Classification of primary progressive aphasia and its variants

ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Section: Methodsmentioning

confidence: 99%

“…Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by early progressive behavioral and/or language deficits 1, 2. Up to 15% of patients with FTD concomitantly develop motor neuron disease (MND), and 10–20% of patients with MND develop FTD,3 suggesting that the two disorders lie on a clinical continuum.…”

Section: Introductionmentioning

confidence: 99%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

“…The Institutional Review Board (IRB) of each contributing site previously approved study protocols. Patients were diagnosed by a multidisciplinary consensus panel using current (at the time of study enrollment) consensus diagnostic criteria for bvFTD,11, 12 svPPA,13 and nfvPPA 13. Baseline CSF samples were matched with baseline clinical and radiographic data within 90 days of sample collection.…”

Section: Methodsmentioning

confidence: 99%

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Ljubenkov

Staffaroni

Rojas

et al. 2018

ObjectiveThe prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42 was examined in frontotemporal dementia subtypes.MethodsWe compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.ResultsNeurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1‐42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP‐43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia.InterpretationHigh cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1‐42 also predict some measures of disease aggressiveness in frontotemporal dementia.

“…Fifty‐one participants were included in the experiment (mean age 67.6 years (range 51–84), 22 females), comprising 32 patients fulfilling consensus criteria for a syndrome of FTD33, 34 (10 bvFTD, 6 rtvFTD, 7 svPPA, 9 nfvPPA) recruited via our specialist cognitive disorders clinic, and 19 age‐matched healthy individuals with no history of neurological or psychiatric illness recruited via our departmental research database. No participant had a history of cardiac arrhythmia, and none was taking cardiac rate‐limiting medication.…”

Section: Methodsmentioning

confidence: 99%

Cardiac responses to viewing facial emotion differentiate frontotemporal dementias

Marshall

Hardy

Allen

et al. 2018

ObjectiveTo establish proof‐of‐principle for the use of heart rate responses as objective measures of degraded emotional reactivity across the frontotemporal dementia spectrum, and to demonstrate specific relationships between cardiac autonomic responses and anatomical patterns of neurodegeneration.MethodsThirty‐two patients representing all major frontotemporal dementia syndromes and 19 healthy older controls performed an emotion recognition task, viewing dynamic, naturalistic videos of facial emotions while ECG was recorded. Cardiac reactivity was indexed as the increase in interbeat interval at the onset of facial emotions. Gray matter associations of emotional reactivity were assessed using voxel‐based morphometry of patients’ brain MR images.ResultsRelative to healthy controls, all patient groups had impaired emotion identification, whereas cardiac reactivity was attenuated in those groups with predominant fronto‐insular atrophy (behavioral variant frontotemporal dementia and nonfluent primary progressive aphasia), but preserved in syndromes focused on the anterior temporal lobes (right temporal variant frontotemporal dementia and semantic variant primary progressive aphasia). Impaired cardiac reactivity correlated with gray matter atrophy in a fronto‐cingulo‐insular network that overlapped correlates of cognitive emotion processing.InterpretationAutonomic indices of emotional reactivity dissociate from emotion categorization ability, stratifying frontotemporal dementia syndromes and showing promise as novel biomarkers. Attenuated cardiac responses to the emotions of others suggest a core pathophysiological mechanism for emotional blunting and degraded interpersonal reactivity in these diseases.