Clinicopathological correlations in behavioural variant frontotemporal dementia

Abstract

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

“…Diagnostic information from postmortem brain examination, using previously described methods,14 was used if available. If autopsy data was not available (whether it was not obtained or the patient was still alive), but an FTD‐causing mutation was identified, gene status was used to identify the putative FTLD major molecular class.…”

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

“…Rarely, patients with C9orf72 -bvFTD develop atypical non-epileptic spells of unclear etiology [155]. Anatomically, sporadic and C9orf72 -bvFTD are more similar than they are different, with most patients showing early, prominent atrophy in anterior insula, anterior cingulate, amygdala, and striatum [108, 127], but C9orf72 -bvFTD more conspicuously involves the medial pulvinar thalamus [72, 84, 131]. Morphometric deficits in this structure, which emerge as early as the 3 rd decade in presymptomatic expansion carriers [73, 116], may produce targeted cortico-striato-thalamic network dysfunction [72].…”

“…Converging research across multiple groups, cohorts, and studies has shown that the anterior cingulate and ventral anterior insular (i.e. frontoinsular) cortex represent the earliest and most consistently affected cortical regions in bvFTD [108, 125, 127, reviewed in 128]. At the microscopic scale, our group [64, 126] and now two others [121, 122, 167] have shown that the von Economo neurons (VENs), found almost exclusively within the anterior cingulate and frontoinsular cortices, are among the earliest-affected and most vulnerable neurons in bvFTD, whether the syndrome is due to FTLD-TDP, -tau, or -FUS [64, 121, 122, 126, 167].…”

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

“…In FTD, the vulnerable circuits and cell types have just begun to emerge within the past decade. In the behavioral variant (bvFTD), the most common FTD syndrome, early degeneration involves the anterior cingulate (ACC) and ventral anterior insular (i.e., frontoinsular, FI) cortices [8, 66, 87], regardless of the underlying pathological cause [54]. These regions serve as the cortical hubs of a large-scale “salience network” [67] critical for social-emotional-autonomic function and are home to the morphologically distinctive von Economo neurons (VENs) [68, 79] and fork cells [53].…”