Frontotemporal Lobar Degeneration Spectrum Research Articles

017 A network model of semantic dementia

Semantic dementia (SD) is a unique syndrome in the frontotemporal lobar degeneration spectrum. Typically presenting as a progressive, fluent anomic aphasia, SD is the paradigmatic disorder of semantic memory with...

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

White matter damage in frontotemporal lobar degeneration spectrum

White matter damage in frontotemporal lobar degeneration spectrum

White matter damage in frontotemporal lobar degeneration spectrum

White matter damage in frontotemporal lobar degeneration spectrum

Semantic Dementia: a specific network-opathy

Semantic dementia (SD) is a unique syndrome in the frontotemporal lobar degeneration spectrum. Typically presenting as a progressive, fluent anomic aphasia, SD is the paradigmatic disorder of semantic memory with a characteristic anatomical profile of asymmetric, selective antero-inferior temporal lobe atrophy. Histopathologically, most cases show a specific pattern of abnormal deposition of protein TDP-43. This relatively close clinical, anatomical and pathological correspondence suggests SD as a promising target for future therapeutic trials. Here, we discuss outstanding nosological and neurobiological challenges posed by the syndrome and propose a pathophysiological model of SD based on sequential, regionally determined disintegration of a vulnerable neural network.

A progranulin mutation associated with cortico-basal syndrome in an Italian family expressing different phenotypes of fronto-temporal lobar degeneration

Cortico-basal syndrome (CBS) is a rare neurodegenerative disease characterised by movement and cognitive disorders. It occurs along the spectrum of fronto-temporal lobar degeneration (FTLD), which also includes fronto-temporal dementia (FTD) and progressive supranuclear palsy (PSP). FTLD has recently been shown to be associated with mutations in GRN gene, coding for progranulin, a multifunctional secreted glycoprotein involved in cell cycle, inflammation and tissue repair. We describe the case of a 73-year-old man suffering from CBS with a family history of cognitive disorders belonging to the clinical spectrum of FTLD. Sequencing analysis of GRN in this patient revealed that the C157KfsX97 null mutation has been already described by Le Ber et al. in a French patient affected by an apparently sporadic form of FTD. This report confirms the variability of clinical phenotypes associated with the same mutation and emphasises the importance of genetic analysis in cases with a clear familiarity, as well as in apparently sporadic forms.

Language disorders in degenerative dementias

Background Progressive selective deterioration of language is caused by cerebral lesions involved in processes of language elaboration and is characteristic of several forms of dementia such as Alzheimer’s disease (AD) and Frontemporal dementia (FTD), that are neurodegenerative dementia and epidemiologically relevant. AD language disturbances are characterized by difficulties in word selection: language becomes impaired, simple and often lacking of syntactic structures. In the Frontotemporal lobar degeneration spectrum, the language disorder is a key symptom not only for FTD, but also of two specific forms that are Primary Progressive Aphasia and Semantic Dementia. Language disorder is characterised by reduction of verbal initiative evolving towards a complete mutism. Echolalia and perseveration are frequently observed In a calabrian population in which FTD is highly prevalent [1], FTD patients have been identified as carriers or non carriers of the Progranulin (GRN) c.1145insA mutation [2]. The patients groups (GRN+ e GRN-) were compared with respect to the language disturbances and age at onset.

New Insights into Biological Markers of Frontotemporal Lobar Degeneration Spectrum

In the last decade, there has been enormous progress in our understanding of Frontotemporal Lobar Degeneration (FTLD). Published clinicopathological series have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the Progressive Supranuclear Palsy (PSP), and the Corticobasal Degeneration (CBD) syndrome. From a neuropathological point of view, two broad pathological subdivisions of FTLD are currently recognized: a) tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau, that encompasses FTLD with Pick bodies, PSP and CBD, and b) tau-negative pathology, mainly characterized by ubiquitin/TDP-43-immunoreactive inclusions and in some cases due to Progranulin mutations. Several biological markers in cerebrospinal fluid and in blood have been evaluated to identify monogenic forms of FTLD and to differentiate either FTLD spectrum disorders or FTLD from other neurodegenerative disorders. The proposed biomarkers are primarily related to the mechanisms underlying the accumulation of the abnormal proteins in FTLD such as Tau, TDP-43 and Progranulin. These biomarkers may support the accurate diagnosis of the specific diseases causing FTLD, can be useful in assessing efficacy during pharmacological trials, and may help in identifying new molecular targets for treatment approaches. In this review, we summarise the most recent findings on biological markers and their usefulness in clinical practice for the diagnosis and management of FTLD.

The heritability and genetics of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

Pattern of behavioral disturbances in corticobasal degeneration syndrome and progressive supranuclear palsy

A careful characterization of behavioral abnormalities in corticobasal degeneration syndrome (CBDS) and progressive supranuclear palsy (PSP) by reliable tools is still lacking. Literature data provided evidence of the usefulness of the Frontal Behavioral Inventory (FBI) to operationalize such disturbances, particularly in the frontotemporal lobar degeneration spectrum. The study aimed to evaluate the frequency and pattern of presentation of behavioral disturbances in a large sample of CBDS and PSP patients by FBI. Sixty-eight CBDS and 57 PSP patients entered the study and underwent a standardized clinical and neuropsychological battery, and a structural brain imaging study. Behavioral disturbances were carefully analyzed by FBI. FBI scores were relatively low in both groups, being 6.7 +/- 8.2 and 5.6 +/- 6.1 in CBDS and PSP, respectively. Comparison of the behavioral profile between CBDS and PSP patients showed significant differences in apathy were more frequent in the latter (57.9% vs. 33.8%, P = 0.007), and the presence of alien hand/apraxia more frequent in the former group 39.7% vs. 10.5%, P = 0.001). Apathy correlated neither with age nor with motor disturbances as measured by UPDRS-III. Overall, the most frequent behavioral abnormalities present in both groups (>25%) were aspontaneity and logopenia. Aphasia (27.9%) and irritability (35.3%) were more frequent in CBDS compared to PSP, even if not statistically different. The present study has provided measures of behavioral disturbances in a population of PSP and CBDS patients, and further confirms the usefulness of the FBI scale.

Presymptomatic Generalized Brain Atrophy in Frontotemporal Dementia Caused by CHMP2B Mutation

Background/Aims:CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. Methods: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. Results: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B gene mutation carriers. Conclusions: This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum.

Neuroimaging in Dementia

Although dementia is a clinical diagnosis, neuroimaging often is crucial for proper assessment. Magnetic resonance imaging (MRI) and computed tomography (CT) may identify nondegenerative and potentially treatable causes of dementia. Recent neuroimaging advances, such as the Pittsburgh Compound-B (PIB) ligand for positron emission tomography imaging in Alzheimer's disease, will improve our ability to differentiate among the neurodegenerative dementias. High-resolution volumetric MRI has increased the capacity to identify the various forms of the frontotemporal lobar degeneration spectrum and some forms of parkinsonism or cerebellar neurodegenerative disorders, such as corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, and spinocerebellar ataxias. In many cases, the specific pattern of cortical and subcortical abnormalities on MRI has diagnostic utility. Finally, among the new MRI methods, diffusion-weighted MRI can help in the early diagnosis of Creutzfeldt-Jakob disease. Although only clinical assessment can lead to a diagnosis of dementia, neuroimaging is clearly an invaluable tool for the clinician in the differential diagnosis.

Establishing short-term prognosis in Frontotemporal Lobar Degeneration spectrum: Role of genetic background and clinical phenotype

Background Establishing the short-term prognosis in Frontotemporal Lobar Degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. No reliable neuropsychological assessment balancing all FTLD aspects is available yet, thus no clear-cut follow-up study has been performed. Objective To evaluate the rate of progression and the predictors of worsening in FTLD patients. Methods One-hundred twenty-seven FTLD patients entered the study and were re-evaluated at 1-year follow-up. A statistical driven approach on wide neuropsychological, behavioral, and functional data was applied to identify homogeneous groups both at baseline and at follow-up within FTLD. Three set of predictors on disease progression were considered: (i) the demographic characteristics, (ii) the genetic background, i.e. Apolipoprotein E ( APOE) genotype, Tau haplotype, and functional polymorphisms affecting serotonin and dopamine pathways, and (iii) the clinical phenotype. Results Among FTLD, two groups of patients were recognized on the basis of the overall assessment, thus termed for different disease severity as “good performers” and “bad performers”. At 1-year follow-up, almost 30% of FTLD patients progressed from “good” to “bad” performances, whilst 70% maintained stable “good” performances. APOE ɛ4 allele, Tau H2 haplotype and behavioral variant FTD phenotype were associated with worse prognosis over time. Conclusions This preliminary study proposed genetic and clinical predictors in FTLD progression. The identification of disease-modifying predictors of prognosis opens a new avenue in studying FTLD, and may contribute to define outcomes and to monitor pharmacological targets.

Longitudinal decline in autopsy-defined frontotemporal lobar degeneration

The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

New Genes, New Dilemmas: FTLD Genetics and Its Implications for Families

After Alzheimer's disease, frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in persons less than 65 years of age. Up to 40% of FTLD cases have a positive family history. Research on these families has led to the discovery of four disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). MAPT and PGRN are responsible for the largest number of familial cases. Each of these genes differs by disease mechanism. Moreover mutations in both genes are associated with significant interfamilial and intrafamilial phenotypic variation. Genetic counseling needs to address the differences between the PGRN and MAPT mutations as well as the variation in clinical symptoms. The aims of this article are to describe the genetics of the FTLD spectrum and aid in the genetic counseling of individuals who may carry genetic mutations.

MAPT S305I mutation: implications for argyrophilic grain disease

Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal fluency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diffuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were observed, whereas classical neurofibrillary tangles, Pick bodies, and neuritic plaques were absent. The tau-positive abnormal structures were composed only of 4R-tau isoforms and, ultrastructurally, straight filaments. Neuronal loss was greatest in the medial temporal cortex, hippocampus, and amygdala. These pathological features resemble AgD. The novel S305I substitution has a strong effect on MAPT exon 10 splicing, thereby causing a striking increase in 4R-tau isoforms. Our observation not only widens the phenotypic spectrum of FTLD with MAPT mutation but also underpins the notion that the predominance of similar neuropathological findings in sporadic AgD cases may be viewed as features of a distinct disease entity.

The Frontal Behavioural Inventory (Italian version) differentiates frontotemporal lobar degeneration variants from Alzheimer's disease

The objective was to evaluate the construct validity of the Italian version of the Frontal Behavioural Inventory (FBI) and its usefulness in the differential diagnosis of dementias. Standard criteria were used in the clinical diagnosis of dementias in 83 patients and 33 agematched healthy volunteers. The FBI scale was translated from English into Italian language and back-translated. Cronbach's alpha, inter-rater and test-retest reliability, FBI convergent validity and discriminant analysis were calculated. FBI profile was compared between patients affected by frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). The FBI showed a high internal consistency and inter-rater reliability and it distinguished normal behavioural conditions from those presented in FTLD or AD. An 86.8% diagnostic accuracy was calculated by the discriminant analysis, selecting only age at disease onset and FBI, and particularly distinguishing behavioural variants within the FTLD spectrum. FTLD patients showed a characteristic behavioural profile. The FBI might be a reliable and useful diagnostic tool for dementias in clinical practice.

Frontotemporal Dementia: Recommendations for Therapeutic Studies, Designs, and Approaches

Frontotemporal dementia (FTD) is one of three neurobehavioural syndromes produced by frontotemporal lobar degeneration. Despite the importance of FTD as a cause of dementia, especially in younger age groups, and a rationale for therapies targeting serotonergic and dopaminergic systems, there have been no large scale treatment trials in FTD. Moreover, there is no consensus on standards to facilitate comparison across therapeutic trials. This paper reviews the literature on therapeutic trials in FTD and outlines general recommendations for standards related to the development of future treatment studies in this disorder. Drugs tested in FTD include trazodone, galantamine, idazoxan, lithium plus fluoxetine, lithium plus paroxetine, SSRIs, 1-deprenyl, moclobemide, methylphenidate, piracetam, rivastigmine, donepezil, olanzapine, risperidone, amantadine, guanfacine, allopurinol, and bromocriptine. Improvement has been reported in FTD for all drugs except piracetam, guanfacine and galantamine, although there was improvement on galantamine in primary progressive aphasia. Whereas improvement has been reported for paroxetine and other SSRIs, as well as idazoxan and methylphenidate, paroxetine and idazoxan have also been reported to cause a decline in function, and a marginally significant decline has been reported for methylphenidate. In addition, patients with Pick's disease, which is part of the spectrum of frontotemporal lobar degeneration, showed improvement on calcium EDTA. Six studies are double-blind placebo-controlled trials: two reports of cases using idazoxan and group trials using trazodone, paroxetine, galantamine and methylphenidate. It is recommended that experts in FTD arrive at a consensus to define standards for all clinical trials in FTD. These should include standards for diagnostic criteria, tests of severity, experimental design, and outcome measures.

Frontotemporal Lobar Degeneration: Current Concepts in the Light of Recent Advances

Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD.

Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome

Corticobasal syndrome (CBS) is a rare cognitive and movement disorder characterized by asymmetric rigidity, apraxia, alien-limb phenomenon, cortical sensory loss, myoclonus, focal dystonia, and dementia. It occurs along the clinical spectrum of frontotemporal lobar degeneration (FTLD), which has recently been shown to segregate with truncating mutations in progranulin (PGRN), a multifunctional growth factor thought to promote neuronal survival. This study identifies a novel splice donor site mutation in the PGRN gene (IVS7+1G-->A) that segregates with CBS in a Canadian family of Chinese origin. We confirmed the absence of the mutant PGRN allele in the RT-PCR product which supports the model of haploinsufficiency for PGRN-linked disease. This report of mutation in the PGRN gene in CBS extends the evidence for genetic and phenotypic heterogeneity in FTLD spectrum disorders.