Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations

Frontotemporal dementia comprises a group of clinical syndromes that are characterised by progressive changes in behaviour, executive function, or language. The term frontotemporal lobar degeneration encompasses the neurodegenerative diseases that give rise to these clinical syndromes and involve proteinopathies associated with frontotemporal network dysfunction. Improvements in clinical, genetic, and molecular characterisation have provided new insights into frontotemporal dementia and frontotemporal lobar degeneration, with a much broader range of signs and symptoms at presentation than has been previously considered. Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition. Advances in plasma and CSF biomarkers, and innovations in structural and functional imaging, will prove useful for future clinical trials in people with frontotemporal dementia

The Cortical Basal ganglia Functional Scale (CBFS): Development and preliminary validation

OBJECTIVE: To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs). BACKGROUND: 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders. METHODS: A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity. RESULTS: The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs. CONCLUSIONS: The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments

Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials

INTRODUCTION: Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials. METHODS: Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS). RESULTS: Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change. CONCLUSION: Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.Methods337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.ResultsDRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.ConclusionsWe conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD

Diffusion tensor imaging of Parkinson's disease, multiple system atrophy and progressive supranuclear palsy: a tract-based spatial statistics study

Although often clinically indistinguishable in the early stages, Parkinson's disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have distinct neuropathological changes. The aim of the current study was to identify white matter tract neurodegeneration characteristic of each of the three syndromes. Tract-based spatial statistics (TBSS) was used to perform a whole-brain automated analysis of diffusion tensor imaging (DTI) data to compare differences in fractional anisotropy (FA) and mean diffusivity (MD) between the three clinical groups and healthy control subjects. Further analyses were conducted to assess the relationship between these putative indices of white matter microstructure and clinical measures of disease severity and symptoms. In PSP, relative to controls, changes in DTI indices consistent with white matter tract degeneration were identified in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, superior cerebellar peduncle, medial lemniscus, retrolenticular and anterior limb of the internal capsule, cerebral peduncle and external capsule bilaterally, as well as the left posterior limb of the internal capsule and the right posterior thalamic radiation. MSA patients also displayed differences in the body of the corpus callosum corticospinal tract, cerebellar peduncle, medial lemniscus, anterior and superior corona radiata, posterior limb of the internal capsule external capsule and cerebral peduncle bilaterally, as well as the left anterior limb of the internal capsule and the left anterior thalamic radiation. No significant white matter abnormalities were observed in the PD group. Across groups, MD correlated positively with disease severity in all major white matter tracts. These results show widespread changes in white matter tracts in both PSP and MSA patients, even at a mid-point in the disease process, which are not found in patients with PD

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy

Plasma neurofilament light chain predicts progression in progressive supranuclear palsy

Objective: Blood‐based biomarkers for neurodegenerative conditions could improve diagnosis and treatment development. Neurofilament light chain (NfL), a marker of axonal injury, is elevated in cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP). The goal of this study was to determine the diagnostic and prognostic value of plasma NfL in patients with PSP. Methods: Plasma NfL was measured with ultrasensitive digital immunoassay‐based technology at baseline and 1‐year follow‐up in a pilot cohort of 15 PSP patients and 12 healthy controls, and a validation cohort of 147 PSP patients. Mixed linear models tested the ability of plasma NfL to predict neurological, cognitive and functional decline, and brain atrophy. Results: Baseline mean plasma NfL levels were elevated in PSP patients (31 ± 4 pg/mL, vs. control, 17.5 ± 1 pg/mL, P < 0.05) and this difference persisted at follow‐up. A cutoff value of 20 pg/mL related to the diagnosis of PSP with a sensitivity of 0.80 and specificity of 0.83 (positive likelihood ratio = 4.7 and a negative likelihood radio of 0.24). Patients with higher NfL levels had more severe neurological (PSPRS, −36.9% vs. −28.9%, P = 0.04), functional (SEADL, −38.2% vs. −20%, P = 0.03), and neuropsychological (RBANS, −23.9% vs. −12.3%, P = 001) deterioration over 1 year. Higher baseline NfL predicted greater whole‐brain and superior cerebellar peduncle volume loss. Plasma and CSF NfL were significantly correlated (r = 0.74, P = 0.002). Interpretation: Plasma NfL is elevated in PSP and could be of value as a biomarker both to assist clinical diagnosis and to monitor pharmacodynamic effects on the neurodegenerative process in clinical trials

Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease

Objective: To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically diagnosed Alzheimer disease syndromes (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses. Methods: We measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression, and survival, and cortical thickness. Results: Plasma NfL, but not plasma t-tau, discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology-confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone. Conclusion: Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S. Classification of Evidence: This study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance vs plasma t-tau in FTLD and AD

Diagnostic Accuracy of Magnetic Resonance Imaging Measures of Brain Atrophy Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Degeneration

The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations.To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases.This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021.The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases.Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI.In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice