Neuroimaging and Clinical Biomarkers in the Familial and Sporadic FTD Spectrum – from the Presymptomatic to the Symptomatic Disease Stage

Frontotemporal dementia (FTD) is the second most common type of early-onset dementia, in which symptoms commonly become apparent before the age of 65. The clinical spectrum is heterogeneous, ranging from a predominant behavioural manifestation (behavioural variant FTD; bvFTD) to progressive language deterioration (primary progressive aphasia; PPA) and parkinsonism. 10-30% of FTD cases have an autosomal dominant pattern of inheritance. Mutations in the progranulin (GRN) and microtubule-associated protein tau (MAPT) genes, and a repeat expansion in chromosome 9 open reading frame 72 (C9orf72) are the three most common causes. Familial FTD allows the identification of pathogenic mutation carriers in their presymptomatic phase – a critical time-window for treatment as the pathological damage is at its minimum and potentially still reversible. However, with promising avenues opening for disease-modifying therapies in clinical trials, we currently lack robust biomarkers for (familial) FTD. These biomarkers will be essential for improving diagnostic accuracy, staging and prognosis, onset prediction, and monitoring disease progression and treatment response. In this thesis, we have therefore investigated potential neuroimaging and neuropsychological biomarkers in the familial and sporadic FTD spectrum

Qualitative Assessment of Verbal Fluency Performance in Frontotemporal Dementia

Background/Aims: Verbal fluency is impaired in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA). This study explored qualitative differences in verbal fluency (clustering of words, switching between strategies) between FTD and PPA variants. Methods: Twenty-nine patients with behavioral variant FTD (bvFTD) and 50 with PPA (13 nonfluent/agrammatic, 14 semantic, and 23 logopenic) performed a semantic and letter fluency task. Clustering (number of multiword strings) and switching (number of transitions between clustered and nonclustered words) were recorded by two independent raters. Between-group differences, associations with memory, language, and executive functioning, and longitudinal change (subsample) in clustering and switching were examined. Results: Interrater reliability was high (median 0.98). PPA patients generated (a) smaller (number of) clusters on semantic and letter fluency than bvFTD patients (p < 0.05). Semantic variant patients used more switches than nonfluent/agrammatic or logopenic variant patients (p < 0.05). Clustering in semantic fluency was significantly associated with memory and language (range standardized regression coefficients 0.24-0.38). Switching in letter fluency was associated with executive functioning (0.32-0.35). Conclusion: Clustering and switching in verbal fluency differed between patients with subtypes of FTD and PPA. Qualitative aspects of verbal fluency provide additional information on verbal ability and executive control which can be used for clinically diagnostic purposes

Differences in Discriminability and Response Bias on Rey Auditory Verbal Learning Test Delayed Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease

Objective:Episodic memory is impaired in Alzheimer's disease (AD) dementia but thought to be relatively spared in behavioral variant frontotemporal dementia (bvFTD). This view is challenged by evidence of memory impairment in bvFTD. This study investigated differences in recognition memory performance between bvFTD and AD.Method:We performed a retrospective analysis on the recognition trial of the Rey Auditory Verbal Learning Test in patients with bvFTD (n = 85), AD (n = 55), and control participants (n = 59). Age- A nd education-adjusted between-group analysis was performed on the total score and indices of discriminative ability and response bias. Correlations between recognition and measures of memory, language, executive functioning, and construction were examined.Results:Patients with AD had a significantly lower total recognition score than patients with bvFTD (control 28.8 ± 1.5; bvFTD 24.8 ± 4.5; AD 23.4 ± 3.6, p <.01). Both bvFTD and AD had worse discriminative ability than controls (A' control 0.96 ± 0.03; bvFTD 0.87 ± 0.03; AD 0.84 ± 0.10, p <.01), but there was no difference in response bias (B" control 0.9 ± 0.2; bvFTD 1.6 ± 1.47; AD 1.4± 1.4, p <.01). AD had worse discriminability than bvFTD (p <.05). Discriminability was associated with memory for both patient groups (median correlation coefficient r =.34) and additionally associated with language (r =.31), but not executive functioning (r =-.03) in bvFTD. Response bias was unrelated to other cognitive functions (r =-.02).Conclusions:Discriminability, but not response bias, differentiated patients with bvFTD from AD. The presence of an impaired discrimination index suggests a "pure" (recognition) memory deficit in bvFTD

Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study

Objective Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF). Methods Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31). Results GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up. Interpretation We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials

Qualitative Assessment of Longitudinal Changes in Phenocopy Frontotemporal Dementia

Phenocopy frontotemporal dementia (phFTD) shares core characteristics with behavioral variant frontotemporal dementia (bvFTD), yet without associated cognitive deficits and brain abnormalities on conventional magnetic resonance imaging (MRI), and without progression. Using advanced MRI techniques, we previously observed subtle structural and functional brain changes in phFTD similar to bvFTD. The aim of the current study was to follow these as well as cognition in phFTD over time, by means of a descriptive case series. Cognition, gray matter (GM) volume and white matter (WM) microstructure, and perfusion of 6 phFTD patients were qualitatively compared longitudinally (3-years follow-up), and cross-sectionally with baseline data from 9 bvFTD patients and 17 controls. For functional brain changes, arterial spin labeling (ASL) was performed to assess GM perfusion. For structural brain changes, diffusion tensor imaging was performed to assess WM microstructure and T1w imaging to assess GM volume. MRI acquisition was performed at 3T (General Electric, US). Clinical profiles of phFTD cases at follow-up are described. At follow-up phFTD patients showed clinical symptomatology similar to bvFTD, but had a relatively stable clinical profile. Longitudinal qualitative comparisons in phFTD showed some deterioration of language and memory function, a stable pattern of structural brain abnormalities and increased perfusion over time. Additionally, both baseline and follow-up cognitive scores and structural values in phFTD were generally in between those of controls and bvFTD. Although a descriptive case series does not allow for strong conclusions, these observations in a unique longitudinal phFTD patient cohort are suggestive of the notion that phFTD and bvFTD may belong to the same disease spectrum. They may also provide a basis for further longitudinal studies in phFTD, specifically exploring the structural vs. functional brain changes. Such studies are essential for improved insight, accurate diagnosis, and appropriate treatment of phFTD

Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer's disease

Introduction: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. Early differentiation between both types of dementia may be challenging due to heterogeneity and overlap of symptoms. Here, we apply resting state functional magnetic resonance imaging (fMRI) to study functional brain connectivity differences between AD and bvFTD. Methods: We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls from two centers specialized in dementia. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region-to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. Results: Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between (a) lateral visual cortical network and lateral occipital and cuneal cortex, and (b) auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. Conclusion: We showed that the pathophysiology

Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia

Introduction: We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD). Methods: Presymptomatic MAPT (n = 15) and GRN mutation carriers (n = 31), and healthy controls (n = 39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression. Results: MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p < 0.05). Cognitive decline in ScreeLing phonology (p = 0.046) and letter fluency (p = 0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p = 0.025) for an underlying MAPT mutation. Discussion: Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD

Correction to: Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

The original version of this article unfortunately contained a mistake. The presentation of Table 1 was incorrect. The original article has been corrected. The corrected Table 1 is given below. (Table presented.)

Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

Introduction: Trials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations. Methods: We examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and describe

Correction to: Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

The original version of this article unfortunately contained a mistake. The presentation of Table 1 was incorrect. The original article has been corrected. The corrected Table 1 is given below. (Table presented.)