Initial complaints in frontotemporal lobar degeneration

AIMS: Frontotemporal lobar degeneration (FTLD) is probably underrecognized. The goal of this study was to investigate initial complaints of both patients and their caregivers at first specialist referral. Also, we tried to assess whether misrecognition of symptoms contributed to diagnostic delay. METHODS: The case notes of all patients diagnosed with FTLD at the VU University Medical Center, Alzheimer Center of Amsterdam, The Netherlands, since 1998 were retrospectively reviewed. Only patients of whom detailed information of first specialist referral was available were included. The diagnosis of FTLD was based on the clinical diagnostic criteria of Neary and Snowden, supported by ancillary investigations. RESULTS: Forty-six patients with FTLD were included. Twenty-one patients had frontotemporal dementia (FTD), 17 semantic dementia (SD) and 8 progressive nonfluent aphasia (PA). The majority of the FTD patients presented without complaints or with somatic complaints and nearly a quarter of them expressed memory complaints. The presenting complaints of most of their caregivers differed from the patients' complaints and often consisted of cognitive complaints. In SD and PA, language problems but also forgetfulness were presented. Misrecognition of the initial symptoms in some cases seemed to have contributed to diagnostic delay. CONCLUSION: Presenting complaints in FTLD can be misleading. In our cohort, memory complaints occurred relatively often. A multidisciplinary approach, including a structured behavioral interview, is important to recognize symptoms of FTLD.     

Epidemiology of frontotemporal lobar degeneration

A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick's disease. The aim of this study was to review the epidemiologic studies of FTLD in western countries and to compare them with those in Japan. A community-based study of early-onset dementia in London revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund-Manchester criteria in contrast to 34% of cases with Alzheimer's disease (AD) in a sample of 185 cases. The Cambridge Group has recently examined the prevalence of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD (29%) had a positive family history. Of our consecutive 330 outpatients with dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215 (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified. There was no family history in all subtypes of FTLD. Epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy is supposed to be mainly based on the role of heredity.     

Comparison of family histories in FTLD subtypes and related tauopathies

Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.     

Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration

Objective To correlate clinical diagnosis and genetic features with different pathological substrates in patients with frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD). Methods 32 cases with pathological proven FTLD or CBD were selected. Patients were classified clinically as frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), CBD or FLTD with motor neuron disease (FLTDMND). Coding exons 1 and 9–13 of MAPT and exons 0–12 of the PGRN gene were screened by direct sequencing. Regarding the neuropathological findings, cases were classified as tau-positive, ubiquitinpositive tau-negative (FTLD-U), neuronal intermediate filaments inclusions disease (NIFID), dementia lacking distinctive histology (DLDH) or CBD. Results 17 patients were clinically diagnosed with FTD. Ten showed tau pathology, 3 FTLD-U, 1 NIFID and 3 DLDH. All patients clinically classified as FTLD-MND (6 patients) or SD (3 patients) were FTLD-U. Tau-positive pathology was the substrate of the three patients with PNFA. All three patients classified clinically as CBD presented neuropathologic features of CBD. The three individuals with familial history of early onset FTD and tau-positive pathology carried the P301L mutation in the MAPT gene. One out of 3 cases with FTLD-U and intranuclear inclusions carried a mutation in the PGRN gene. Conclusions We found that pathology underlying sporadic FTD is heterogeneous and not predictable. MAPT mutations and clinical diagnosis of PNFA and CBD were associated with tau-positive pathology. The presence of signs of lower MND and SD correlated with FTLD-U.A genetic study of MAPT is only recommended when familial history of early onset DFT is present. * Other members of the Catalan collaborative Study Group for FTLD are listed in the Appendix.     

Difficulties in detecting behavioral symptoms of frontotemporal lobar degeneration across cultures

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychologic characteristics of more than 300 patients diagnosed with FTLD in the United States, Greece, and Turkey. We find that patients with the frontal variant of frontotemporal dementia (FTD) are diagnosed at an earlier age and report earlier symptom onset in the United States than in Greece or Turkey. Furthermore, neuropsychologic measures indicate that at diagnosis, FTD patients in the United States are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage.     

Frontotemporal lobar degeneration: clinical and pathological relationships

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.     

The heterogeneity of frontotemporal dementia with regard to initial symptoms, qEEG and neuropathology

OBJECTIVES/METHODS: Ten patients with neuropathologically verified frontotemporal dementia (FTD) were analysed for neuropathological features in relation to first presenting and dominating symptoms, age at onset and duration of dementia, as well as to EEG/quantitative EEG. RESULTS: Cases with a late onset (> 65 years) initially presented language disturbances, while the early onset group (< 65 years) showed predominantly behavioural symptoms and mood alterations as early features. The late onset group presented combined cortical-subcortical degeneration including white matter pathology, while early onset cases showed pathology predominantly in the cortex. EEG was normal in the late onset group, while it was mildly and variably abnormal in those with early onset. CONCLUSIONS: Within this small sample of clinical and neuropathological FTD, cases with late vs early onset differed with respect to initial symptoms, EEG findings and regional distribution of brain pathology.     

Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.     

Neuropathological background of phenotypical variability in frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.     

A volumetric magnetic resonance imaging study of the amygdala in frontotemporal lobar degeneration and Alzheimer's disease

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer's disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants.     

Frontotemporal dementia: a clinically complex diagnosis

OBJECTIVE: To compare the time taken to establish a clinical diagnosis of Frontotemporal dementia (FTD) relative to a diagnosis of early onset Alzheimer's dementia (AD). METHODS: The data came from 89 patients under the age of 65 years, 52 of whom met the Manchester-Lund criteria for Frontotemporal dementia; 20 of these came from Lund University Hospital in Sweden. The other 32 patients with FTD along with 37 subjects who fulfilled the ICD-10 criteria for early onset Alzheimer's disease were recruited from four memory clinics and two neurology departments in Norway. RESULTS: For FTD patients in Norway it took 59.2 months (SD 36.1) from the onset of illness until a clinical FTD diagnosis was made. The corresponding time period for FTD patients in Sweden is 49.5 months (SD 24.5) and for AD patients in Norway 39.1 months (SD 19.9). The time from the first visit to a medical doctor until a diagnosis was made for the FTD patients in Norway was 34.5 months (SD 22.6), for the Swedish FTD patients 23.1 months (SD 22.4) and for the AD patients 25.9 months (SD 13.1). In all, 71% of FTD patients and 30% of AD patients initially received a non-dementia diagnosis. CONCLUSION: More knowledge about early presenting cognitive and behavioural signs of FTD is needed in both primary and secondary health care to reduce the time period needed to establish a clinical diagnosis of FTD.     

Frontotemporal dementia: patient characteristics,cognition, and behaviour

OBJECTIVES: To describe sociodemographic data of patients with frontotemporal dementia (FTD), to compare the cognitive profile of patients with FTD with that of severity-matched patients with Alzheimer's disease using the CERAD neuropsychological battery (CERAD-NP), to investigate the frequency of behavioural disturbances, and to examine the relation between FTD-specific non-cognitive behavioural symptoms of patients with FTD with age and sex. METHODS: Fifty outpatients were diagnosed with FTD according to the Lund-Manchester consensus criteria. Cognitive impairment was assessed in 30 patients using the CERAD-NP. Severity of dementia was rated on the Clinical Dementia Rating (CDR). Eleven non-cognitive symptoms were rated by severity. To compare CERAD-NP results between patients with FTD and AD, 30 patients with AD were matched for age, sex, and global severity of cognitive performance. RESULTS: The average age at onset of first symptoms was 57.8 years. Eighteen patients (36%) had a positive family history of dementia. On the CERAD-NP patients with FTD performed significantly better than patients with AD on word list learning, delayed verbal recall and visuoconstruction (p < 0.05). There were no significant differences between FTD and AD on naming and verbal fluency tasks. The most frequent non-cognitive behavioural symptoms in FTD were loss of insight, speech abnormality, and apathy. Non-cognitive behavioural symptoms were more frequent in younger and in male than in older patients and in female patients. CONCLUSIONS: The CERAD-NP is a valuable clinical instrument for the cognitive evaluation of patients with suspected FTD. Complementary short tests of attention and executive function may be recommended. To enhance diagnostic sensitivity informant interviews should focus on non-cognitive behavioural changes, taking advantage of standardised questionnaires.     

Frequency of early and late-onset dementias in a Japanese memory disorders clinic

The aim of this study was to compare the diagnostic profiles of patients with early (age<65 years) and late (age>or=65 years) onset of dementia in a memory disorders clinic in Japan. A total of 512 consecutive memory clinic patients were evaluated using clinical information and results of examinations. Diagnosis of dementia was made according to DSM-III-R, and that of subtypes according to standard diagnostic criteria. A total of 464 patients met the criteria for dementia. Amongst late-onset patients (n=430), Alzheimer's disease (AD) (48.1%) was the most frequent cause of dementia, followed by AD with cerebrovascular disease (CVD) (31.4%), vascular dementia (VaD) (9.1%), dementia with Lewy bodies (DLB) (3.7%), frontotemporal lobar degeneration (FTLD) (1.6%), and others (5.8%). On the contrary, amongst early onset patients (n=34), the most common dementia diagnosis was AD (38.2%), followed by VaD (23.5%), FTLD (14.7%), AD with CVD (5.9%), DLB (2.9%), and others (17.6%). FTLD and VaD were significantly more common in the early onset group. All patients, but one, with DLB and Parkinson's disease dementia were late-onset. The relative frequencies of AD, VaD, and DLB in our series are consistent with epidemiologic findings in several Western countries; however, the frequency of FTLD is not consistent with the previous findings presenting high frequency in late-onset patients in some Western countries.     

Frontotemporal lobar degeneration: new understanding brings new approaches

Frontotemporal dementia (FTD) describes a group of clinical syndromes united by underlying frontotemporal lobar degeneration (FTLD) pathology. The clinical syndromes associated with FTLD are heterogeneous and are based on whether the patients present with behavioral, language, or motor impairments. FTLD is at the center of a paradigm shift in neurodegenerative diseases, with thought being given at diagnosis of underlying disease. There is pathologic heterogeneity of certain clinical syndromes such as behavioral variant FTD. Differentiation between the proteinopathies will become imperative as protein-specific treatments become available. This review provides an overview of FTLD, with an update of recent discoveries.     

Charting Frontotemporal Dementia: From Genes to Networks

Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous syndrome that is characterized by overlapping clinical symptoms involving behavior, personality, language and/or motor functions and degeneration of the frontal and temporal lobes. The term frontotemporal lobar degeneration (FTLD) is used to describe the proteinopathies associated with clinical FTD. Emerging evidence from network‐based neuroimaging studies, such as resting state functional MRI and diffusion tensor MRI studies, have implicated specific large‐scale brain networks in the pathogenesis of FTD syndromes, suggesting a new paradigm for explaining the distributed and heterogeneous spreading patterns of pathological proteins in FTLD. In this review, we overview recent research on the study of FTD syndromes as connectivity disorders in symptomatic patients as well as genotype‐specific changes in asymptomatic FTD‐related gene mutation carriers. Characterizing brain network breakdown in these subjects using neuroimaging may help anticipate the diagnosis and perhaps prevent the devastating impact of FTD.     

The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein

Pathological examinations, using a panel of tau and other antibodies, were performed on the brains from 55 consecutively acquired cases of frontotemporal lobar degeneration (FTLD). Clinically, these comprised 31 cases of frontotemporal dementia (FTD), 10 cases of motor neurone disease inclusion dementia (MNDID), seven cases of progressive aphasia (PA), four cases of semantic dementia (SD) and three cases of progressive apraxia (PAX). Tau pathology, in the form of neurofibrillary tangles (NFTs) and glial cell tangles, was present in six cases of FTD with parkinsonism linked to chromosome 17, five of these cases resulting from +16 splice-site mutation and one from +13 mutation in the tau gene. The insoluble tau proteins were comprised mostly of four-repeat (4-R) isoforms. Eight other cases of FTD, one of PA and all three cases of PAX showed tau-positive inclusions (Pick bodies) and swollen cells (Pick cells), characteristic of Pick's disease. In these cases, the insoluble tau proteins were present in most instances as three-repeat (3-R) tau isoforms, although two cases with a mixture of 3-R and 4-R isoforms were seen. One other case of FTD showed an unusual pathology characterized by massive extracellular deposition of tau protein, composed of 4-R tau isoforms, within white matter without neuronal or glial cell inclusions. However, 33 (60%) of 55 FTLD cases showed no tau pathology in the brain, except for the rare NFTs, composed of a mix of 3-R and 4-R isoforms, in some of the more elderly cases. Of these 33 cases, 13 had FTD, 10 had MNDID, six had PA and four had SD. The pathological changes present were those of a superficial cortical laminar microvacuolation with mild subpial and subcortical gliosis; the 10 MNDID cases had ubiquitin-positive inclusions in the cerebral cortex and hippocampus. These 33 nontau FTLD cases, along with five Alzheimer's disease (AD) and six Huntington's disease (HD) cases with severe pathology, showed a variable loss of soluble tau proteins, broadly comparable with the extent of neuronal loss from the cortex and loss of the intracortical perikaryal marker, NeuN, but unrelated to proteins within afferent projection fibres such as neurofilament and alpha-synuclein. Levels of tau mRNA were decreased in parallel in the tau-negative FTLD cases and in the severe AD and HD cases. Hence, the loss of tau from these 33 nontau FTLD cases is just one aspect of a neurodegenerative process that destroys many components of the nerve cell machinery and does not represent a specific disordering of the cell's ability to form tau proteins or incorporate these into microtubules.     

Amyotrophic Lateral Sclerosis: ethical issues from diagnosis to end of life

The variable clinical course of Amyotrophic Lateral Sclerosis (ALS) confronts the clinician, the patient and caregivers with many ethical challenges from the moment of breaking the news of the diagnosis and throughout the relentlessly progressive trajectory of the disease. Each patient faces the prospect of life-threatening bulbar and respiratory muscle dysfunction that may ensue soon after disease onset or after months or years of progressive weakness. This reality eventually forces the patient to choose life extension via gastrostomy tube insertion, mechanical ventilation or both or to forego these treatments in favor of terminal palliative care. Faced with these prospects some patients contemplate voluntary cessation of food and water, physician assisted suicide or euthanasia. Depending upon the presence and severity of frontotemporal dementia (FTD) related to frontotemporal lobar degeneration (FTLD) the capacity to make these forced choices may be compromised. Clinicians caring for ALS patients should appreciate and communicate the significance of life threatening symptoms, monitor capacity for decision making, anticipate and manage multiple possible end of life scenarios, and aggressively manage symptoms.     

Neuropsychology of frontal type dementia]

The clinical conceptual change in frontal type dementia is reviewed in discussing its relationships to several related concepts such as Pick's disease, frontotemporal dementia (FTD), semantic dementia (SD) and frontotemporal lobar degeneration. We analyzed frontal type dementia selected from a consecutive series of our outpatients as to the details of neuropsychological symptoms, psychiatric symptoms, and abnormal behaviors. In our series of 143 patients with primary degenerative dementia, there were 16 cases of FTD and 6 cases of SD. Patients with two types of FTD and patients with SD were not distinguishable by neuropsychological examinations, behavioral abnormalities and psychiatric symptoms assessed with the Neuropsychiatric Inventory except for aphasia. The clinical picture of frontal type dementia involves frontal lobe symptoms such as disinhibition, apathy and stereotypy. Semantic memory loss for words, objects or faces suggestive of temporal lobe involvement developed only in patients with SD, and not in patients with FTD. Certain behavioral symptoms seen in frontal type dementia may respond to selective serotonin reuptake inhibitors. In care for patients with frontal type dementia, behavioral disturbances can be diminished and the quality of life can be improved by using their preserved procedural memory, pathological stereotypic behavior and stimulus-bound behavior such as utilization behavior and environmental dependency syndrome.