Frontotemporal Dementia: clinical, genetic, and pathological heterogeneity

The current clinical syndrome frontotemporal dementia (FTD) was first described in 1892 by the Czech psychiatrist Arnold Pick. He described a patient with aphasia and behavioural changes with on macroscopic examination marked left frontotemporal atrophy. In 1911, Alois Alzheimer described the detailed microscopic changes, including argyrophilic neuronal inclusions, which are still known as Pick bodies. The term Pick’s disease was introduced in 1926 and was used till the early 90’s to describe the clinical and pathological entity. To date, Pick’s disease is used for a neuropathological subgroup of FTD patients. FTD encompasses distinct canonical syndromes: the behavioural variant of FTD (bvFTD), and two language variants, semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is accompanied by motor neuron disease (MND) in 5 – 15 % of the cases. FTD patients characteristically present at presenile age with variable behavioural changes and language disturbances. The clinical syndrome FTD is part of a wide clinicopathological spectrum designated by the term frontotemporal lobar degeneration (FTLD). The last few years have seen major advances in our understanding of FTD, its genetic causes and pathological substrates. In 1994, a genetic-epidemiological study on FTD was started at the Erasmus University Medical Center of Rotterdam. Since then, over 400 patients have been included in our FTD cohort. The aim of this thesis was to describe and determine the relationship between the clinical presentation, genetics and pathology of FTD, with emphasis on the hereditary form of FTD

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis

Variation at GRN 3′-UTR rs5848 Is Not Associated with a Risk of Frontotemporal Lobar Degeneration in Dutch Population

Background: A single nucleotide polymorphism (rs5848) located in the 3′- untranslated region of GRN has recently been associated with a risk of frontotemporal lobar degeneration (FTLD) in North American population particularly in pathologically confirmed cases with neural inclusions immunoreactive for ubiquitin and TAR DNA-binding protein 43 (TDP-43), but negative for tau and alpha-synuclein (FTLD-TDP). Methodology/Principal Findings: In an effort to replicate these results in a different population, rs5848 was genotyped in 256 FTLD cases and 1695 controls from the Netherlands. Single SNP gender-adjusted logistic regression analysis revealed no significant association between variation at rs5848 and FTLD. Fisher's exact test, failed to find any significant association between rs5848 and a subset of 23 pathology confirmed FTLD-TDP cases. Conclusions/Significance: The evidence presented here suggests that variation at rs5848 does not contribute to the etiology of FTLD in the Dutch population

Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mild-moderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00–0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset ≤40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16–119 months). In our total clinical FTD cohort, we found 11 patients (0.03; 95% CI: 0.01–0.05) with bvFTD, negative family history, and age at onset ≤40 years. Caudate atrophy was present in 10 out of 136 MRIs, and included all four FUS-cases. The newly identified FTLD-FUS has a frequency of 11% in FTLD-U, and an estimated frequency of three percent in our clinical FTD cohort. The existence of this pathological subtype can be predicted with reasonable certainty by age at onset ≤40 years, negative family history, bvFTD and caudate atrophy on MRI

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

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia

BACKGROUND AND OBJECTIVES: Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS: In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (&gt;3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline.RESULTS: We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p &lt; 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p &lt; 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p &lt; 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION: NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.</p

Plasma proteome profiling identifies changes associated to AD but not to FTD

Background Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. Methods Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. Results Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. Conclusions We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts

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

Symmetrical Corticobasal Syndrome Caused by a Novel c.314dup Progranulin Mutation

Corticobasal syndrome (CBS) is characterised by asymmetrical parkinsonism and cognitive impairment. The underlying pathology varies between corticobasal degeneration, progressive supranuclear palsy, Alzheimer’s disease, Creutzfeldt–Jakob disease and frontotemporal lobar degeneration sometimes in association with GRN mutations. A 61-year-old male underwent neurological examination, neuropsychological assessment, MRI, and HMPAO-SPECT at our medical centre. After his death at the age of 63, brain autopsy, genetic screening and mRNA expression analysis were performed. The patient presented with slow progressive walking disabilities, non-fluent language problems, behavioural changes and forgetfulness. His family history was negative. He had primitive reflexes, rigidity of his arms and postural instability. Later in the disease course he developed dystonia of his left leg, pathological crying, mutism and dysphagia. Neuropsychological assessment revealed prominent ideomotor and ideational apraxia, executive dysfunction, non-fluent aphasia and memory deficits. Neuroimaging showed symmetrical predominant frontoparietal atrophy and hypoperfusion. Frontotemporal lobar degeneration (FTLD)-TDP type 3 pathology was found at autopsy. GRN sequencing revealed a novel frameshift mutation c.314dup, p.Cys105fs and GRN mRNA levels showed a 50% decrease. We found a novel GRN mutation in a patient with an atypical (CBS) presentation with symmetric neuroimaging findings. GRN mutations are an important cause of CBS associated with FTLD-TDP type 3 pathology, sometimes in sporadic cases. Screening for GRN mutations should also be considered in CBS patients without a positive family history

Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia

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