Pharmacotherapy for behavioural manifestations in frontotemporal dementia: An expert consensus from the European Reference Network for Rare Neurological Diseases (ERN-RND).

Background And Purpose: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers.

Investigation of the concentration and isotopic composition of Cu, Fe and Zn in human biofluids in the context of Alzheimer's disease via tandem and multi-collector inductively coupled plasma-mass spectrometry.

Studies on essential trace elements in the context of Alzheimer's disease (AD) concluded that Cu, Fe and Zn interact with amyloid-β, accelerating plaque formation in the brain. Additionally, Cu and Fe in the vicinity of plaques produce reactive oxygen species (ROS) resulting in oxidative stress, whereas Zn plays a role in the antioxidant defence as a co-factor for antioxidants. In this work, the Cu, Fe and Zn concentrations and isotope ratios were determined in whole blood, blood serum and cerebrospinal fluid of 10 patients diagnosed with AD and 8 control individuals, using tandem (ICP-MS/MS) and multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS), respectively.

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia.

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations.

Therapy-Induced Electrophysiological Changes in Primary Progressive Aphasia: A Preliminary Study.

Aims: This preliminary study aimed to investigate therapy-induced electrophysiological changes in persons with primary progressive aphasia (PPA). The investigated event-related potential (ERP) components associated with language processing were the mismatch negativity, P300, N400, and P600.

Methods: A linguistic ERP test battery and standardized language assessment were administered in four patients with PPA of which two received speech-language therapy (SLT) and two did not receive therapy.

A case series of verbal semantic processing in primary progressive aphasia: Evidence from the N400 effect.

Background: The semantic variant of primary progressive aphasia (PPA) is typically associated with a loss of semantic knowledge. Research on the semantic processing in the other clinical variants of PPA is, however, rather sparse and limited to off-line behavioural studies.

Aims: This study aimed to investigate verbal semantic processing in patients with the three variants of PPA by the event-related potential technique.

The Electrophysiological Correlates of Phoneme Perception in Primary Progressive Aphasia: A Preliminary Case Series.

: This study aimed to investigate phoneme perception in patients with primary progressive aphasia (PPA) by using the event-related potential (ERP) technique. These ERP components might contribute to the diagnostic process of PPA and its clinical variants (NFV: nonfluent variant, SV: semantic variant, LV: logopenic variant) and reveal insights about phoneme perception processes in these patients. : Phoneme discrimination and categorization processes were investigated by the mismatch negativity (MMN) and P300 in eight persons with early- and late-stage PPA (3 NFV, 2 LV, 2 SV, and 1 PPA-NOS; not otherwise specified) and 30 age-matched healthy adults.

GAD65 Autoimmune Encephalitis: A Cause of Rapidly Evolving Frontotemporal Atrophy.

We describe a patient who presented with subacute onset of short-memory impairment, disorientation, and gait instability, with progressive deterioration. Workup demonstrated glutamic acid decarboxylase antibody-related encephalitis. Aggressive immunotherapy with high-dose intravenous corticoids, followed by slow oral taper, plasmapheresis, rituximab, and cyclophosphamide did not halt disease progression.

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified.

Using a second-person approach to identify disease-specific profiles of social behavior in frontotemporal dementia and Alzheimer's disease.

Changes in social behavior are recognized as potential symptoms of behavioral-variant frontotemporal dementia (bvFTD) and semantic dementia (SD), yet objective ways to assess these behaviors in natural social situations are lacking. This study takes a truly social (or second-person) approach and examines changes in real-world social behavior in different dementia syndromes, by analyzing non-scripted social interactions in bvFTD patients (n = 20) and SD patients (n = 20), compared to patients with Alzheimer's disease (AD) (n = 20). Video recordings of 10-min conversations between patients and behavioral neurologists were analyzed for the presence of socially engaging (e.

Language and Speech Markers of Primary Progressive Aphasia: A Systematic Review.

Purpose This systematic review aimed to establish language and speech markers to support the clinical diagnosis of primary progressive aphasia (PPA) and its clinical phenotypes. Our first objective was to identify behavioral language and speech markers of early-stage PPA. Our second objective was to identify the electrophysiological correlates of the language and speech characteristics in PPA.

Clinical variability and onset age modifiers in an extended Belgian GRN founder family.

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree.

Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

Background: In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers.

Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia.

Background: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS).

Objective: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS.

Methods: Of 218 consecutive patients with FTD, 10.

Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion.

Importance: Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors.

Objective: To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations.

Design, Setting, And Participants: This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating.

ATXN2 trinucleotide repeat length correlates with risk of ALS.

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS.

Comparing Longitudinal Behavior Changes in the Primary Progressive Aphasias.

Background: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants.

Objective: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time.

Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort.

We identified in a cohort of patients with frontotemporal dementia (n = 481) or amyotrophic lateral sclerosis (n = 147), 10 index patients carrying a TBK1 loss of function mutation reducing TBK1 expression by 50%. Here, we describe the clinical and pathological characteristics of the 10 index patients and six of their affected relatives carrying a TBK1 mutation. Six TBK1 carriers were diagnosed with frontotemporal dementia, seven with amyotrophic lateral sclerosis, one with both clinical phenotypes and two with dementia unspecified.

Frontotemporal dementia and its subtypes: a genome-wide association study.

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899).

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease.

Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia.

Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4.

Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum.

An expanded G4C2 hexanucleotide repeat in the proximal regulatory region of C9orf72 is a frequent cause of neurodegenerative diseases in the frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) spectrum. Although primarily characterized by variably abundant pathological inclusions of TDP-43 protein, the lesion load was extended to TDP-43-negative, p62-positive neuronal and glial inclusions in extended regions of the central nervous system (CNS), particularly in cerebellum, where they may be characteristic of a C9orf72 repeat expansion. Disease mechanisms associated with repeat expansion disorders, including haploinsufficiency, RNA toxicity, and abnormal translation of expanded repeat sequences, are beginning to emerge.

Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort.

Objective: To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation.

Design: Patient series.

Setting: Dementia clinics in Flanders, Belgium.

Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients.

UBQLN2 and PFN1 were recently associated with amyotrophic lateral sclerosis (ALS). We investigated a role for these ALS genes in frontotemporal lobar degeneration (FTLD). We screened 328 FTLD, 17 FTLD-ALS, and 157 ALS patients.