Boeve, Brad

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Abstract Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer’s disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10–20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer’s disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer’s Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59–0.91) and Alzheimer’s disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer’s subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment.

Abstract Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer’s Disease Neuroimaging Initiative, n = 53) and who had Alzheimer’s disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer’s Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer’s disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer’s disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.