Review: Clinical,genetic and neuroimaging features of frontotemporal dementia

Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal‐dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule‐associated protein tau being the commonest causes. In the other two‐thirds, the disorder is sporadic, although recent genome‐wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10 years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.     

Odour identification in frontotemporal lobar degeneration

Abstract Little information is available concerning olfactory processing in frontotemporal lobar degeneration (FTLD). We undertook a case-control study of olfactory processing in three male patients fulfilling clinical criteria for FTLD. Odour identification (semantic analysis) and odour discrimination (perceptual analysis) were investigated using tests adapted from the University of Pennsylvania Smell Identification Test. General neuropsychometry and structural volumetric brain magnetic resonance imaging (MRI) were also performed. The three patients with FTLD exhibited a disorder of olfactory processing with the characteristics of a predominantly semantic (odour identification) deficit. This olfactory deficit was more prominent in patients with greater involvement of the temporal lobes on MRI. Central deficits of odour identification may be more common in FTLD than previously recognised, and these deficits may assist in clinical characterisation.     

Senile onset frontotemporal lobar degeneration with TAR‐DNA binding protein 43 proteinopathy primarily presenting with wasteful habits

We present an autopsied case of a senile Japanese woman with sporadic frontotemporal lobar degeneration (FTLD) presenting as frontotemporal dementia. Disease onset was at the age of 70 and presented as a behaviour disorder, particularly involving wasteful habits. The patient had repeated incidents of making expensive purchases and then had difficulty making payments. Following these symptoms, she showed other changes of character such as lethargy and apathy. She gradually showed signs of parkinsonism including rigidity and bradykinesia, and in the terminal stage, an akinetic mutism state with quadriplegia in flexion was observed. Head magnetic resonance imaging revealed severe frontotemporal lobe atrophy with severe lateral ventricular dilatation and frontal white matter degeneration. At autopsy, the brain weighed 930 g and the frontotemporal cerebral cortex showed neuron loss with gliosis, tissue rarefaction and spongiform change, particularly in the superficial layers. Pathologic degeneration was more severe in the anterior portion of the frontal lobe with extensive white matter degeneration. Immunostaining for phosphorylated TAR‐DNA binding protein 43 (TDP‐43) revealed numerous neuronal cytoplasmic inclusions and extensive short dystrophic neuritis, particularly in the frontotemporal cortex. Many TDP‐43‐positive cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. The patient was pathologically diagnosed with FTLD with TDP‐43‐positive inclusions (FTLD‐TDP) without motor neuron disease. The immunohistochemical findings corresponded to type A of the FTLD‐TDP pathology classification system.     

Frontotemporal lobar degeneration and ubiquitin immunohistochemistry

We set out to determine the frequency of the different pathologies underlying frontotemporal degeneration (FTD) in our brain bank series, by reviewing all cases of pathologically diagnosed FTD over the last 12 years. We identified and reviewed 29 cases of FTD and classified them using the most recent consensus criteria with further histological analysis of 6 initially unclassifiable cases. Detailed histological analysis of these 6 cases revealed variable numbers of ubiquitin-positive (tau and alpha-synuclein-negative) inclusions in 5 cases, consistent with the diagnosis of frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). As a consequence of the current re-evaluation, 18 (62%) of the 29 cases with FTD have underlying pathology consistent with FTLD-U. Therefore in our brain bank series of frontotemporal degeneration, most cases were non-tauopathies with FTLD-U accounting for 62% of all the diagnoses.     

Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases

Globular glial tauopathies (GGTs) are four‐repeat tauopathies characterized by the presence of two types of tau‐positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs – a 76‐year‐old woman and a 70‐year‐old man – in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray‐white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.     

Disrupted sleep and circadian patterns in frontotemporal dementia

Background:  A study of the pattern of Sleep/Wake disturbance in frontotemporal dementia (FTD).
Methods:  Sleep diaries and prolonged actigraphy were used to record the activity, sleep and wake of 13 patients with a clinical diagnosis of FTD. These were compared with diaries and actigraphy from normal age/sex matched controls and also to a population with probable Alzheimer's disease (AD).
Results:  There was significant sleep/wake disturbance in FTD. This occurred throughout the course of the illness and the nature of the sleep disturbance was different to patients with AD. FTD subjects showed increased nocturnal activity and decreased morning activity compared with controls, suggesting possible phase delay. Sleep diary data confirmed decreased sleep efficiency and decreased total sleep in all FTD patients.
Conclusions:  We describe significant sleep disturbance in non-institutionalized patients with FTD and suggest that early sleep disturbance may help differentiate between FTD and AD.     

Frontotemporal dementia: remembering images from the past

Frontotemporal dementia (FTD) is the most common form of primary degenerative dementia after Alzheimer's disease that affects people in middle age. The average delay in reaching an accurate diagnosis has been reported to be around 3 years. We report a case of FTD in a 35-year-old female who presented with complex symptoms and no clear physical signs. This case draws attention to the problems inherent in the traditional functional-organic divide that continues to characterize investigation and diagnosis in modern psychiatric practice, and highlights the importance of reevaluating the results of previous "normal" investigations in the light of the developing clinical picture.     

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family

Background: Frontotemporal dementia with parkinsonism linked to chromosome 17q21–22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes. Objectives To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation. Methods: Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband. Results: The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1–2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3–5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene. Conclusions: The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations. Received: 23 September 2002, Received in revised form: 13 January 2003, Accepted: 27 January 2003 Correspondence to: Dr. A. Lossos     

The Middelheim Frontality Score: a behavioural assessment scale that discriminates frontotemporal dementia from Alzheimer's disease

BACKGROUND: Despite striking neuropsychological and behavioural differences between Alzheimer's disease (AD) and frontotemporal dementia (FTD), clinical diagnostic criteria failed to discriminate FTD from AD patients. We therefore developed the Middelheim Frontality Score (MFS), a disease-long clinical and behavioural assessment tool that measures frontal lobe features, and set up this prospective study in clinically diagnosed AD and FTD patients to assess discriminatory power and intra- and inter-rater variability. METHODS: Patients with probable AD (n = 400) and FTD (n = 62) were included. The MFS was obtained by summating the scores obtained in a standardized fashion on ten items yielding a total maximal score of 10. Information was obtained through an interview of the patient and her/his caregiver, clinical files and behavioural observation. RESULTS: Comparing mean total MFS scores, FTD patients (6.3 +/- 1.8) had significantly higher scores than AD patients (3.1 +/- 1.8) (p < 0.001). Distribution of scores on individual MFS items was significantly different between both disease groups (chi(2) = 76.2; p < 0.001). A moderately positive and highly significant correlation was shown between the total MFS score and diagnosis FTD (r = 0.478; p < 0.0001). Applying a total MFS score of 5 as discriminatory cut-off, a specificity of 89.0% and a sensitivity of 88.7% were achieved. Intra- and inter-rater variability was calculated in a different study population by means of retest correlation, revealing moderate to strong positive correlations of high statistical significance. CONCLUSIONS: The MFS is a clinical and behavioural assessment scale that measures frontal lobe features and that was shown to reliably discriminate FTD from AD patients.     

Frontotemporal dementia with trans‐activation response DNA‐binding protein 43 presenting with catatonic syndrome

Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto‐temporal lobes. A neuropathological examination revealed extensive trans‐activation response DNA‐binding protein 43 (TDP‐43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) type C, which was also confirmed by the band pattern of C‐terminal fragments of TDP‐43 on western blotting of sarkosyl‐insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP‐43‐positive structures. Further studies are expected to confirm further clinical ‐ pathological correlations to FTLD.     

Review: An update on clinical,genetic and pathological aspects of frontotemporal lobar degenerations

The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.     

Neuropsychiatric symptoms of progressive supranuclear palsy in a dementia clinic

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by supranuclear gaze palsy, postural instability, akinesia and other parkinsonism. Recently, the relationship between PSP and frontotemporal dementia (FTD) has been recognized, which includes clinical, pathological, biochemical and genetic features. However, there have been few studies that directly compared neuropsychiatric symptoms between PSP and FTD. The aim of the present study was to investigate comprehensive psychiatric and behavioural symptoms in PSP and compared them with those in FTD. Methods: Patients with PSP (n = 10) and FTD (n = 13) were selected on the basis of inclusion/exclusion criteria from a consecutive series in the dementia clinic of Kumamoto University Hospital. We assessed their comprehensive neuropsychiatric features by using the Neuropsychiatric Inventory (NPI), the Stereotypy Rating Inventory (SRI) and a specific antisocial behaviour checklist. Results: There were no significant differences in the total NPI and NPI subscale scores between the two groups. Both groups showed quite a similar pattern in the features of neuropsychiatric symptoms: apathy showed the highest score, followed by aberrant motor behaviour and disinhibition. The PSP group was significantly lower in the total SRI and eating and cooking behaviour scores than those in the FTD group. The prevalence of antisocial behaviours in PSP (50%) was equal to those in the FTD group (46%). Conclusions: In a dementia clinic, the neuropsychiatric profile in patients with PSP closely resembled those in the FTD group. The present results suggest that PSP should be considered as not only a movement disorder, but also a disorder with a wide range of neuropsychiatric symptoms.     

No evidence of association between frontotemporal dementia and major European mtDNA haplogroups

Background and purpose:  Mitochondrial DNA (mtDNA) inherited variability (haplogroup/sub-haplogroup) is currently emerging as not being neutral with respect to several complex traits like neurodegenerative diseases. Here we investigated the association of European mtDNA haplogroups/sub-haplogroups with frontotemporal dementia (FTD).
Method and Results:  A case-control study was carried out on 114 patients with FTD (68 sporadic and 46 familial) and 180 controls, matched for age, gender and ethnicity. No association was found.
Conclusions:  European mtDNA haplogroups/sub-haplogroups are unlikely to play a major role in the risk of developing the disease.