Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapy trials are mostly focused on the symptomatic phase, future ...studies will move earlier in the disease aiming to prevent symptom onset. This review summarizes the recent work to better understand this presymptomatic period.
The presymptomatic phase can be split into preclinical and prodromal stages. The onset of the preclinical phase is defined by the first presence of pathological inclusions of tau, TDP-43 or fused in sarcoma in the brain. Definitive biomarkers of these pathologies do not yet exist for FTD. The prodromal phase is defined by the onset of mild symptoms. Recent work has highlighted the wide phenotypic spectrum that occurs, with the concept of mild cognitive ± behavioural ± motor impairment (MCBMI) being put forward, and additions to scales such as the CDR plus NACC FTLD now incorporating neuropsychiatric and motor symptoms.
It will be important to better characterize the presymptomatic period moving forward and develop robust biomarkers that can be used both for stratification and outcome measures in prevention trials. The work of the FTD Prevention Initiative aims to facilitate this by bringing together data from natural history studies across the world.
Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages ...and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.
To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.
This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.
Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.
A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 58.1% male; mean SD age at recruitment, 68.3 8.7 years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve AUC, 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).
These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.
The primary progressive aphasias are a heterogeneous group of focal ‘language-led’ dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the ...progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including ‘clinical pearls’ that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic ‘roadmap’. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.
Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are ...increased in Alzheimer’s disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia PPA, n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1–42 (Aβ42), with each other, and with age and disease duration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration. Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD.
Abstract The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia ...(nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschl's gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions.
Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in ...this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals. Seventeen patients with behavioural variant frontotemporal dementia four female; mean (standard deviation) age 64.8 (6.8) years, 12 with semantic variant primary progressive aphasia four female; 66.9 (7.0) years, nine with non-fluent variant primary progressive aphasia five female; 67.4 (8.1) years and 22 healthy controls 12 female; 68.6 (6.8) years passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development.
Automatic motor mimicry is essential to the normal processing of perceived emotion, and disrupted automatic imitation might underpin socio-emotional deficits in neurodegenerative diseases, ...particularly the frontotemporal dementias. However, the pathophysiology of emotional reactivity in these diseases has not been elucidated. We studied facial electromyographic responses during emotion identification on viewing videos of dynamic facial expressions in 37 patients representing canonical frontotemporal dementia syndromes versus 21 healthy older individuals. Neuroanatomical associations of emotional expression identification accuracy and facial muscle reactivity were assessed using voxel-based morphometry. Controls showed characteristic profiles of automatic imitation, and this response predicted correct emotion identification. Automatic imitation was reduced in the behavioural and right temporal variant groups, while the normal coupling between imitation and correct identification was lost in the right temporal and semantic variant groups. Grey matter correlates of emotion identification and imitation were delineated within a distributed network including primary visual and motor, prefrontal, insular, anterior temporal and temporo-occipital junctional areas, with common involvement of supplementary motor cortex across syndromes. Impaired emotional mimesis may be a core mechanism of disordered emotional signal understanding and reactivity in frontotemporal dementia, with implications for the development of novel physiological biomarkers of socio-emotional dysfunction in these diseases.
Background
With the commencement of clinical trials in frontotemporal dementia (FTD), robust biomarkers that can detect the earliest signs of the disease and also measure treatment effect, are ...essential. Pen and paper assessments are laborious, administered infrequently, and can rely on subjective reporting. Using digital devices allows for more frequent, often continuous, assessment from home, whilst producing a wealth of objective data. The Early Detection of Frontotemporal dementia (EDoF) study aims to develop a series of digital measures that may be useful for the diagnosis of FTD and for outcome measures in trials.
Method
The EDoF study includes: a computerised cognitive battery, a mobile eye tracking device, a novel app that passively measures cognitive function by monitoring smartphone metadata, speech and language analysis using machine learning algorithms, actigraphy, and gait analysis. These measures are being validated in a large control population before being tested in symptomatic and presymptomatic genetic FTD within the Genetic FTD Initiative (GENFI) study.
Result
We are currently recruiting participants to the initial arms of the study, with over 1,300 healthy controls having already completed the computerized cognitive battery. The mobile eye tracking device measures eye movement abnormalities but also uses instructionless eye movement tasks to measure executive function and social cognition. Pilot eye tracking data shows abnormalities of these tasks in symptomatic FTD, and also for antisaccadic eye movements in presymptomatic FTD. Normative data for all of the measures will be generated helping to assess construct validity and retest reliability.
Conclusion
EDoF is the first study aiming to use a comprehensive set of digital measures to detect early FTD. It may also prove useful for home monitoring within future therapeutic trials of FTD.
Laughter is a fundamental communicative signal in our relations with other people and is used to convey a diverse repertoire of social and emotional information. It is therefore potentially a useful ...probe of impaired socio-emotional signal processing in neurodegenerative diseases. Here we investigated the cognitive and affective processing of laughter in forty-seven patients representing all major syndromes of frontotemporal dementia, a disease spectrum characterised by severe socio-emotional dysfunction (twenty-two with behavioural variant frontotemporal dementia, twelve with semantic variant primary progressive aphasia, thirteen with nonfluent-agrammatic variant primary progressive aphasia), in relation to fifteen patients with typical amnestic Alzheimer's disease and twenty healthy age-matched individuals. We assessed cognitive labelling (identification) and valence rating (affective evaluation) of samples of spontaneous (mirthful and hostile) and volitional (posed) laughter versus two auditory control conditions (a synthetic laughter-like stimulus and spoken numbers). Neuroanatomical associations of laughter processing were assessed using voxel-based morphometry of patients' brain MR images. While all dementia syndromes were associated with impaired identification of laughter subtypes relative to healthy controls, this was significantly more severe overall in frontotemporal dementia than in Alzheimer's disease and particularly in the behavioural and semantic variants, which also showed abnormal affective evaluation of laughter. Over the patient cohort, laughter identification accuracy was correlated with measures of daily-life socio-emotional functioning. Certain striking syndromic signatures emerged, including enhanced liking for hostile laughter in behavioural variant frontotemporal dementia, impaired processing of synthetic laughter in the nonfluent-agrammatic variant (consistent with a generic complex auditory perceptual deficit) and enhanced liking for numbers (‘numerophilia’) in the semantic variant. Across the patient cohort, overall laughter identification accuracy correlated with regional grey matter in a core network encompassing inferior frontal and cingulo-insular cortices; and more specific correlates of laughter identification accuracy were delineated in cortical regions mediating affective disambiguation (identification of hostile and posed laughter in orbitofrontal cortex) and authenticity (social intent) decoding (identification of mirthful and posed laughter in anteromedial prefrontal cortex) (all p < .05 after correction for multiple voxel-wise comparisons over the whole brain). These findings reveal a rich diversity of cognitive and affective laughter phenotypes in canonical dementia syndromes and suggest that laughter is an informative probe of neural mechanisms underpinning socio-emotional dysfunction in neurodegenerative disease.
The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, ...antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages.
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