Citations

AbstractBackgroundAs the only optically accessible part of the central nervous system, the retina represents an intriguing opportunity for the detection of biomarkers for Alzheimer’s disease (AD). This study evaluated the performance of the Retinal Deep PhenotypingTM platform, a digital biomarker platform comprising a hyperspectral retinal camera and image analysis algorithms, for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in older adults. A set of phenotypic features that correlates with the cerebral amyloid status as determined by amyloid PET scan were identified and used to train a classifying algorithm.MethodHyperspectral retinal images acquired with a Mydriatic Hyperspectral Retinal Camera from 194 participants (age ≥ 50 years), including cognitively normal and cognitively impaired (mild cognitive impairment and dementia) across 5 imaging sites were processed in order to train the model. Of these 194 participants, 73 individuals (38%) were amyloid‐positive, as confirmed by unanimous readings of PET scans by a panel of 3 expert reviewers. The pre‐processed hyperspectral images were segmented into various anatomical sites, and a texture‐based approach was used to extract several thousands of spatial‐spectral features. The most relevant features for the classification task were selected using a minimum redundancy maximum relevance (MRMR) algorithm and used to train a linear support vector machine (SVM) classifier. A nested, cross‐validation technique was used to evaluate the performance of the classifier.ResultThe resulting model based on the 17 most significant features showed high performance to discriminate between amyloid positive and negative subjects with an area under the receiver operating curve (AUCROC) of 0.87 (95% CI: 0.83 – 0.92).ConclusionThe Retinal Deep PhenotypingTM platform shows promise for detecting the likely cerebral amyloid PET status in adults 50 years and older from a simple, non‐invasive retinal scan and could provide an accessible means to identify individuals with abnormal cerebral amyloid in a clinical or drug development context. This phenotyping platform provides a flexible approach that could also be used for the detection of multiple biomarkers involved in cognitive decline from the same hyperspectral images of the retina.

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

AbstractBackgroundThe Neurodegenerative Research Group (NRG) at Mayo clinic has followed patients with degenerative speech and/or language disorders for over a decade. In this presentation I will present data from this cohort to inform a broader discussion about the importance of apraxia of speech (AOS) and its subtypes, heterogeneity within the agrammatic PPA variant, and perils of mixed phenotypes.MethodWe reviewed the NRG database to identify patients who initially presented with isolated (PPAOS), AOS in conjunction with agrammatic aphasia (AOS‐PAA), isolated agrammatic aphasia (PAA), and patients who had PAA or AOS overlapping with another degenerative diagnosis. Data from the following clinical instruments were abstracted: WAB AQ (aphasia severity), UPDRS III (parkinsonism), WAB Praxis (ideomotor apraxia), and the MoCA (cognitive ability). We assessed the effect of baseline diagnosis and AOS subtype on these outcomes over time using Bayesian linear mixed effects models. We qualitatively reviewed longitudinal diagnostic trajectories. Preliminary analyses were done on available autopsy data.ResultPAA was associated with greater aphasia at baseline and more rapid decline; PPAOS was associated with normal language at baseline and slow decline; and PAA‐AOS with intermediate baseline aphasia and decline. However, for those with AOS longitudinal decline differed based on AOS subtype: prosodic PPAOS was associated with the slowest decline and phonetic PAA‐AOS with the fastest. Some patients met criteria for non‐PPA disorders during follow up. However, compared to patients who met criteria for these disorders at enrollment, the speech/language‐first patients remained qualitatively distinct, and neither resembled the cases that were mixed at onset. Preliminary autopsy data suggests that AOS is predictive of tau and that the specific tauopathy may be related to the initial syndrome and AOS subtype.ConclusionThe differences between PAA, PAA‐AOS and PPAOS suggest that these disorders should not be lumped. In fact, the longitudinal trajectories are sufficiently different that doing so would add noise to observational and interventional studies. Instead, more detailed phenotyping, including AOS subtype, can aid prognostication and may improve prediction of the underlying pathology. Finally, caution should be exercised when considering PPAOS and PPA patients for other FTLD diagnostic categories.

Abstract An emerging area of research extends work on couple functioning and physical health to gut health, a critical marker of general health and known to diminish with age. As a foray into this area, we conducted a pilot study to determine feasibility of data collection (questionnaires and a stool sample) among older adult couples. Participants were recruited from the community using a variety of methods including social media. Among 41 persons responding with interest across recruitment sources, 32 were contacted for screening. Inclusion criteria were: age 60+, marriage or cohabiting partnership, and English speaking/understanding. Exclusion criteria were a gastrointestinal disorder, receiving enteric nutrition, use of antibiotics (past month), cancer treatment (past 6 months), and a +COVID-19 diagnosis (past 2 months). Among 31 eligible couples, 30 consented. All 60 participants completed questionnaires and provided a stool sample using DNAgenotek’s OMR-200 collection kit, chosen for its ease and because samples can be stored at room temperature for 60 days. Sample characteristics were: M (SD) age = 66.57 (4.78); 53.3% female; 91.7% White; 1.7% Latinx; and 78.3% college-educated. 2 couples were same-sex. 43% reported at least one health condition and 25% reported use of a proton pump inhibitor (which can affect the gut microbiome), though none daily. Relational well-being was moderate-high on average per measures of dyadic adjustment and intimacy. Despite original plans to recruit couples in-person from a retirement community, remote operations were feasible via online assessment and study-coordinated shipping, a necessary yet fruitful shift due to the SARS-CoV-2 pandemic.

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Abstract Aims Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP‐43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP‐43 pathology (FTLD‐TDP). Methods The study included 146 autopsy‐confirmed cases of FTLD‐TDP and 55 cases of FTLD‐TDP with motor neuron disease (FTLD‐MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated‐tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72 , GRN and MAPT was performed on select cases. Results We found 72 cases (36%) with primary age‐related tauopathy (PART), 85 (42%) with ageing‐related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD‐TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. Conclusion The coexistence of TDP‐43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP‐43‐positive astrocytic plaques may suggest that CBD and FTLD‐TDP were independent disease processes in the two patients with both tau and TDP‐43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

Abstract Venomous snakebite is an important cause of preventable death. The World Health Organization (WHO) set a goal to halve snakebite mortality by 2030. We used verbal autopsy and vital registration data to model the proportion of venomous animal deaths due to snakes by location, age, year, and sex, and applied these proportions to venomous animal contact mortality estimates from the Global Burden of Disease 2019 study. In 2019, 63,400 people (95% uncertainty interval 38,900–78,600) died globally from snakebites, which was equal to an age-standardized mortality rate (ASMR) of 0.8 deaths (0.5–1.0) per 100,000 and represents a 36% (2–49) decrease in ASMR since 1990. India had the greatest number of deaths in 2019, equal to an ASMR of 4.0 per 100,000 (2.3-5.0). We forecast mortality will continue to decline, but not sufficiently to meet the WHO’s goals. Improved data collection should be prioritized to help target interventions, improve burden estimation, and monitor progress.

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

Abstract The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer’s Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin–eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a ‘neuron-to-inclusion’ score (TDP-type C mean score – neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.