Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals.

Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aß42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aß42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.

Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease.

INTRODUCTION: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline. METHODS: We measured levels of amyloid beta (Aß)X-40 and AßX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aß42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia. RESULTS: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AßX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION: Our results suggest that assessing the plasma AßX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD. HIGHLIGHTS: New plasma Aß42/Aß40 measurement using immunoprecipitation-immunoassay Plasma Aß42/Aß40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Correction: Hansen et al. Persisting Verbal Memory Encoding and Recall Deficiency after mGluR5 Autoantibody-Mediated Encephalitis. Brain Sci. 2023, 13, 1537.

Affiliations: In the published publication [...].

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia.

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 ± 6.09 years; 48.7 % female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memory's mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95 % confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95 % CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

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.

Persisting Verbal Memory Encoding and Recall Deficiency after mGluR5 Autoantibody-Mediated Encephalitis.

BACKGROUND: Metabotropic glutamate receptors type 5 (mGluR5) play a central role in persistent forms of synaptic plasticity and memory formation. Antibodies to mGluR5 have been reported to be clinically associated with memory impairment. Here, we report on a patient with persistent amnestic cognitive impairment in a single cognitive domain after resolution of mGluR5-associated encephalitis. METHODS: We report on the clinical data of a patient in our Department of Psychiatry and Psychotherapy who underwent several diagnostic investigations including a detailed neuropsychological examination, magnetic resonance imaging, and cerebrospinal fluid analysis involving the determination of neural autoantibodies. RESULTS: A 54-year-old woman presented to our memory clinic with pleocytosis 4 months after remission of probable anti-mGluR5-mediated encephalitis, revealing initial pleocytosis and serum proof of anti-mGluR5 autoantibodies (1:32). A neuropsychological examination revealed mild cognitive impairment in verbal memory encoding and recall. The patient received immunotherapy with corticosteroids, and a subsequent cerebrospinal fluid analysis 1.5 months after the onset of encephalitis confirmed no further signs of inflammation. CONCLUSIONS: Our results suggest that although immunotherapy resulted in the remission of anti-mGluR5 encephalitis, a verbal memory encoding and recall dysfunction persisted. It remains unclear whether the reason for the persistent verbal memory impairment is attributable to insufficiently long immunotherapy or initially ineffective immunotherapy. Because mGluR5 plays an essential role in persistent synaptic plasticity in the hippocampus, it is tempting to speculate that the mGluR5 antibody-antigen complex could lead to persistent cognitive dysfunction, still present after the acute CNS inflammation stage of encephalitis.

[Evaluation of satisfaction with and relief vs. workload by a general practitioner-centered dementia care project: early information and support in dementia (FIDEM) in Göttingen, Germany]. / Evaluation zur Zufriedenheit mit und Be­/Entlastung durch ein hausarztzentriertes Demenzversorgungsmodell: Frühe Information und Hilfen bei Demenz (FIDEM) in Göttingen.

BACKGROUND: Early information and support in dementia (FIDEM) is a cross-sectoral, general practitioner-centered network model for the improvement of community-based care of people with dementia and their caregivers by systematically assigning them to non-physician healthcare providers. OBJECTIVE: To describe the implementation of FIDEM in Göttingen, Germany and to exploratorily evaluate satisfaction and relief vs. additional workload. MATERIAL AND METHODS: FIDEM was established in Göttingen in 2017. Community-based and district-based networks consisted of medical (general practitioners) and non-medical cooperation partners (occupational therapists, care counselling, other non-medical care providers) and were instructed to efficiently share information. During biannual network meetings from August 2017 to October 2019, a self-developed questionnaire for quality management and evaluation of the aspects of the project described above was filled out by participants attending the meetings. RESULTS: Consecutive recruitment resulted in 7 networks by October 2019, with participation of 29 general practitioners and 46 non-medical care providers, serving as cooperation partners. Quantitative evaluation of 80 FIDEM cooperation partners revealed high satisfaction ratings with all aspects of the model (M from 7.22 to 7.87 out of possible "10"), with partially higher ratings on the part of primary care physicians. Furthermore, all participants reported a reduction in workload due to participation, which was significantly higher for primary care physicians across all scales (all p-values < 0.001). CONCLUSION: FIDEM has been implemented in Göttingen beyond a funded pilot project phase. High satisfaction ratings and considerable relief in workload suggest the continuation of FIDEM along with a full evaluation and, provided positive results, its consolidation of and transfer to other regions in Germany.

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline.

BACKGROUND AND OBJECTIVES: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI). METHODS: This study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-ß (Aß)42/Aß40, phosphorylated tau (p-tau181), total tau and Aß42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M ± SD: 40.6 ± 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD. RESULTS: In our sample (N = 672, mean age: 70.7 ± 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215; HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups. DISCUSSION: Our results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD.

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.

The myth of brain damage: no change of neurofilament light chain during transient cognitive side-effects of ECT.

Electroconvulsive therapy (ECT) is an effective, safe, and mostly well-tolerated treatment for patients with severe or difficult to treat depression or psychotic disorders. However, a relevant number of patients experience subjective and/or objective cognitive side-effects. The mechanism of these transient deficits is not yet clear. Thus, our study prospectively investigated neurofilament light chain (NfL) concentrations as a highly sensitive biomarker for neuroaxonal damage along with cognitive performance during a course of ECT. Serum NfL concentrations from 15 patients with major depressive disorder receiving ECT were analyzed (1) 24 h before the first ECT, (2) 24 h and (3) 7 days after the last ECT (45 measurements in total). Neuropsychological testing including memory, executive functions and attention was performed at each time-point. NfL concentrations did not change between the three time-points, while a temporary cognitive impairment was found. Even in the subset of patients with the strongest impairment, NfL concentrations remained unchanged. Neuropsychological testing revealed the common pattern of transient cognitive side-effects with reduced performance 24 h post-ECT (global cognition score: p < 0.001; memory: p = 0.043; executive functions: p = 0.002) and return to baseline after 7 days (all p < 0.001). Our study adds to the evidence that neither ECT per se nor the transient cognitive side-effects seem to be associated with an increase of NfL as a marker of neuroaxonal damage. In contrast, we discuss cognitive side effects to be potentially interpreted as a byproduct of ECT's neuroplastic effects.

Case report: Mixed dementia associated with autoantibodies targeting the vesicular glutamate transporter 2.

Background: Autoantibodies against the vesicular glutamate transporter type 2 (VGlut2) can trigger impaired synaptic signaling and are described here for the first time in association with mixed dementia. Methods: We report on a 71-year-old female patient with a dementing syndrome who underwent a thorough dementia diagnosis including neuropsychological testing, magnetic resonance imaging (MRI), 18F-fluorodesoxyglucose positron emission tomography (FDG-PET), and a spinal tap to search for neural autoantibodies. Results: Our patient exhibited mixed dementia. Her CSF revealed elevated ptau 181 protein and a reduced Aß42/40 ratio indicating Alzheimer's disease (AD) pathology. In addition, neuropsychological testing showed a profile consistent with AD with impaired memory, reduced semantic word fluency, naming disorder, and impaired visuoconstructive skills. Nevertheless, in-depth neuropsychological testing also revealed marked psychomotor slowing and visuospatial perceptual impairments that are more indicative of the presence of DLB. Overall, her dementia is more likely of mixed pathology. In addition, we repeatedly detected VGlut2 autoantibodies in her serum. Conclusion: To the best of our knowledge, this report is the first to describe mixed dementia associated with VGlut2 autoantibodies.

Long-Term Course of Neural Autoantibody-Associated Psychiatric Disorders: Retrospective Data from a Specifically Immunopsychiatric Outpatient Clinic.

Background: Autoantibody-associated psychiatric disorders are a new terrain that is currently underrepresented considering immunopsychiatry's potential importance for therapeutic aspects. The aim of our research was thus to present initial pilot data on the long-term clinical course of our patients in an outpatient clinic specializing in autoantibody-associated psychiatric disorders. Methods: Thirty-seven patients were examined clinically in our outpatient clinic at regular intervals over a 1.5-year period. We collected clinical data on their demographics, psychopathology, and cognition, and magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data as well as the status of neural autoantibodies in blood and/or serum. Results: Our main finding was that affective, psychotic, and cognitive symptoms did not change significantly over the 1.5-year period, thus revealing no progression. We divided the entire cohort of autoantibody-positive patients (n = 32) into subgroups consisting of patients with dementia (n = 14), mild cognitive impairment (MCI) (n = 7), psychotic disorders (n = 6), and a CSF profile of Alzheimer's disease (n = 6). Relying on established classification schemes, we identified the following percentages in our autoantibody-positive cohort: 28% with autoimmune encephalitis, 15% with autoimmune psychosis, and 63% with autoimmune psychiatric syndromes. Discussion: These initial pilot results suggest that autoantibody-associated diseases do not show a significantly progressive course in the long-term and are often characterized by impaired verbal memory recall when cognitive impairment progresses to dementia. These initial data need to be verified in larger cohorts. We believe that this pilot study underscores the importance of promoting such a specialized outpatient clinic to better characterize various aspects of autoantibody-mediated psychiatric disorders.

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.

Cerebrospinal Fluid Homer-3 Autoantibodies in a Patient with Amnestic Mild Cognitive Impairment.

(1) Background: Homer-3 antibodies are associated with cerebellar disease ranging from subacute degeneration to cerebellitis. However, cognitive impairment associated with Homer-3 autoantibodies has not been reported until now. (2) Methods: in retrospect, we systematically studied clinical, cranial magnetic resonance imaging (cMRI), electroencephalography (EEG) and lumbar puncture data, including neural autoantibodies of a clinical case. (3) Results: we describe the case of a 56-year-old woman presenting with amnestic mild cognitive impairment in association with serum and CSF detection of Homer-3 autoantibodies and a depressive syndrome. cMRI revealed cerebellar atrophy. CSF analysis showed elevated ptau181 protein. Applying the criteria for an autoimmune psychiatric syndrome revealed a plausible autoimmune basis for the mild cognitive impairment. (4) Discussions: our case report demonstrates an amnestic mild cognitive impairment and depressive symptoms associated with Homer-3 autoantibodies as a novel feature of Homer-3 antibody-related disease. We also propose that cognitive dysfunction might result from impaired AMPAR signaling in the hippocampus induced by Homer-3 antibodies, which will have to be verified in further research.

Apathy in patients with Alzheimer's disease is a cost-driving factor.

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.

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.

Subjective cognitive decline and stage 2 of Alzheimer disease in patients from memory centers.

INTRODUCTION: 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. METHODS: Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study. RESULTS: 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. DISCUSSION: 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.