Symptoms Of Frontotemporal Dementia Research Articles

The Prevalence of Depressive Symptoms in Frontotemporal Dementia: A Meta-Analysis

Background: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. Methods: PubMed, EMBASE and PsychINFO were queried for ‘depression' and/or ‘depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. Results: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. Conclusions: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

Hirotaka Tanabe

Hirotaka Tanabe was a Japanese neuropsychiatrist engaged in neuropsychological research on cerebrovascular disease and dementia. He contributed widely to the symptomatology of dementia, especially in the field of frontotemporal dementia (FTD). He focused on clarifying the clinical features of a language disturbance, termed Gogi-aphasia by Imura (1943), in 7 patients with anterior temporal circumscribed atrophy. He attributed the nature of Gogi-aphasia to a selective impairment of semantic memory for words and proposed that the pathological process of lobar atrophy with temporal predominance might affect the semantic memory system. In addition, he described in detail the behavioral symptoms of FTD. In his later years, he adovocated a neuropsychological approach to psychiatry.

Psychosis in Frontotemporal Dementia

Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", "psychosis", "schizophreni*", "psychotic symptoms", "hallucinations", and "delusions", and it identified 122 articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders.

Cerebrospinal-fluid orexin levels and daytime somnolence in frontotemporal dementia.

Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the cerebrospinal-fluid (CSF) orexin levels in a population of FTD patients and evaluated whether there is a relationship between daytime somnolence and CSF orexin concentrations. CSF orexin levels were measured in a sample of FTD patients (n=11) compared to a population of non-demented controls (n=13) similar for age and sex. Moreover, CSF orexin concentrations were correlated with daytime somnolence investigated by means of the Epworth Sleepiness Scale (ESS) in both FTD patients and controls. FTD patients showed CSF orexin concentrations (164.3±66.45 vs 170.81±42.73pg/mL) and ESS scores (7.45±4.36 vs 3.84±1.82) not different from controls. However, three FTD patients showed pathological daytime sleepiness (ESS>10) coupled with the lowest CSF orexin levels. In addition, we found a significant negative correlation between CSF orexin levels and ESS scores in the FTD population (R=-0.91; p<0.0001), which was not evident in the control group (R=0.16; p>0.05). This is the first study investigating CSF orexin concentrations in FTD. We did not find differences in CSF orexin concentrations between FTD patients and controls. However, a significant negative correlation between daytime somnolence and CSF orexin levels was evident in FTD patients. Moreover, we have found that pathological daytime somnolence was evident in those FTD patients with the lowest CSF orexin levels. Based on these findings, we argued that lower orexin levels may be permissive for increased daytime somnolence in FTD.

Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia.

We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of MAPT (microtubule-associated protein tau) or GRN (progranulin) mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk of frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, structural MRI, and fMRI. We used voxel-based morphometry and tract-based spatial statistics for voxel-wise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsular, anterior midcingulate, and posterior cingulate cortices. Carriers (n = 39) and noncarriers (n = 36) had similar neuropsychological performance, except for lower Letter Digit Substitution Test scores in carriers. Worse performance on Stroop III, Rivermead Behavioral Memory Test, and Happé Cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy in the right uncinate fasciculus was found in carriers compared with controls. Reductions in functional connectivity between anterior midcingulate cortex and frontoinsula and several other brain regions were found in carriers compared with controls and correlated with higher age in carriers, but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found, except for a small cluster of higher volume in the precentral gyrus in carriers. This study demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

PROGRANULIN KNOCK-OUT MICE SHOW SYMPTOMS REMINISCENT OF FRONTOTEMPORAL DEMENTIA

Background: Frontotemporal dementia (FTD), the second most common age-related cognitive decline, has strong genetic underpinnings. Mutations in the progranulin gene reflect 10-15% of genetically identified casesdue to haploinsufficiency of gene products. A preclinical model that may reiterate the FTD phenotype was assessed in a battery of behavioural tests to explore whether: i) hemizygous mice deficient in progranulin reiterate symptoms of FTD. ii) progranulin knock-down or knock-out enhances susceptibility to inflammatory stress (chronic lipopolysaccharide treatment) and results in accelerated phenotypes. Methods: Grn deficient mice were maintained on a C57Bl/6 background and bred in both homozygous and heterozygous cohorts. Prior to assessment in a battery of behavioural tests, mice were treated with vehicle or lipopolisaccharide (LPS, 500 m g/kg daily ip) for 5 weeks. Cohorts were divided into females and males undergoing a series of motor (rotarod, catwalk, home cage activity monitor), emotional (elevated plus maze, social interaction, socially transmitted flavour preference, sucrose preference test) and cognitive tasks (water maze spatial learning, object recognition; social learning of flavour). Results: When tested at the age of 6 months, subtle behavioural deficits were detected in heterozygous, but less in homozygous KO mice. These included weight reductions, lower food consumptions, hyperactivity in the home cage but no circadian anomalies, deficits in cognitive flexibility but no overall spatial learning impairment, subtle motor learning deficits and gait anomalies, lower levels of anxiety but no anhedonia, and reduced sociability. There was no effect of LPS despite the induction of inflammatory responses in control brains. Conclusions: The Grn deficiency model presents with some FTD relevant phenotypes that were revealed here much earlier than in previous reports, but an enhanced susceptibility towards inflammatory agents and a resultant accelerated phenotype was not confirmed. Stronger deficits in heterozygous cohorts confirm that haploinsufficency is an appropriate FTD approach. For homozygous knock-out mice a stronger compensatorymechanismsmay be assumed. Alternatively, complete GRN loss in human patients may induce adult lipofuscinosis expressed as epileptic events and global ataxia, but not all lipofuscinosis variants express cognitive decline. Older cohorts may be instructive in a dissociation of symptoms. Supported by SULSA and TPP Global Development.

Subcortical and Deep Cortical Atrophy in Frontotemporal Dementia due to Granulin Mutations

Background/Aims: Parkinsonism is often associated with symptoms of frontotemporal dementia (FTD), but its pathogenesis has been largely neglected. In genetic inherited FTD-related granulin (GRN) mutations, parkinsonism is an early sign, and it is more common than in sporadic disorders. Our aim was to study grey matter (GM) volume changes in subcortical and deep cortical regions in GRN-related FTD. Methods: A total of 33 FTD patients (13 carriers of the GRN mutation, GRN+, and 20 non-carriers, GRN-) and 12 healthy controls (HC) were included in the study. Each subject underwent an MRI examination (1) for voxel-based morphometry to study GM differences in cortical and subcortical regions, and (2) for a region of interest approach using a probabilistic atlas of subcortical regions (caudate nucleus, putamen, thalamus and amygdala) to assess the regional differences. Results: The GRN+ group showed greater damage in frontotemporal regions than the GRN- group. The FTD patients had greater GM atrophy in the caudate nucleus and in the thalamus bilaterally than the HC. Damage to these subcortical and deep cortical regions was greater in the GRN+ than in the GRN- patients. Discussion: Subcortical and deep cortical involvement is a key feature of FTD, and more pronounced in GRN-related disease. Damage to the caudate region in GRN+ patients may explain the parkinsonism frequently associated since the early stages of the disease.

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Atrophy in distinct corticolimbic networks predicts specific social symptoms in frontotemporal dementia

Atrophy in distinct corticolimbic networks predicts specific social symptoms in frontotemporal dementia

Atrophy in Distinct Corticolimbic Networks Predicts Specific Social Symptoms in Frontotemporal Dementia (P06.055)

Atrophy in Distinct Corticolimbic Networks Predicts Specific Social Symptoms in Frontotemporal Dementia (P06.055)

Neuropsychological Features of Asymptomatic c.709-1G&gt;A Progranulin Mutation Carriers

Mutations in the progranulin (PGRN) gene have been identified as a cause of frontotemporal dementia (FTD). However, little is known about the neuropsychological abilities of asymptomatic carriers of these mutations. The aim of the study was to assess cognitive functioning in asymptomatic c.709-1G>A PGRN mutation carriers. We hypothesized that poorer neuropsychological performance could be present before the development of clinically significant FTD symptoms. Thirty-two asymptomatic first-degree relatives of FTD patients carrying the c.709-1G>A mutation served as study participants, including 13 PGRN mutation carriers (A-PGRN+) and 19 non-carriers (PGRN-). A neuropsychological battery was administered. We found that the A-PGRN+ participants obtained significantly poorer scores than PGRN- individuals on tests of attention (Trail-Making Test Part A), mental flexibility (Trail-Making Test Part B), and language (Boston Naming Test). Poorer performance on these tests in asymptomatic PGRN mutation carriers may reflect a prodromal phase preceding the onset of clinically significant symptoms of FTD.

Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.

Abnormal network connectivity in frontotemporal dementia: Evidence for prefrontal isolation

IntroductionDegraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brain's intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. MethodsResting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. ResultsAcross multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. ConclusionsThe present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may represent a compensatory response to the absence of affective feedback during the planning and execution of behavior. Increased reliance upon prefrontal processes in isolation from subcortical structures appears to be maladaptive and may drive behavioral withdrawal that is commonly observed in later phases of neurodegeneration.

Frontotemporal dementia in eight Chinese individuals

Frontotemporal dementia (FTD) has rarely been reported in Chinese populations. There are many potential reasons for this, including possible hesitancy on the part of patients or families to bring FTD-related symptoms to medical attention. Here, we present data on eight Chinese individuals, all of whom met criteria for the behavioral variant of FTD or the semantic variant of primary progressive aphasia. These patients presented for neurological evaluation at a relatively advanced stage. The mean MMSE score at initial presentation was 15. Behavioral symptoms were common and usually elicited during the medical history only after direct questioning. Delay in presentation was attributed to a variety of issues, including family disagreements about whether the symptoms represented a disease and lack of medical insurance. These cases illustrate that the symptoms of FTD in Chinese-Americans are similar to those in Caucasians but various factors, some potentially culturally relevant, may influence the likelihood and timing of clinical presentation for FTD, as well as other dementias. Additional study of FTD in diverse ethnic groups needs to address barriers to clinical presentation, including factors that may be culturally specific.

Aprosodic Speech and Insular Lesions as Main Features of a Massive Tauopathy in Frontotemporal Dementia (P07.188)

Objective: To describe a patient with a massive and widespread tauopathy who presented with an atypical speech disturbance and MRI findings along 6 years of follow-up. Background The spectrum of frontotemporal dementia is characterized by distinct behavioural changes and aphasia, either non-fluent/agrammatic, semantic, or logopenic together with neuroimaging evidence of different patterns of atrophy related to the underlying pathology. Design/Methods: A 46-year-old woman presented with a 2-year history of progressive personality change. Having been an active, cheerful and empathic woman she started having problems with work colleagues and turned apathetic. Her speech became slow and aprosodic, somehow robotic (see video), without aphasic features. She had a healthy twin sister and another older sister diagnosed of schizophrenia. She progressively worsened, showing a childish and disinhibited behaviour. She never suffered hallucinations, autonomic dysfunction or parkinsonism. She died by accident 6 years after disease onset. Results: She did not developed any of the typical patterns of aphasia described in frontotemporal dementia . Brain MRI showed subcortical hyperintensities involving both insulae, that later spread into both frontal cortices. No gross atrophy was detected. Tests for progranulin, prion protein, CADASIL, sequentiation of the MAPT gene and presenilin-1 were negative. The neuropathological study showed a massive neuronal loss in the frontal cortex with deposits of 4R-Tau in the frontal and insular cortex, striatum, amygdala, hippocampus, entorhinal cortex, hypothalamus, thalamus, locus coeruleus and cerebellum. Deposits were predominantly intracytoplasmatic. There was some scattered deposition of TDP-43 and complete lack of amyloid and alpha-synuclein. Conclusions: Aprosodic speech without aphasia and insular hyperintensities add to the unusual manifestations of frontotemporal dementia. This histologically proven case adds to our knowledge of frontotemporal dementia and also reinforces the crucial role of the insula for the development of the behavioural and speech symptoms in frontotemporal dementia. Disclosure: Dr. Gomez Beldarrain has nothing to disclose. Dr. Ruiz Ojeda has nothing to disclose. Dr. Ferrer Abizanda has nothing to disclose. Dr. Cabrera has nothing to disclose. Dr. Garcia Monco has nothing to disclose.

Behavioral changes on amyotrophic lateral sclerosis (ALS): a case of ALS/FTD TDP-43 proteinopathy

The frontotemporal dementia (FTD) is the second most common form of dementia in patients younger than 65 years, and its behavioral variant (bvFTD) is the most prevalent form1,2. During the last years, the overlapping between FTD and amyotrophic lateral sclerosis (ALS) has been frequently recognized, with symptoms of FTD preceding ALS and vice-versa. Herein, we report a case of ALS, which afterwards presented psychotic and behavioral symptoms, whose neuropathological diagnosis was compatible with bvFTD-ALS with TAR DNA-binding protein 43 (TDP-43) [...]

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members.

Vitamin B12 deficiency associated with symptoms of frontotemporal dementia

We report the case of an elderly patient with cobalamin deficiency who progressively developed cognitive and behavioral symptoms associated with neuropsychiatric disturbances. His neuropsychological profile showed many features suggestive for a frontal-dysexecutive syndrome and was related to a predominant asymmetric (right > left) frontal lobe hypoperfusion. He completely recovered after a treatment with vitamin B12 and follow-up of 7 years showed that his improvement remained stable. Along with the other cases reported in the literature, our case also proves that there are some cases of vitamin B12 deficiency that can manifest with the symptoms of frontotemporal dementia and that they are completely reversible after substitution therapy.

P01-350 - Mania like symptoms in frontotemporal dementia

ObjectivesTo alert to manic like symptoms in frontotemporal dementia (FTD).MethodsReview of literature relevant in medline database.ResultsFrontotemporal dementia (FTD) is a behavioural syndrome caused by generation of the frontal and anterior temporal lobes.Bipolar disorder in dementia and the temporal relation between the two conditions have rarely been studied. There is a increased probability of developing a manic episode in patients with dementia.Those with temporal FTD have impairments in emotional processing and hypomania like behavior. Moria (childish excitement or tendency to joke) or frivolous excitement are common presenting symptoms, and is difficult to distinguish to features in bipolar disease.The correlation between mania like symptoms and FTD can be make with the help of informations of the family and computed tomography imaging. Those with temporal involvement are particularly at risk of developing deficits in emotional processing secondary to atrophy in the amygdale, anterior temporal cortex, and adjacent orbitofrontal cortex.ConclusionsEarly temporal involvement in FTD is associated with frivolous behavior and right temporal involvement is associated with emotional disturbances.Moria or frivolous behavior are common presenting symptoms of FTD and the differential diagnosis is made with the help of informant's reports and computed tomography imaging.

Five cases of frontotemporal dementia with behavioral symptoms improved by Yokukansan

AbstractHerein, we present five cases with frontotemporal dementia whose behavioral symptoms were improved by Yokukansan, a traditional Japanese medicine (Kampo). All five patients were prescribed Yokukansan (7.5 g/day) to reduce their symptoms. The patients' symptoms were evaluated comprehensively using the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI) before and 4 weeks after Yokukansan treatment. The mean (± SD) scores on the NPI and the SRI before treatment were 55.6 ± 5.4 and 22.2 ± 6.5, respectively. After treatment, these scores were 30.0 ± 7.8 and 11.6 ± 7.5, respectively. Yokukansan was effective for the treatment of clinical symptoms in all five patients without adverse effects and significant changes in laboratory data. Although antipsychotic drugs have been used to control behavioral symptoms, their associated adverse effects frequently impact on the activities of daily living and quality of life of treated patients. The present cases suggest significant improvement of behavioral symptoms in frontotemporal dementia with Yokukansan treatment, leading to probable benefit of the use of Yokukansan in individuals with frontotemporal dementia.