Gendron, Tania F.

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

Introduction: Extracranial carotid artery pathology accounts for 15-20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI. Hypothesis: There is a differential proteomic profile of vulnerable and non-vulnerable, thus, these can serve as potential biomarkers for disease progression, stroke prevention, and therapeutic targets. Methods: Consecutive patients undergoing carotid endarterectomy (CEA) were included in the study cohort with pre-operative MRA with VWI. A retrospective chart review was conducted to extract pertinent clinical data including cardiovascular risk factors and medications. The proteomic analysis involved Tandem Mass Tag (TMTpro) labeling of peptides, basic pH HPLC fractionation, and NanoLC-tandem mass spectrometry. Results: A total of sixteen plaques were retrieved from fifteen patients. There were 73.3% male patients. The most common comorbidities were hyperlipidemia (93.3%) and hypertension (80%). 31.2% of patients had symptomatic disease. Eleven plaques were vulnerable in preoperative MRI with VWI. From those, intraplaque hemorrhage was the most common feature (81.1%) . Proteomic analysis revealed 23 relevant proteins significantly elevated in vulnerable plaques, including Proteinase 3 (PRTN3), Phospholipid Transfer Protein (PLTP), and S100 Calcium-Binding Protein A12 (S100A12), with increased abundance exceeding two-fold changes or above (P<0.001). Conversely, three proteins exhibited reduced abundance in vulnerable plaques including Dynamin-3 (DNM3), Transmembrane Protein 181 (TMEM181), and Adducin-3 (ADD3) (P<0.05). All results are summarized in Figure 1A-C and Table I and II. Conclusion: This study contributes to the understanding of protein biomarkers associated with carotid plaque vulnerability, offering insights into disease progression, stroke prevention, and identification of potential therapeutic targets (Figure 1D) . Furthermore, these patients could benefit from early surgical intervention if these biomarkers were to be detected. We present a comprehensive study of multiple proteins with significant bioavailability in explanted plaque specimens that can serve as a foundation for identifying blood biomarkers for future validation studies.

AbstractINTRODUCTIONPlasma amyloid beta42/amyloid beta40 (Aβ42/Aβ40) and phosphorylated tau217 (p‐tau217) identify individuals with primary Alzheimer's disease (AD). They may detect AD co‐pathology in the setting of other primary neurodegenerative diseases, but this has not been systematically studied.METHODSWe compared the clinical, neuroimaging, and neuropathological associations of plasma Aβ42/Aβ40 (mass spectrometry), p‐tau217 (electrochemiluminescence), and neurofilament light ([NfL], single molecule array [Simoa]), as markers of AD co‐pathology, in a sporadic frontotemporal dementia (FTD) cohort (n = 620).RESULTSAβ42/Aβ40 showed no clinicopathological associations. High p‐tau217 was present in amnestic dementia (AmD) presumed to be due to FTD, logopenic primary progressive aphasia (lvPPA), and APOEε4 carriers, and correlated with worse baseline and longitudinal clinical scores, lower hippocampal volumes, and more severe AD co‐pathology (Braak Stage). NfL was elevated in all FTD phenotypes, and correlated with clinical scores and frontotemporal brain volumes.DISCUSSIONPlasma p‐tau217 has clinical, neuroimaging, and neuropathological correlates in sporadic FTD and may identify FTD cases with AD co‐pathology.Highlights Alzheimer's disease (AD) features could be identified with plasma phosphorylated tau217 (p‐tau217) in frontotemporal lobar degeneration (FTLD). Plasma p‐tau217 is a better discriminator of AD co‐pathology and AD‐associated features in FTLD than plasma amyloid beta42/amyloid beta40 (Aβ42/Aβ40) and neurofilament light (NfL). In FTLD, plasma p‐tau217, but not Aβ42/Aβ40 or neurofilament light, has phenotypical, neurocognitive, and neuroimaging correlates suggestive of AD co‐pathology.

AbstractBackgroundGrowth Differentiation Factor 15 (GDF15) is a TGF‐beta superfamily protein upregulated during immune‐mediated stress responses. Peripheral GDF15 is linked to adverse aging across organ systems including the brain. Immune dysregulation is implicated in frontotemporal dementia (FTD) pathogenesis. We examined how plasma GDF15 levels associated with longitudinal cognitive and neurofilament light chain (NfL) trajectories in adults with FTD and controls. Furthermore, we tested the utility of GDF15 as a prognostic biomarker against common inflammatory proteins (CRP and IL6).Method231 adults with FTD (24.35% sporadic FTD syndromes; 19.19% MAPT; 19.56% GRN; 22.14% C9orf72 pathogenic carriers) and 40 normal controls from the ALLFTD Consortium completed longitudinal neuropsychological testing and a blood draw with plasma analyzed on SomaScan V4.0 (baseline only: GDF15, CRP, and IL6) and Simoa (longitudinal: NfL). CRP and IL6 were selected as control markers to test the specificity of GDF15. Linear mixed effects models separately examined longitudinal cognition (global, executive functioning, memory, and language z‐scores) and plasma NfL levels as a function of baseline plasma GDF15, time, and their interaction, controlling for baseline age, sex, and education. Parallel models were conducted for CRP and IL6.ResultIn the whole cohort, higher baseline plasma GDF15 levels associated with steeper global cognitive decline (b = ‐3.91, p = 0.0092) and NfL accumulation (b = 3.88, p = 0.00088) over time. When examining cognitive domains, we found GDF15 only associated with worse executive functioning trajectories (b = ‐3.19, p = 0.0021). In contrast, baseline levels of CRP and IL6 did not display statistically significant relationships with cognitive or NfL trajectories. Prognostic effects of GDF15 remained statistically significant when restricting analyses to those with FTD pathogenic variants (b = ‐2.98, p = 0.0054 [global cognition], b = 2.69, p = 0.0098 [NfL]).ConclusionAdults with FTD and higher baseline peripheral GDF15 levels exhibit accelerated cognitive decline and neurodegeneration. Our results support GDF15 as a potential prognosticator of adverse clinical outcomes in FTD and highlight the relevance of GDF15‐specific pathways in FTD progression. Plasma GDF15 may provide utility over commonly examined inflammatory proteins and further work to explore its clinical value is indicated.

AbstractBackgroundIdentification of useful fluid biomarkers is expected to advance frontotemporal dementia spectrum disorders (FTD) care and therapeutic development. The clinical utility of emerging plasma Amyloid, Tau, and Neurodegeneration (ATN) biomarkers in FTD remains unexplored. This study analyzed ATN patterns by sporadic FTD phenotype, based on amyloid beta1‐42 (Aβ1‐42), amyloid beta1‐40 (Aβ1‐40), phospho‐tau217 (p‐tau217), and neurofilament (NfL) plasma concentrations.MethodThe present study included 625 participants enrolled in ALLFTD (46% female, median age 61 ± 12 years) for whom biomarker data were available. Plasma Aβ1‐42/Aβ1‐40 measures were determined by immunoprecipitation‐mass spectrometry whereas plasma p‐tau217 and NfL concentrations were respectively determined by electrochemiluminescence‐ and fluorescence‐based immunoassays. Biomarker concentrations were compared by phenotype and disease severity with ANOVA. Their diagnostic performance was tested with Receiver Operating Characteristic (ROC) curves, and biomarker relationships with measures of clinical severity were tested through linear regressions controlling for age, sex, and APOE genotype.ResultHigher plasma p‐tau217 and p‐tau217/Aβ1‐42, levels were observed in logopenic primary progressive aphasia (lvPPA) and amnestic dementia (AmD) cohorts, compared to other FTD groups. These biomarkers were not associated with disease severity but were affected by APOE4 genotype. High plasma NfL level was observed in fully symptomatic patients compared to controls, and as a function of disease severity. Plasma Aβ1‐42/Aβ1‐40 level was not different between phenotypes and was not affected by clinical severity. P‐tau217 level, but not Aβ1‐42/Aβ1‐40 or NfL levels showed high discrimination of lvPPA and AmD from other phenotypes (AUC = 0.87 (95% CI 0.77 – 0.96, p < 0.0001, 73% sensitivity, 92% specificity). The p‐tau217/Aβ1‐42 ratio improved this discrimination (AUC = 0.9, 95% CI 0.83 – 1, p < 0.0001, 77% sensitivity, 94% specificity). Plasma Aβ1‐42/Aβ1‐40, p‐tau217, NfL, p‐tau217/Aβ1‐42, p‐tau217/NfL, and (Aβ1‐42 x p‐tau217)/NfL were associated with cognitive (MoCA, CVLT), motor (UPDRS), and social behavior (RSMS) performances at baseline.ConclusionPlasma p‐tau217/Aβ1‐42 identifies, with high specificity, two phenotypes associated with Alzheimer’s disease: lvPPA and AmD. Pending molecular neuroimaging and neuropathological confirmation, this biomarker could be of value to identify primary Alzheimer’s disease pathology or co‐pathology associated with Alzheimer’s disease when sporadic FTD is suspected.

AbstractBackgroundSex differences in neurodegenerative diseases can impact accurate diagnosis and management. Emerging data suggest there may be sex differences in frontotemporal dementia (FTD) prevalence and clinical manifestation. However, prior studies lacked longitudinal assessment and were limited in capturing sex differences in earliest stages of disease (e.g., preclinical). We evaluated how sex impacts longitudinal clinical outcomes in individuals carrying autosomal dominant variants for FTD.Method337 participants carrying pathogenic variants in MAPT, GRN, or C9orf72 completed longitudinal evaluations (2.4 average visits, range = 1‐6), including neuropsychological and functional assessments, and plasma analyzed for neurofilament light chain (NfL). FTLD Clinical Dementia Rating Scale (FTLD‐CDR) classified disease stage at study entry (FTLD‐CDR = 0: asymptomatic; FTLD‐CDR = 0.5: MCI; FTLD‐CDR> 0.5: Dementia). Linear mixed‐effects models evaluated the effect of sex on longitudinal clinical trajectories, including the effect of disease stage at study entry.ResultMale and female carriers were similarly distributed with respect to baseline demographics and most clinical outcomes. However, women exhibited higher baseline NfL than men. Not accounting for disease stage, men and women did not show statistical differences on cognitive, functional, or NfL trajectories. However, when accounting for disease stage, there was a significant interaction between baseline disease stage, sex, and time on cognitive, NfL, and functional trajectories. While sex differences were not statistically significant among asymptomatic carriers, women with MCI/dementia evidenced more rapid cognitive, NfL and functional decline over time compared to men. To evaluate the role of pathology burden, we tested the interaction between baseline NfL, sex, and time on clinical outcomes stratified by disease stage. In asymptomatic participants, women showed an attenuated adverse relationship between baseline NfL and clinical trajectories compared to men. No statistically significant sex differences were evident in the relationship between baseline NfL and clinical outcomes in participants with MCI/dementia.ConclusionIn familial FTD, women evidenced steeper clinical declines than men after symptom onset. Accounting for pathology, baseline NfL was a stronger predictor of clinical decline in asymptomatic men compared to women. NfL may be a less sensitive prognostic tool for clinical progression in women with FTD, particularly early in disease. This may reflect early “cognitive resilience” to neurodegeneration in women.