Graff‐Radford, Neill R.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

Abstract Introduction Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD‐MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD‐MC and could help predict risk for dementia during trial enrollment. Methods We created a dementia risk score by entering standardized gray‐matter volumes from 231 DIAD‐MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD‐MC followed longitudinally. Results Our risk score separated asymptomatic versus demented DIAD‐MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD‐MC participants for prevention trials.

Objective: To determine if subcortical, brainstem and cerebellar lesion pattern characteristics of the different types of tau‐negative frontotemporal lobar degeneration (FTLD) would be similar to neocortical and hippocampal patterns [Type 1 has neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN), type 2 mainly DN, and type 3 mainly NCI (Mackenzie et al., 2006)]. Design/Methods: We analyzed 40 cases of tau‐negative FTLD from Mayo Clinic, Florida. For each case, 12 standardized sections covering 16 different brain regions or nuclei were sampled including neocortex, hippocampus, subcortical grey, brainstem and cerebellum. TDP‐43 immunohistochemistry was performed and abnormal immunoreactivity semiquantitated. Results: Thirty‐six cases were classified into one of the three types. For subcortical grey and brainstem regions, we did not see predominance of DN in type 2, and the density of NCI and DN were similar in type 3. Type 2 cases had significantly more NCI in basal ganglia compared to the other types (p<0.05). We found a trend that fine DN in hippocampal CA1 region was more frequent in type 1 compared to type 2 and 3 (p=0.07). A novel finding was that NCI were Pick body‐like in type 2 but granular‐like in type 3. Conclusion: This study extends the patterns of pathology previously described in the three variants of tau‐negative FTLD and shows how subcortical areas are affected by TDP‐43.

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.

AbstractPatients with early‐onset Alzheimer's disease (EOAD) are commonly excluded from large‐scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial‐ready network. LEADS will follow 400 amyloid beta (Aβ)‐positive EOAD, 200 Aβ‐negative EOnonAD that meet National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age‐matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post‐mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Abstract Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer’s disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain’s connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer’s disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer’s disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer’s disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer’s disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer’s sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer’s disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer’s disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer’s disease.

AbstractTo examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.