Citations

Abstract Introduction This study investigated the impact of visual editing of sleep recordings for use in predicting neurodegenerative disorder (NDD) risk. Methods All participants underwent in-home Sleep Profiler studies. Forty-four were diagnosed with mild cognitive impartment (MCI = 40) or Alzheimer’s disease (AD = 4)(MCI/AD: 55% women, 72.6+/-8.6 years), 26 with REM sleep behavior disorder (RBD: women = 27%, age = 67+/-9.8), and 29 were controls (NC: women = 69%, age = 63+/-11.5). A 4-class machine learning algorithm used age plus eight sleep biomarkers to assign NDD risk probabilities. Records with CG-assigned probabilities >70% were labeled Probably-Normal, and from 45-70% Likely-Normal. Similar thresholds were used to assign Likely- or Probably-Abnormal. NDD risk characterizations were generated based on auto-scoring (“auto”), and again after the recordings were visually edited for accuracy (“edited”). Results Comparing the auto- vs. edited-NDD classifications in the MCI/AD group, the same NDD risk classifications were observed in 91% (39/43), with 2 cases shifting from Likely-Normal to Probably-Normal, one shifted from Likely-AD to Likely-Normal with AD Indications, and one changed from Probably-AD to Likely-AD. The same NDD risk classifications were observed in 81% (21/26) of the RBD cases, 3 shifted from Probably-Abnormal to Likely-Abnormal, one shifted from Likely-Normal to Probably-Normal, and one changed from Likely-Abnormal to Likely-Normal. The same NDD risk classifications were observed in 86% of the NC group, with 4 cases shifting from Likely-Normal to Probably-Normal. Conclusions These findings suggest that the likelihood of a gross misclassification of NDD risk resulting from auto-detected sleep biomarkers is relatively low with inconsistencies directed toward slightly increased NDD risk classifications.

Abstract A workgroup assembled by the Alzheimer’s Association recently described a conceptual framework for Alzheimer’s disease biological staging based on amyloid and tau PET imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer’s disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer’s Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer’s Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer’s disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer’s disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer’s Disease Neuroimaging Initiative cohort. This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer’s disease into four biological stages with distinct characteristics.

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Abstract INTRODUCTION Primary age‐related tauopathy (PART) is defined by neurofibrillary tangles (NFTs) with absent‐minimal amyloid beta (Aβ) plaques. Currently, definitive diagnosis of PART occurs with autopsy. This study investigated whether [ 18 F]fluorodeoxyglucose positron emission tomography (FDG‐PET) could detect PART‐related metabolic changes and assessed the impact of common co‐pathologies. METHODS We performed a retrospective cross‐sectional study of 88 individuals (mean age 85.6) with autopsy‐confirmed PART (Braak I to IV; Thal phases 0 to 2) who underwent ante mortem FDG‐PET. Visual ratings and standardized uptake value ratios (SUVRs) were analyzed in medial and lateral temporal lobes, inferior temporal pole, precuneus, and posterior cingulate regions. RESULTS Medial temporal hypometabolism was observed in PART, in the presence of co‐pathologies. Argyrophilic grain disease and TAR DNA‐binding protein 43 were associated with greater hypometabolism ( p < 0.01). Lewy body disease affected parietal regions. DISCUSSION FDG‐PET reveals that PART‐related hypometabolism occurs when co‐pathologies are present, but PART alone appears to have minimal effect on medial temporal lobe hypometabolism. Highlights FDG‐PET hypometabolism worsens with Braak NFT stage. FDG‐PET detects mild lateral temporal lobe hypometabolism in PART alone. PART alone has a minimal effect on medial temporal lobe hypometabolism. Medial temporal hypometabolism is worse in PART with TDP‐43 and especially AGD. The presence of LBD contributes to parietal hypometabolism on FGD‐PET in PART.

Background Dementia with Lewy bodies (DLB) is a common degenerative dementia, but no studies investigate bereaved caregiver experiences. Objective To investigate the experiences of caregivers three months after the death of persons with DLB using a mixed-methods approach. Methods Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were followed prospectively every 6 months until the person with DLB died. Caregivers completed a study visit with questionnaires and a semi-structured interview ∼3 months later. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of post-death measures with pre-death patient and caregiver variables. Thematic analysis was used to analyze the interviews. Results Seventy-three caregivers completed visits (mean 3.5 months post-death). Most of the caregivers were women (82.2%) and spouses (76.7%) or adult children (17.8%). Over 40% had scores indicating risk for clinical depression. Post-death caregiver experiences (depression, quality of life, grief, resilience) correlated with pre-death caregiver experiences. Post-death experiences did not associate with patient characteristics, disease-related symptoms, or healthcare services used in the last 6 months of life. Trajectories for caregiver measures from pre- to post-death visits varied widely. Interview themes included grief and sadness, anger, guilt and regret, relief, appreciation/gratitude, and adjusting to a new normal. Conclusions The finding that pre-death caregiving experiences have the strongest association with post-death experiences emphasizes the critical importance of accessible and evidence-based caregiver support before and after the death of a person with DLB. Research is needed to develop interventions for current and bereaved caregivers of individuals with DLB. Trial registration information NCT04829656 (submitted 2021-03-22).

Abstract Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease‐modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging‐Alzheimer's Association) and alpha‐synucleinopathy and dopaminergic degeneration (Neuronal α‐synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha‐synuclein (α‐synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.

Abstract INTRODUCTION When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid‐beta‐peptide (Aβ) related pathology are discordant, therapeutic decision‐making becomes uncertain. METHODS Using data from patients with mild cognitive impairment ( n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints. RESULTS Discordant groups for brain Aβ status (CSF+/PET− and CSF−/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF−/PET− group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures. DISCUSSION In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET− or CSF−/PET+ brain amyloid patterns did not exhibit incipient decline. Highlights Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF‐PET discrepant persons with MCI tend to have less abnormal values initially. CSF‐PET discrepant persons with MCI have a benign prognosis at 4 years.