Frontotemporal Lobar Degeneration Patients Research Articles

Cerebrospinal fluid/serum albumin ratio in patients with Lewy body disease: a systematic review and meta-analysis

BackgroundAbnormal cerebrospinal fluid (CSF)/serum albumin ratio (Qalb) levels have been observed in patients with cognitive impairment. Few studies have specifically focused on Lewy Body Disease (LBD), and the results were controversial. Thus, we conducted this systematic review and meta-analysis to investigate Qalb levels in patients with LBD by including data from different studies.MethodWe systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for a collection of studies containing studies comparing Qalb levels in patients with LBD and healthy controls (including healthy controls and other dementia subtypes). In the initial search, 86 relevant papers were retrieved. Standardized mean differences (SMD) in Qalb levels were calculated using a random effects model.ResultsA total of 13 eligible studies were included. Mean Qalb levels were significantly higher in patients with LBD compared to healthy older adults [standardized mean difference (SMD): 2.95, 95% confidence interval (CI): 0.89–5.00, Z = 2.81, p = 0.005]; and were significantly higher in patients with LBD than in patients with Alzheimer’s disease (AD) (SMD: 1.13, 95% CI: 0.42–1.83, Z = 3.15, p = 0.002);whereas mean Qalb levels were significantly higher in patients with frontotemporal lobar degeneration (FTLD) compared to those with AD (SMD: 1.13, 95% CI,0.14–2.13, Z = 2.24, p = 0.03).ConclusionQalb levels were significantly elevated in LBD patients compared with normal older adults and were higher than those in AD patients and FTLD patients, which helped in the differential diagnosis of LBD from other neurodegenerative diseases.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024496616.

Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%–25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones.Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration.

Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.

Phosphomimetic substitutions in TDP-43’s transiently α-helical region suppress phase separation

Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates of several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer’s disease, to the point that the presence of phosphorylated TDP-43 is considered a hallmark of some of these diseases. The majority of known TDP-43 phosphorylation sites detected in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients is located in the low-complexity domain (LCD), the same domain that has been shown to be critical for TDP-43 liquid-liquid phase separation (LLPS). However, the effect of these LCD phosphorylation sites on TDP-43 LLPS has been largely unexplored, and any work that has been done has mainly focused on sites near the C-terminal end of the LCD. Here, we used a phosphomimetic approach to explore the impact of phosphorylation at residues S332 and S333, sites located within the transiently α-helical region of TDP-43 that have been observed to be phosphorylated in disease, on protein LLPS. Our turbidimetry and fluorescence microscopy data demonstrate that these phosphomimetic substitutions greatly suppress LLPS, and solution NMR data strongly suggest that this effect is at least in part due to the loss of α-helical propensity of the phosphomimetic protein variant. We also show that the S332D and S333D substitutions slow TDP-43 LCD droplet aging and fibrillation of the protein. Overall, these findings provide a biophysical basis for understanding the effect of phosphorylation within the transiently α-helical region of TDP-43 LCD on protein LLPS and fibrillation, suggesting that phosphorylation at residues 332 and 333 is not necessarily directly related to the pathogenic process.

Association of Choroid Plexus Volume With Serum Biomarkers, Clinical Features, and Disease Severity in Patients With Frontotemporal Lobar Degeneration Spectrum.

Choroid plexus (ChP) is emerging as a key brain structure in the pathophysiology of neurodegenerative disorders. In this observational study we investigated ChP volume in a large cohort of frontotemporal lobar degeneration (FTLD) spectrum patients to explore a possible link between ChP volume and other disease-specific biomarkers. Participants included patients meeting clinical criteria for a probable syndrome in the FTLD spectrum. Structural brain MRI imaging, serum neurofilament light (NfL) and serum phosphorylated-Tau181 (p-Tau181), cognitive and behavioral data were collected. MRI ChP volumes were obtained from an ad-hoc segmentation model based on a Gaussian Mixture Models (GMM) algorithm. Three-hundred and sixteen patients within FTLD spectrum were included in this study, specifically 135 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD), 75 primary progressive aphasia (PPA), 46 progressive supranuclear palsy (PSP), 60 corticobasal syndrome (CBS). In addition, 82 age-matched healthy subjects were recruited as controls (HC). ChP volume was significantly larger in FTLD patients compared with HC, across the clinical subtype. Moreover, we found a significant difference in ChP volume between HC and patients stratified for disease-severity based on CDRplus NACC FTLD, including patients at very early stage of the disease. Interestingly, ChP volume correlated with serum NfL, cognitive/behavioural deficits, as well as with patterns of cortical atrophy. Finally, ChP volume seemed to discriminate HC from FTLD patients better than other previously identified brain structure volumes. Considering the clinical, pathological, and genetic heterogeneity of the disease, ChP could represent a potential biomarker across the FTLD spectrum, especially at the early stage of disease. Further longitudinal studies are needed to establish its role in disease onset and progression. This study provides Class III evidence that choroid plexus volume, as measured on MRI scan, can assist in differentiating patients with FTLD from healthy controls, and in characterizing disease severity.

Comparative assessment of regional tau distribution by Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer's & frontotemporal lobar degeneration patients.

Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.

Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination.

Heterozygous mutations in the granulin (GRN) gene, resulting in the haploinsufficiency of the progranulin (PGRN) protein, is a leading cause of frontotemporal lobar degeneration (FTLD). Complete loss of the PGRN protein causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Polymorphisms in the GRN gene have also been associated with several other neurodegenerative diseases, including Alzheimer's disease (AD), and Parkinson's disease (PD). PGRN deficiency has been shown to cause myelination defects previously, but how PGRN regulates myelination is unknown. Here, we report that PGRN deficiency leads to a sex-dependent myelination defect with male mice showing more severe demyelination in response to cuprizone treatment. This is accompanied by exacerbated microglial proliferation and activation in the male PGRN-deficient mice. Interestingly, both male and female PGRN-deficient mice show sustained microglial activation after cuprizone removal and a defect in remyelination. Specific ablation of PGRN in microglia results in similar sex-dependent phenotypes, confirming a microglial function of PGRN. Lipid droplets accumulate in microglia specifically in male PGRN-deficient mice. RNA-seq analysis and mitochondrial function assays reveal key differences in oxidative phosphorylation in male versus female microglia under PGRN deficiency. A significant decrease in myelination and accumulation of myelin debris and lipid droplets in microglia were found in the corpus callosum regions of FTLD patients with GRN mutations. Taken together, our data support that PGRN deficiency leads to sex-dependent alterations in microglia with subsequent myelination defects.

Incidence of syndromes associated with Frontotemporal Lobar Degeneration (S19.004)

<h3>Objective:</h3> To assess FTLD epidemiology across Europe. The FRONTotemporal dementia Incidence European Research Study (FRONTIERS) was established for this purpose. <h3>Background:</h3> Diagnostic incidence data for syndromes associated with Frontotemporal Lobar Degeneration (FTLD) in multinational studies is urgent in light of upcoming therapeutic approaches. <h3>Design/Methods:</h3> Retrospective population-based study conducted from June 1^st, 2018 to May 31^st, 2019 in thirteen tertiary FTLD research clinics from the UK, Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy. All new FTLD-associated cases (hereafter: incident FTLD) during the study period were counted, with a combined catchment population of over 11,000,000 person-years. Random intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. <h3>Results:</h3> Based on 267 identified cases (mean age±standard deviation=66.7±9.02; female=41.6%), the annual incidence rate for FTLD in Europe was 2.36 per 100,000 person-years (95% Confidence Intervals [CI]=1.59–3.51). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71. Overall, the incidence was higher among men (2.84 per 100,000 person-years; 95% CI=1.88–4.27) than among women (1.91 per 100,000 person-years; 95% CI=1.26–2.91). Behavioural variant frontotemporal dementia was the most common phenotype (40.07%), followed by primary progressive aphasia (28.46%) and extrapyramidal phenotypes (25.84%). Frontotemporal dementia with amyotrophic lateral sclerosis was the rarest phenotype (5.62%). Almost 35% of FTLD patients presented a family history of dementia. The estimated number of new FTLD cases in Europe is approximately 12,000 people per year. <h3>Conclusions:</h3> FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD epidemiology may contribute to appropriate health and social care planning, and in the design of future clinical trials. <b>Disclosure:</b> Dr. Logroscino has nothing to disclose. Marco Piccininni has received research support from Center for Stroke Research Berlin (private donations). Caroline Graff has nothing to disclose. Dr. Hardiman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave Pharmaceuticals. Dr. Hardiman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cytokinetics . Dr. Hardiman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hardiman has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Taylor and Francis. The institution of Dr. Hardiman has received research support from Science Foundation Ireland. The institution of Dr. Hardiman has received research support from HRB. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Ludolph has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen . Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Pharma AG . Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharma. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biologix FZCo.. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biologix FZCo.. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biologix FZCo.. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ludolph has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. The institution of Dr. Moreno has received research support from Instituto de Salud Carlos III. The institution of Dr. Moreno has received research support from Tau Consortium. Markus Otto has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Markus Otto has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axon Neuroscience. Markus Otto has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Markus Otto has a non-compensated relationship as a Sponor of research with Federal ministry of education and research that is relevant to AAN interests or activities. Anne Remes has nothing to disclose. James Rowe, BA BM BCh PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. James Rowe, BA BM BCh PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SV Health. James Rowe, BA BM BCh PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astex. James Rowe, BA BM BCh PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Asceneuron. James Rowe, BA BM BCh PhD has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GE Healthcare. The institution of James Rowe, BA BM BCh PhD has received research support from Janssen. The institution of James Rowe, BA BM BCh PhD has received research support from Lilly. The institution of James Rowe, BA BM BCh PhD has received research support from AZ Medimmune. James Rowe, BA BM BCh PhD has received publishing royalties from a publication relating to health care. Harro Seelaar, MD, PhD has nothing to disclose. Dr. Solje has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Diagnostics. Dr. Solje has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Solje has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Solje has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Solje has received research support from Instrumentarium Science Foundation. Dr. Solje has received research support from The Finnish Brain Foundation. Dr. Solje has received research support from Orion Research Foundation. The institution of Dr. Solje has received research support from Sigrid Juselius Foundation. The institution of Dr. Solje has received research support from Finnish Medical Foundation. The institution of Dr. Solje has received research support from EU-JPND. The institution of Dr. Solje has received research support from Orion Corpporation. Elka Stefanova has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACTAVIS d.o.o. Elka Stefanova has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Krka d.o.o.. The institution of Elka Stefanova has received research support from Alzheimer Association. Elka Stefanova has a non-compensated relationship as a lecturing on EAN autumn school with EAN that is relevant to AAN interests or activities. Latchezar Traykov has nothing to disclose. Vesna Jelic has nothing to disclose. Melissa Thaeri Rydell has nothing to disclose. Niall Pender has nothing to disclose. Sarah Anderl-Straub has nothing to disclose. Myriam Barandiaran has nothing to disclose. Alazne Gabilondo Lopez, MD has nothing to disclose. Suvi-Johanna Kruger has nothing to disclose. Dr. Murley has nothing to disclose. An immediate family member of Timothy Rittman has received personal compensation for serving as an employee of Crossref. An immediate family member of Timothy Rittman has received personal compensation for serving as an employee of MDPI. Timothy Rittman has received personal compensation in the range of $5,000-$9,999 for serving as a Study clinician with Oxford Biomedica. Timothy Rittman has received personal compensation in the range of $0-$499 for serving as a Reviewer with National Institute for Health and Clinical Excellence. Emma L van der Ende has nothing to disclose. Dr. Van Swieten has nothing to disclose. Paivi Hartikainen, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Paivi Hartikainen, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Paivi Hartikainen, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Paivi Hartikainen, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Paivi Hartikainen, MD has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Gorana Mandic-Stojmenovic has nothing to disclose. Shima Meherabian has nothing to disclose. Luisa Benussi has nothing to disclose. Antonella Alberici has nothing to disclose. Maria Teresa Dell’Abate has nothing to disclose. The institution of Dr. Zecca has received research support from Ente Ospedaliero Cantonale. Barbara Borroni has nothing to disclose.

Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer's Disease and Frontotemporal Dementia.

Alzheimer's disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers (Amyloid β42, p-Tau181, t-Tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43)) were determined by single molecule array technology (SIMOA®) in control subjects (n = 22), mild cognitive impairment due to AD (MCI-AD, n = 33), mild dementia due to AD (n = 12), and FTLD (n = 11) patients. The correlations between plasma and cerebrospinal fluid (CSF) levels and the accuracy of plasma biomarkers for AD early diagnosis and discriminating from FTLD were analyzed. As result, plasma p-Tau181 and NfL levels correlated with the corresponding CSF levels. Additionally, plasma p-Tau181 showed good accuracy for distinguishing between the controls and AD, as well as discriminating between AD and FTLD. Moreover, plasma NfL could discriminate dementia-AD vs. controls, FTLD vs. controls, and MCI-AD vs. dementia-AD. Therefore, the determination of these biomarkers in plasma is potentially helpful in AD spectrum diagnosis, but also discriminating from FTLD. In addition, the accessibility of these potential early and specific biomarkers may be useful for AD screening protocols in the future.

Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study.

Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95%. Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

Plasma GFAP:NfL discriminates FTLD‐tau from FTLD‐TDP

AbstractBackgroundBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) with tau (FTLD‐tau) from TDP‐43 (FTLD‐TDP). In FTLD patients with autopsy‐ or mutation‐confirmed pathology, we tested the glial fibrillary acidic protein (GFAP) to neurofilament light chain (NfL) ratio (GFAP/NfL) in plasma. We validated application of GFAP/NfL ratio in an independent sample of frontotemporal dementia (FTD).MethodsTraining sample was composed of 105 FTLD‐TDP and 44 FTLD‐tau participants, with pathology confirmed by either autopsy or pathogenic mutations (MAPT, C9orf72, GRN, TARDBP). Average accumulations of postmortem tau, TDP‐43, and amyloid across neocortical, limbic and brainstem regions were scored on a 0‐3 scale. Regression tested differences in analytes (log transformed) across FTLD‐tau and FTLD‐TDP, covarying for age, interval to death, and sex. Regression tested association of analytes (log transformed) with postmortem tau and TDP‐43 accumulation, covarying for postmortem amyloid‐β and plasma‐to‐death interval. Receiver operating characteristic (ROC) analyses and area under the curve (AUC) analyses were performed in patients with negligible secondary pathology. We defined an optimal cut‐point to discriminate FTLD‐tau from FTLD‐TDP using plasma GFAP/NfL. We tested the defined cut‐point in an independent validation sample of FTD patients with a clinical diagnosis of progressive supranuclear palsy (PSP) with likely tau (FTD‐tau; n=33) or diagnosis of amytrophic lateral sclerosis (ALS) with likely TDP‐43 (FTD‐TDP; n=35).ResultsPlasma GFAP was lower in FTLD‐TDP than FTLD‐tau (β=‐0.24, p=0.021) with small effect size (partial η2=0.082). Plasma NfL was higher in FTLD‐TDP than FTLD‐tau (β=0.57, p=1.0e‐05) with medium effect size (partial η2=0.24). GFAP/NfL was significantly lower in FTLD‐TDP than FTLD‐tau (β=‐0.82, SE=0.13, p=2.2e‐09) with large effect size (partial η2=0.39). Higher plasma GFAP was associated with higher postmortem tau accumulation (β=0.15, p=0.032). Higher levels of plasma NfL were associated with increased TDP‐43 burden (β=0.2, p=0.024). ROC revealed excellent discrimination by plasma GFAP/NfL in the autopsy/test sample (AUC=0.89). In the validation sample, plasma GFAP/NfL had good overall discrimination accuracy (AUC=0.85); there was 0.79 sensitivity and 0.77 specificity when applying the training‐derived GFAP/NfL threshold.ConclusionPlasma GFAP and NfL relate to pathological accumulation of tau and TDP‐43, respectively. The plasma ratio of GFAP/NfL is a promising candidate to discriminate FTLD‐tau from FTLD‐TDP.

Initial Reports of ALLFTD Participant Internet and Social Media Usage Survey

AbstractBackgroundThe ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study, is the unification of prior FTD research studies, ARTFL and LEFFTDS. ALLFTD aims to evaluate sporadic (s‐) and familial (f‐) frontotemporal lobar degeneration (FTLD) patients and asymptomatic family members of f‐FTLD patients, characterizing the cohorts longitudinally and informing clinical trial design.MethodALLFTD participants completed the ALLFTD‐specific, Internet and Social Media (ISM) Usage Survey. This survey was created to learn more about participants’ ISM habits. The survey asks participants to report on the frequency with which they use ISM for personal reasons and contains additional questions about reasons for use and general gaming and social media habits.ResultIn conjunction with their scheduled ALLFTD visit, 194 participants completed the ALLFTD ISM Usage Survey. Fifty one percent of participants identified as female. The mean age was 56.6 (SD 14.61), and the mean education level was 15.9 (SD 3.53). Most participants reported using ISM 1‐5 hours per day (56.7%). Participants also reported using ISM at less common frequencies: more than 5 hours per day (12.9%), less than 1 hour per day (13.9%), weekly (3.1%), 2‐3 times a week (2.1%), 2‐3 times a month (2.1%), and never (9.3%). “Moderate and Severely impaired” participants (CDR© + NACC FTLD &gt; = 2) reported using ISM less frequently than “mildly symptomatic” participants (CDR© + NACC FTLD = 1, p&lt;0.0001), and those who are “normal and questionably impaired” CDR© + NACC FTLD &lt; = 0.5, p&lt;0.0001). Those who are mildly symptomatic reported using ISM at a similar frequency to those who are normal or questionably impaired (p&lt;0.01). When reporting on personal use, most participants stated that they used the internet for email (45.5%), news (37.5%), social media (32.4%), and entertainment (33.5%). Additionally, most participants reported playing games (56.2%) and using social media (59.8%). Participants predominantly indicated that they use social media to connect with family and friends (90.5%). Comparison of ISM usage frequency to reported anxiety, agitation, or depression on the NPI‐Q found evidence of a difference in ISM usage frequency; directional comparison studies are forthcoming.ConclusionFrequency of ISM usage is consistent between ALLFTD participants. Additional analyses of ISM usage are forthcoming.

Transcriptome wide correlations with neuropathological hallmarks in the frontal cortex of FTLD patients

AbstractBackgroundA key pathological event in frontotemporal lobar degeneration (FTLD) is the alteration of the RNA metabolism. Despite this, no study has characterized the diversity of RNA species using high‐throughput sequencing approaches and correlated them with the main neuropathological hallmarks across FTLD subtypes.MethodTotal and small RNA sequencing was performed in the frontal cortex of patients neuropathologically diagnosed with FTLD‐TDP (including non‐mutation carriers [sFTLD‐TDP;n = 9], and carriers of the C9orf72 repeat expansion [FTLD‐C9;n = 11]), FTLD‐tau (n = 13, six carrying the p.P301L mutation in MAPT) and controls without neuropathological alterations in the same brain region (n = 7). Gene and miRNA co‐expression modules were identified using WGCNA. Cell‐type proportions were estimated through cell‐type deconvolution using MuSiC. Gene ontology enrichment analyses were performed using Metascape. We assessed in the frontal cortex the presence of pTDP43 (in sFTLD‐TDP and FTLD‐C9), dipeptide repeats and RNA foci (in FTLD‐C9), and tau aggregates (in FTLD‐tau) through quantitative immunohistochemistry and correlated their density with transcriptome‐wide RNA alterations.ResultOur results indicate statistically significant correlations between gene and miRNA co‐expression modules, neuropathological changes and cell‐type proportions specific for each FTLD subtype. The most significant findings include: in sFTLD‐TDP, the density of pTDP43 positively correlated with a gene co‐expression module (R = 0.9,p = 0.04) enriched with splicing functions (p&lt;1×10−8), which directly correlated with a miRNA co‐expression module (R = 0.77,p = 5×10−4) and the proportion of a microglial subpopulation (R = 0.69,p = 4×10−3). In FTLD‐C9, the density of poly(GP) repeats inversely correlated with the proportion of a neuronal subpopulation (R = ‐0.62,p = 0.041), and negatively correlated with a gene co‐expression module (R = ‐0.67,p = 0.024) enriched with protein phosphorylation functions (p&lt;1×10−4). In FTLD‐tau, the density of tau aggregates negatively correlated with the proportion of a neuronal subpopulation (Fig.1A;R = ‐0.77,p = 0.003) and positively correlated with a miRNA (Fig.1B;R = 0.88,p = 8.8×10−5) and a gene (Fig.1C;R = 0.65,p = 0.016) co‐expression module enriched in genes with neuron ensheathing functions (Fig.1D;p&lt;1×10−20).ConclusionOur data demonstrate selective vulnerability of cell‐subtypes to neuropathological changes. In addition, we describe striking correlations between the main neuropathological hallmarks of each FTLD subtype and specific gene and miRNA co‐expression modules, including their hub genes and miRNAs which might be used as biomarkers to identify the FTLD neuropathological substrate in vivo, and reveal novel molecular mechanisms amenable for therapeutic intervention in FTLD.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607)

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90–110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association.

Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer's disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.

Early-stage differentiation between Alzheimer's disease and frontotemporal lobe degeneration: Clinical, neuropsychology, and neuroimaging features.

Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common forms of neurodegenerative dementia. Although both of them have well-established diagnostic criteria, achieving early diagnosis remains challenging. Here, we aimed to make the differential diagnosis of AD and FTLD from clinical, neuropsychological, and neuroimaging features. In this retrospective study, we selected 95 patients with PET-CT defined AD and 106 patients with PET-CT/biomarker-defined FTLD. We performed structured chart examination to collect clinical data and ascertain clinical features. A series of neuropsychological scales were used to assess the neuropsychological characteristics of patients. Automatic tissue segmentation of brain by Dr. Brain tool was used to collect multi-parameter volumetric measurements from different brain areas. All patients' structural neuroimage data were analyzed to obtain brain structure and white matter hyperintensities (WMH) quantitative data. The prevalence of vascular disease associated factors was higher in AD patients than that in FTLD group. 56.84% of patients with AD carried at least one APOE ε4 allele, which is much high than that in FTLD patients. The first symptoms of AD patients were mostly cognitive impairment rather than behavioral abnormalities. In contrast, behavioral abnormalities were the prominent early manifestations of FTLD, and few patients may be accompanied by memory impairment and motor symptoms. In direct comparison, patients with AD had slightly more posterior lesions and less frontal atrophy, whereas patients with FTLD had more frontotemporal atrophy and less posterior lesions. The WMH burden of AD was significantly higher, especially in cortical areas, while the WMH burden of FTLD was higher in periventricular areas. These results indicate that dynamic evaluation of cognitive function, behavioral and psychological symptoms, and multimodal neuroimaging are helpful for the early diagnosis and differentiation between AD and FTLD.

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Relationship between CSF tau biomarkers and structural brain MRI measures in frontotemporal lobar degeneration

BackgroundRecently in the field neurodegenerative diseases increasing attention has been pointed to CSF biomarkers and their integration with neuroimaging (1). Frontotemporal lobar degeneration (FTLD) refers to a heterogeneous group of clinical syndromes with different underlying proteinopathies including tau pathology. CSF biomarkers have been proposed as diagnostic and prognostic factors. Aim of our study was to evaluate the relationship between CSF tau biomarkers and structural MRI brain measures in FTLD. MethodsWe included early FTLD patient. All included patients underwent lumbar puncture to evaluate amyloid, total-tau (t-tau), phospho-tau 181 (p-tau); p-tau/t-tau ratio was also calculated; brain MRI was performed to estimate whole brain volume, volume of principal deep grey matter structures and regional cortical thickness. ResultsDemographic characteristics of the 28 included patients were as follows: female/male: 9/19; mean ± SD age: 68.1 ± 7.8 years. The p-tau/t-tau ratio was significantly correlated with whole brain volume (r = 0.69; p: 0.001), left putamen volume (r = 0.55 p: 0.009), left pallidum volume (r = 0.41; p: 0.01), right accumbens area (r = 0.47; p: 0.02). P-tau/t tau ratio showed also a significant correlation with cortical thickness of left temporal lobe (r = 0.74; p: 0.001) and right lateral orbital frontal cortex (r = 0.45; p: 0.03). Linear regression showed a significant relationship between p-tau/t-tau ratio and left temporal pole (p = 0.01; r2: 0.60) and brain volume (p:0.002; r2: 0.56) after controlling for age and gender. ConclusionsOur data suggest that CSF biomarkers, especially p-tau/t-tau ratio, could play a role as prognostic factor in FTLD. Further longitudinal investigations are needed to confirm these findings.

YKL-40 changes are not detected in post-mortem brain of patients with Alzheimer’s disease and frontotemporal lobar degeneration

BackgroundYKL-40 (Chitinase 3-like I) is increased in CSF of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) patients and is therefore considered a potential neuroinflammatory biomarker. Whether changed YKL-40 levels in the CSF reflect dysregulation of YKL-40 in the brain is not completely understood yet. We aimed to extensively analyze YKL-40 levels in the brain of AD and different FTLD pathological subtypes. The direct relationship between YKL-40 levels in post-mortem brain and ante-mortem CSF was examined in a small set of paired brain-CSF samples.MethodYKL-40 was analyzed in post-mortem temporal and frontal cortex of non-demented controls and patients with AD and FTLD (including FTLD-Tau and FTLD-TDP) pathology by immunohistochemistry (temporal cortex: 51 controls and 56 AD and frontal cortex: 7 controls and 24 FTLD patients), western blot (frontal cortex: 14 controls, 5 AD and 67 FTLD patients), or ELISA (temporal cortex: 11 controls and 7 AD and frontal cortex: 14 controls, 5 AD and 67 FTLD patients). YKL-40 levels were also measured in paired post-mortem brain and ante-mortem CSF samples from dementia patients (n = 9, time-interval collection: 1.4 years) by ELISA.ResultsWe observed that YKL-40 post-mortem brain levels were similar between AD, FTLD, and controls as shown by immunohistochemistry, western blot, and ELISA. Interestingly, strong YKL-40 immunoreactivity was observed in AD cases with cerebral amyloid angiopathy (CAA; n = 6). In paired CSF-brain samples, YKL-40 concentration was 8-times higher in CSF compared to brain.ConclusionOur data suggest that CSF YKL-40 changes may not reflect YKL-40 changes within AD and FTLD pathological brain areas. The YKL-40 reactivity associated with classical CAA hallmarks indicates a possible relationship between YKL-40, neuroinflammation, and vascular pathology.

Resting state functional brain networks associated with emotion processing in frontotemporal lobar degeneration

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). In patients and controls, correlations were investigated between each emotion construct and rs-FC changes within critical networks. Mean rs-FC of the clusters significantly associated with CATS scoring were compared among FTLD groups. FTLD patients had pathological CATS scores compared with controls. In controls, increased rs-FC of the cerebellar and visuo-associative networks correlated with better scores in emotion-matching and discrimination tasks, respectively; while decreased rs-FC of the visuo-spatial network was related with better performance in the affect-matching and naming. In FTLD, the associations between rs-FC and CATS scores involved more brain regions, such as orbitofrontal and middle frontal gyri within anterior networks (i.e., salience and default-mode), parietal and somatosensory regions within visuo-spatial and sensorimotor networks, caudate and thalamus within basal-ganglia network. Rs-FC changes associated with CATS were similar among all FTLD groups. In FTLD compared to controls, the pattern of rs-FC associated with emotional processing involves a larger number of brain regions, likely due to functional specificity loss and compensatory attempts. These associations were similar across all FTLD groups, suggesting a common physiopathological mechanism of emotion processing breakdown, regardless the clinical presentation and pattern of atrophy.