Citations

Abstract Normal brain aging is accompanied by patterns of functional and structural change. Alzheimer's disease (AD), a representative neurodegenerative disease, has been linked to accelerated brain aging at respective age ranges. Here, we developed a deep learning-based brain age prediction model using fluorodeoxyglucose (FDG) PET and structural MRI and tested how the brain age gap relates to degenerative cognitive syndromes including mild cognitive impairment, AD, frontotemporal dementia, and Lewy body dementia. Occlusion analysis, performed to facilitate interpretation of the model, revealed that the model learns an age- and modality-specific pattern of brain aging. The elevated brain age gap in dementia cohorts was highly correlated with the cognitive impairment and AD biomarker. However, regions generating brain age gaps were different for each diagnosis group of which the AD continuum showed similar patterns to normal aging in the CU.

Abstract Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

Background: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. Methods: A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populations with DLB. Studies were included if they enrolled participants with DLB and met the National Institutes of Health criteria for a clinical trial. Data were collected using standardized forms. Outcome measures were categorized according to core and supportive features of DLB. Results: After de-duplication, 58 trials were identified. The most common cognitive outcome measures were the Mini Mental State Examination (n=24) and Cognitive Drug Research computerized Assessment System (n=5). The Clinician’s Assessment of Fluctuations was the most commonly used measure for fluctuations (n=4). Over half of studies used the Neuropsychiatric Inventory to assess behavioral symptoms (n=31). The Unified Parkinson’s Disease Rating Scale was frequently used for motor assessment (n=23). Conclusions and Relevance: Clinical trial outcomes used in DLB are rarely validated in this population and some lack face validity. There is a need to validate existing scales in DLB and develop DLB-specific outcome measures.

Hypertension is highly prevalent in the elderly population and microinfarcts are the most common vascular brain pathology identified in older adults at autopsy. We investigated the associations between systolic and diastolic blood pressures measured antemortem and the presence of microinfarcts at autopsy. Study subjects (n=302; age range=71-95) were participants in the population-based Mayo Clinic Study of Aging autopsy study, who had blood pressure measurements recorded during life. We investigated both cross-sectional systolic and diastolic blood pressure measurements at the baseline visit and the change in blood pressure (slope). Presence and location (subcortical or cortical) of chronic microinfarcts was abstracted from the autopsy reports. Of the 302 study subjects, 47 (16%) had cerebral microinfarcts, and, of those, 18 (38%) had subcortical microinfarcts and 29 (62%) had only cortical microinfarcts. The baseline blood pressures were not different between subjects with no microinfarcts, subcortical microinfarcts, and only cortical microinfarcts. In a logistic regression model including time between last blood pressure measurement and death, a greater decline in systolic [OR= 1.06 (1.01, 1.11); p=0.02]) and greater decline in diastolic [OR= 1.11 (1.02, 1.20); p=0.01] blood pressures were predictors of the presence of subcortical microinfarcts at autopsy. However, these variables were not associated with the presence of cortical microinfarcts. In conclusion, microinfarcts are common in the older adult population, and most of them are located in the cortex. A greater decline in both systolic and diastolic blood pressures and their association with subcortical microinfarcts, but not with cortical microinfarcts, may have implications for aggressive lowering of blood pressure in the elderly population.

Abstract Introduction A phase 2b clinical trial, HEADWAY‐DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). Methods HEADWAY‐DLB was a multinational, double‐blind, randomized, placebo‐controlled study. Two hundred sixty‐nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale–Part III (UPDRS‐III). Results Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS‐III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. Discussion Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY‐DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.

Abstract Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer’s disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer’s disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = −0.39, P = 0.04) and amyloid-PET uptake (r = −0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer’s disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer’s disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer’s disease co-pathology in patients with DLB is associated with more Alzheimer’s disease-like changes in functional connectivity. Furthermore, we found an association between the brain’s functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer’s disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.

ABSTRACT Background and Purpose Neurodegeneration of the substantia nigra in Lewy body disease is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. Our objective was to measure iron deposition in the substantia nigra in patients with probable dementia with Lewy bodies (pDLB) and patients who are at risk for pDLB by quantitative susceptibility mapping (QSM). Methods Participants included pDLB ( n = 36), mild cognitive impairment with at least one core feature of DLB (MCI‐LB; n = 15), idiopathic rapid eye movement sleep behavior disorder (iRBD; n = 11), and an age‐and gender‐matched clinically unimpaired control group ( n = 102). QSM was derived from multi‐echo 3D gradient recalled echo MRI at 3T, and groups were compared on mean susceptibility values of the substantia nigra and its relation to parkinsonism severity. Results Patients with pDLB had higher susceptibility in the substantia nigra compared to controls ( p < 0.001) and MCI‐LB ( p = 0.043). The susceptibility of substantia nigra showed an increasing trend from controls to iRBD and MCI‐LB, and to pDLB ( p < 0.001). Parkinsonism severity was not associated with the mean susceptibility in the substantia nigra in the patient groups. Conclusions Our data suggested that QSM is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in pDLB. The trend of increasing susceptibility from controls to iRBD and MCI‐LB, and to pDLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity.

Abstract Introduction Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (formed in 2018) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Seven participating sites have contributed n=170 polysomnographically-confirmed RBD patients. Data includes past medical and family history, self-report questionnaires, and neuropsychological, motor, sensory, and autonomic function testing. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer’s Disease and Related Dementias for future analysis. A final diagnosis for each subject was determined through an adjudication process by NAPS Consortium PIs; subjects were categorized as ether: 1) isolated RBD, 2) RBD+, 3) Early Symptomatic, or 4) Phenoconverted. Results Of the n=170 subjects, there were n=39 isolated RBD, n=81 RBD+, n=45 Early Symptomatic, and n=4 Phenoconverted. Isolated RBD subjects have no other early neurodegeneration signs/symptoms, those with RBD+ have at least one other identifiable early/mild symptom. The early symptomatic group includes those with mild or subjective cognitive impairment, pure autonomic failure, or possible multiple systems atrophy. The Phenoconverted group consists of those with Dementia with Lew Bodies, Dementia NOS, Parkinson’s Disease, or Parkinson’s NOS. The distribution of impairment across the 5 major domains (motor, cognitive, autonomic, sensory, and psychiatric) for each of the 4 groups will be described. Conclusion This interim analysis presents data on n=170 subjects. The target enrollment is n=360 across the 7 original sites plus 3 new sites. Future work will follow these subjects longitudinally to assess rates and predictors of phenoconversion. Support (if any) NIH NIA R34 AG056639 (YJ, BB)

Abstract Introduction REM sleep behavior disorder (RBD) is characterized by disruptive, violent dream enactment behaviors (DEB), necessitating symptomatic treatment to prevent injury and reduce DEB frequency and severity. Melatonin and clonazepam are regarded as RBD therapeutic mainstays, although outcomes data remains limited. We surveyed RBD patients to determine their outcomes following melatonin, clonazepam, and melatonin-clonazepam combination therapy. Methods Mayo Clinic RBD Patient Registry participants received an electronic survey concerning treatment type(s) and dose(s), efficacy, and adverse effects. The primary outcome was treatment efficacy, determined by comparing DEB frequency/severity ratings on a visual analog scale (VAS). Adverse effects severity was assessed by Likert scales. We comparatively analyzed VAS before and after treatment and adverse effects between treatments using non-parametric statistical tests. Results Sixty-eight of 109 patients responded (62.3%; 64 had analyzable data) with a mean age of 67.7 years. Fifty-seven (85%) were men, with mean RBD symptom duration of 13.9 years. Patients receiving each treatment were: melatonin=30, clonazepam=8, and combination=12; 14 received other or no treatment. Baseline VAS ratings were similar between groups. Only melatonin (p=0.003) and combination therapy (p=0.039) improved VAS ratings; clonazepam monotherapy did not improve VAS. Only melatonin monotherapy was reported to lower VAS compared to untreated patients (p=0.02). Optimally effective mean dosages were melatonin 9.95±5.06 mg and clonazepam 0.81±0.48 mg. Patient frequencies reporting one or more moderately-severe side effect(s) were similar between melatonin (15%), clonazepam (7%), and combination therapies (9%). Twenty-five (36.8%) patients had received only one medication trial, while 41.2% required more than one medication. Of these, 15 (22.1%) tried 2 and 13 (19.1%) tried 3 or more treatments. Conclusion Melatonin therapy at an approximate mean 10 mg dosage improved patient-reported DEB frequency/severity on VAS, compared between both previous intraindividual baseline ratings and with untreated patients, while clonazepam monotherapy did not, without differential adverse effects. Clonazepam monotherapy data were limited. These data inform future prospective melatonin symptomatic therapy trials for RBD. Additionally, 41.2% required more than one RBD pharmacological treatment, suggesting a current therapeutic gap and unmet need for future development of biologically-informed, evidence-based symptomatic RBD therapeutics. Support (if any):