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A growing body of literature suggests that chronic-pain patients suffer from problems in various neuropsychological domains, including executive functioning. In order to better understand which components of executive functioning (inhibition, shifting and/or updating) might be especially affected by pain and which mechanisms might underlie this association, we conducted a systematic review, including both chronic-pain studies as well as experimental-pain studies. The chronic-pain studies (N = 57) show that pain is associated with poorer executive functioning. The fi ndings of experimental-pain studies (N = 28) suggest that this might be a bidirectional relationship: Pain can disrupt executive functioning, but poorer executive functioning might also be a risk factor for higher vulnerability to pain. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Participation in multimodal leisure activities, such as playing a musical instrument, may be protective against brain aging and dementia in older adults (OA). Potential neuroprotective correlates underlying musical activity remain unclear. Objective: This cross-sectional study investigated the association between lifetime musical activity and resting-state functional connectivity (RSFC) in three higher-order brain networks: the Default Mode, Fronto-Parietal, and Salience networks. Methods: We assessed 130 cognitively unimpaired participants (≥ 60 years) from the baseline cohort of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Lifetime musical activity was operationalized by the self-reported participation in musical instrument playing across early, middle, and late life stages using the Lifetime of Experiences Questionnaire (LEQ). Participants who reported musical activity during all life stages (n = 65) were compared to controls who were matched on demographic and reserve characteristics (including education, intelligence, socioeconomic status, self-reported physical activity, age, and sex) and never played a musical instrument (n = 65) in local (seed-to-voxel) and global (within-network and between-network) RSFC patterns using pre-specified network seeds. Results: Older participants with lifetime musical activity showed significantly higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal as well as frontal regions, namely the right temporal pole and the right precentral gyrus extending into the superior frontal gyrus, compared to matched controls. There were no significant group differences in global RSFC within or between the three networks. Conclusion: We show that playing a musical instrument during life relates to higher RSFC of the medial prefrontal cortex with distant brain regions involved in higher-order cognitive and motor processes. Preserved or enhanced functional connectivity could potentially contribute to better brain health and resilience in OA with a history in musical activity. Trial registration: German Clinical Trials Register (DRKS00007966, 04/05/2015). [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology—not just arterial hypertension—impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition. Methods: We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function—derived from multiple neuropsychological tests using confirmatory factor analysis—, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). Results: Subjects with hypertension or Aβ positivity presented the largest WMH volumes (pFDR < 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aβ: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aβ: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aβ: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aβ: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aβ: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aβ: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (pFDR < 0.05). Aβ positivity was negatively associated with cognitive performance (direct effect—memory: − 0.33 ± 0.08, pFDR < 0.001; executive: − 0.21 ± 0.08, pFDR < 0.001; PACC5: − 0.29 ± 0.09, pFDR = 0.006; ΔPACC5: − 0.34 ± 0.04, pFDR < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect—memory: − 0.05 ± 0.02, pFDR = 0.029; executive: − 0.04 ± 0.02, pFDR = 0.067; PACC5: − 0.05 ± 0.02, pFDR = 0.030; ΔPACC5: − 0.09 ± 0.03, pFDR = 0.043) and WMH in the optic radiation partially mediated that between Aβ positivity and memory (indirect effect—memory: − 0.05 ± 0.02, pFDR = 0.029). Conclusions: Posterior white matter is susceptible to hypertension and Aβ accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. Trial registration: German Clinical Trials Register (DRKS00007966, 04/05/2015). [ABSTRACT FROM AUTHOR]

Introduction: Different psychotherapeutic interventions for late-life depression (LLD) have been proposed, but their evaluation in large, multicenter trials is rare. Objective: The present study evaluated the efficacy of a specific cognitive behavioral therapy (CBT) for LLD (LLD-CBT) in comparison with a supportive unspecific intervention (SUI), both administered in a specialist psychiatric outpatient setting. Methods: In this randomized, controlled, parallel group trial, we recruited participants (≥60 years) with moderate to severe depression at 7 trial sites in Germany. Participants were randomly assigned to the LLD-CBT or SUI group. The primary outcome was depression severity at the end of treatment measured by change on the Geriatric Depression Scale (GDS). Secondary outcomes included change in observer-rated depression, anxiety, sleep ratings, and quality of life throughout the treatment phase and at 6-month follow-up. Results: Between October 1, 2018, and November 11, 2020, we randomly assigned 251 patients to either LLD-CBT (n = 126) or SUI (n = 125), of whom 229 provided primary-outcome data. There was no significant between-group difference in the change in GDS scores at the end of treatment (estimated marginal mean difference: −1.01 [95% CI: −2.88 to 0.86]; p = 0.287). Secondary analyses showed significant improvements in several outcomes after 8 weeks and at follow-up in both treatment arms. Conclusions: Our data suggest that LLD-specific CBT and a supportive unspecific treatment both provide clinical benefit in patients with moderate to severe LLD without evidence for superiority of LLD-CBT. [ABSTRACT FROM AUTHOR]

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-Aβ42/Aβ40 (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. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer's disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD).Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD.Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n = 82 "AD relatives"; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n =  236 healthy controls without FHAD from the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD ("SCD-plus score"). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group.Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group.Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression. [ABSTRACT FROM AUTHOR]