetic movements did not. Three significant clusters between scores of impaired self-awareness in general and for dyskinetic movements were identified linking behavioral measures with the functional connectivity of the inferior frontal gyrus, the right insular cortex, the supplementary motor area, and the precentral gyrus among others. Impaired self-awareness for hypokinetic movements did not have any neural correlate. CONCLUSIONS: Clinical data is comparable with results from previous studies applying the same structured approach to measure impaired self-awareness in Parkinson's Disease. Functional connectivity analyses were conducted for the first time to evaluate neural correlates thereof. This data does not support a connection between impaired self-awareness of motor symptoms and dispositional mindfulness.

A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer's Disease Continuum.

BACKGROUND: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. OBJECTIVE: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer's disease (ADN). METHODS: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-ß)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. RESULTS: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. CONCLUSION: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.

Linking early-life bilingualism and cognitive advantage in older adulthood.

Previous studies have identified bilingualism as a protective factor against dementia. Here we aimed to test whether being bilingual at different life stages impacts cognition and brain structure in older adulthood. We included 746 participants from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Assessment of bilingualism at 3 life stages (early: 13-30, middle: 30-65 and late: over 65 years old) was determined with the Lifetime of Experiences Questionnaire. Individuals reporting bilingualism (i.e., daily use of L2) in the early life stage outperformed monolinguals on learning & memory, working-memory, executive functions and language. Bilingualism in middle life stage showed a significant advantage on learning & memory, while no effect of bilingualism in old life stage was identified. Brain gray matter volume was not associated with L2 use and did not differ between groups. However, stronger correlations between brain gray matter volume in selected brain regions and cognitive performance were found in bilingual participants in the early and middle life stages. Our results indicate that bilingualism in early life might provide a long-lasting protective effect on cognition and shape the brain to sustain cognitive performance in older adulthood.