Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

2021 ◽  
Author(s):  
Aurelie Bussy ◽  
Jake Levy ◽  
Raihaan Patel ◽  
Lani Cupo ◽  
Tristin Best ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Symptom Onset ◽  
Psychiatric Symptoms ◽  
Neuropsychiatric Symptoms ◽  
Chromosome 9 ◽  
Volume Loss ◽  
Subcortical Structures ◽  
Reading Frame ◽  
Preclinical Phase

Recent studies have suggested that cerebellar and subcortical structures are impacted early 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 clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.

scholarly journals Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

2020 ◽  
Vol 91 (9) ◽  
pp. 975-984 ◽  
Author(s):  
Tamara Paulo Tavares ◽  
Derek G V Mitchell ◽  
Kristy KL Coleman ◽  
Brenda L Coleman ◽  
Christen L Shoesmith ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neuropsychiatric Symptoms ◽  
Family Members ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Reading Frame ◽  
Memory Impairments ◽  
Mutation Carriers ◽  
Composite Indices ◽  
Initial Symptoms

ObjectivesThe clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.MethodsThe current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.ResultsThe most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.ConclusionPreclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

Autoimmunity and Frontotemporal Dementia

2018 ◽  
Vol 15 (7) ◽  
pp. 602-609 ◽  
Author(s):  
Antonella Alberici ◽  
Viviana Cristillo ◽  
Stefano Gazzina ◽  
Alberto Benussi ◽  
Alessandro Padovani ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Language Impairment ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Bibliographic Databases ◽  
Extensive Literature ◽  
Genetic Studies ◽  
Reading Frame ◽  
Current State ◽  
Extensive Evaluation

Background: Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Genetic studies identified mutations causing the disease, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, which contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions. However, in the majority of sporadic FTD patients, the mechanisms triggering Tau or TDP43 protein deposition are still to be uncovered. Objective: We aimed to present an extensive evaluation of literature data on immune homeostasis in FTD, in order to provide potentially evidence-based approaches for a disease still orphan of any treatment. Methods: A structured search of bibliographic databases from peer-reviewed literature was pursued focusing on autoimmunity in the brain and FTD. Results: One-hundred-fourteen papers were included in this review. The majority of studies (32) were represented by extensive literature revision on immunity, central nervous system (CNS) and autoimmunity; neuroimaging papers (11) in autoimmune diseases were evaluated, and immunomodulatory approaches (25) were revised. Six papers were found specifically related to FTD and autoimmune hypothesis, the other papers referring to current state of art on FTD. Conclusion: Overall this review contribute to expand the knowledge of a possible immune hypothesis in FTD, suggesting therapeutic perspectives in autoimmune related neurodegeneration, to reduce or revert the disease.

scholarly journals The Genetics of Monogenic Frontotemporal Dementia

2015 ◽  
Vol 9 (3) ◽  
pp. 219-229 ◽  
Author(s):  
Leonel T. Takada
Keyword(s):  
Frontotemporal Dementia ◽  
Autosomal Dominant ◽  
Positive Family History ◽  
Chromosome 9 ◽  
Complex Phenotype ◽  
Reading Frame ◽  
Protein Tau ◽  
Paget Disease ◽  
Fused In Sarcoma ◽  
Spectrum Disorders

ABSTRACT Around 10-15% of patients diagnosed with frontotemporal dementia (FTD) have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin) and C9orf72(chromosome 9 open reading frame 72) are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND) can be caused by mutations in C9orf72and other genes, such as TARDBP(TAR DNA-binding protein), FUS(fused in sarcoma), UBQLN2(ubiquilin 2). Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP(valosing containing protein) and other recently identified genes.

scholarly journals Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jacqueline Dominguez ◽  
Jeryl Tan Yu ◽  
Yi Jayne Tan ◽  
Arlene Ng ◽  
Ma Fe De Guzman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Positive Family History ◽  
Clinical Manifestations ◽  
The Philippines ◽  
Chromosome 9 ◽  
Genetic Modifiers ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

scholarly journals Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

2018 ◽  
Vol 89 (8) ◽  
pp. 851-858 ◽  
Author(s):  
Raphael Schneider ◽  
Paul McKeever ◽  
TaeHyung Kim ◽  
Caroline Graff ◽  
John Cornelis van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Degree Relative ◽  
Sporadic Alzheimer’S Disease ◽  
Diagnostic Biomarkers ◽  
Reading Frame ◽  
Protein Tau ◽  
Mutation Carriers ◽  
Receiver Operator Characteristics

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Neuropsychiatric Symptoms, Caregiver Burden and Distress in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease

2015 ◽  
Vol 40 (5-6) ◽  
pp. 268-275 ◽  
Author(s):  
Thais Bento Lima-Silva ◽  
Valéria Santoro Bahia ◽  
Viviane Amaral Carvalho ◽  
Henrique Cerqueira Guimarães ◽  
Paulo Caramelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Dementia ◽  
Sex Education ◽  
Caregiver Burden ◽  
Psychiatric Symptoms ◽  
Neuropsychiatric Symptoms ◽  
Clinical Dementia Rating ◽  
Behavioral Variant Frontotemporal Dementia ◽  
Significant Difference

Background/Aims: We aimed to compare caregiver burden and distress in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) and to investigate which factors contribute to caregivers' burden and distress. Methods: Fifty patients and their caregivers were invited to participate. Among the patients, 20 had a diagnosis of bvFTD and 30 had AD. Caregivers and patients were statistically equivalent for age, sex, education and dementia severity according to Clinical Dementia Rating. The protocol included the Short Zarit Burden Inventory, the Neuropsychiatric Inventory (NPI), Disability Assessment for Dementia (DAD), the Cornell Scale for Depression in Dementia (CSDD), Addenbrooke's Cognitive Examination-Revised, the Executive Interview with 25 Items, Direct Assessment of Functional Status and the Geriatric Anxiety Inventory (GAI). Results: In the NPI, caregivers of bvFTD patients reported a higher presence and severity of neuropsychiatric symptoms and caregiver distress compared to caregivers of AD patients. There was no significant difference in the perceived burden. In bvFTD, DAD and GAI scores were significantly correlated with burden, whereas in AD, burden was correlated with CSDD and NPI scores. Psychiatric symptoms were associated with distress in both groups. Conclusions: Caregivers of bvFTD patients experienced higher levels of distress than caregivers of AD patients. Patients' functional limitations were associated with burden of caregivers of bvFTD patients, whereas neuropsychiatric symptoms were associated with caregiver strain in both groups.

scholarly journals Comparing the Neuropsychiatric Profile of Patients with Alzheimer Disease Who Present Spared versus Impaired Executive Functioning

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Ezequiel Gleichgerrcht ◽  
Anabel Chade ◽  
Teresa Torralva ◽  
María Roca ◽  
Facundo Manes
Keyword(s):  
Alzheimer Disease ◽  
Executive Functioning ◽  
Neuropsychological Tests ◽  
Motor Behavior ◽  
Psychiatric Symptoms ◽  
Neuropsychiatric Symptoms ◽  
Significant Difference ◽  
Repetitive Motor ◽  
Shed Light

Background. A “dysexecutive” group of patients with Alzheimer disease (AD) has been previously identified, and these patients have been found to present higher frequency of psychiatric symptoms and more pronounced functional impact. This study aimed at evaluating the frequency of neuropsychiatric symptoms in patients with early AD who present with impaired executive functioning.Methods. Thirty patients with early AD diagnosis were divided into a spared (SEF) and an impaired (IEF) executive functioning group according to their performance scores on neuropsychological tests. Their closest relatives or caregivers completed the Cambridge behavioral inventory (CBI), which assesses behavioral symptoms grouped into 13 categories.Results. A significant difference was exclusively found between SEF and IEF in terms of the frequency of stereotypies and repetitive motor behavior (U=60.5,P=.024).Conclusions. The presence of stereotypies could be associated with a dysexecutive profile in AD patients. These results shed light on the role of frontal circuitry in the expression of motor symptoms in AD and prompt for further research that will contribute to the differential diagnosis both of different subtypes of AD and other types of dementia.

scholarly journals The Role of Chinese Herbal Therapy in Methamphetamine Abuse and its Induced Psychiatric Symptoms

2021 ◽  
Vol 12 ◽  
Author(s):  
Lin Chen ◽  
Qin Ru ◽  
Qi Xiong ◽  
Mei Zhou ◽  
Kai Yue ◽  
...  
Keyword(s):  
Psychiatric Symptoms ◽  
Neuropsychiatric Symptoms ◽  
Herbal Medicines ◽  
Comprehensive Treatment ◽  
Therapeutic Effects ◽  
Chinese Herbal Medicines ◽  
Chinese Herbal ◽  
Chinese Herbal Therapy ◽  
Psychiatric Impairments

Repeated intake of methamphetamine (METH) leads to drug addiction, the inability to control intake, and strong drug cravings. It is also likely to cause psychiatric impairments, such as cognitive impairment, depression, and anxiety. Because the specific neurobiological mechanisms involved are complex and have not been fully and systematically elucidated, there is no established pharmacotherapy for METH abuse. Studies have found that a variety of Chinese herbal medicines have significant therapeutic effects on neuropsychiatric symptoms and have the advantage of multitarget comprehensive treatment. We conducted a systematic review, from neurobiological mechanisms to candidate Chinese herbal medicines, hoping to provide new perspectives and ideas for the prevention and treatment of METH abuse.

scholarly journals Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

2020 ◽  
pp. jnnp-2020-324647
Author(s):  
Virgilio Kmetzsch ◽  
Vincent Anquetil ◽  
Dario Saracino ◽  
Daisy Rinaldi ◽  
Agnès Camuzat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Chromosome 9 ◽  
Differentially Expressed ◽  
Reading Frame ◽  
Expression Levels ◽  
Clinical Onset ◽  
Plasma Microrna ◽  
A Prospective Study ◽  
Lateral Sclerosis

ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.

scholarly journals Dominant Frontotemporal Dementia Mutations in 140 Cases of Primary Progressive Aphasia and Speech Apraxia

2015 ◽  
Vol 39 (5-6) ◽  
pp. 281-286 ◽  
Author(s):  
Eoin P. Flanagan ◽  
Matthew C. Baker ◽  
Ralph B. Perkerson ◽  
Joseph R. Duffy ◽  
Edythe A. Strand ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Age At Onset ◽  
Primary Progressive Aphasia ◽  
Genetic Mutation ◽  
Chromosome 9 ◽  
Apraxia Of Speech ◽  
Degree Relative ◽  
Reading Frame ◽  
Progressive Aphasia ◽  
Primary Progressive

Background: Mutations in three genes [chromosome 9 open-reading-frame 72 (C9ORF72); microtubule-associated protein tau (MAPT) and progranulin (GRN)] account for the vast majority of familial, and a proportion of sporadic, frontotemporal dementia (FTD) cases. Progressive apraxia of speech (PAOS) is a type of FTD characterized by speech production deficits without a known cause. Methods: We therefore assessed for genetic mutations in C9ORF72, MAPT and GRN in 40 prospectively recruited PAOS patients. For comparison, we also assessed these mutations in 100 patients with primary progressive aphasia (PPA), including logopenic PPA (n = 54), nonfluent/agrammatic PPA (n = 17), semantic PPA (n = 16), and unclassifiable PPA (n = 13). Results: The mean age at onset of PAOS patients was 66.7 years (± 9.3); 50% were women. Ten patients (25%) had ≥1 first-degree relative with a neurodegenerative disease. No mutations were found in any PAOS patient. In comparison, 36% of the PPA patients had a family history and 5 (5%) had a genetic mutation detected: MAPT (n = 0), GRN (n = 3) and C9ORF72 (n = 2). Conclusions: Although limited by an overrepresentation of logopenic PPA, which frequently predicts Alzheimer's disease pathology, this study suggests that mutations in the three genes most commonly associated with FTD are not associated with PAOS and are not commonly associated with PPA.

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