Frontotemporal degenerative dementias

Frontotemporal dementia (FTD) is a clinical term now used for a group of dementing neurodegenerative disorders marked clinically by general predominance of symptoms referable to the frontal lobes. Symptoms may include changes in language ability with expressive or receptive aphasia, and changes in personality, including disinhibited, obsessive, hyperoral, hypersexual, repetitive, and perseverative behaviors. Memory is often affected, but is usually not a primary symptom. Characteristically, analytic, navigational, and other visuospatial abilities may be quite preserved. The clinical symptomatology of FTD contrasts with the general predominance of temporal and parietal symptoms in the most common neurodegenerative disorder, Alzheimer's disease (AD). FTD symptoms also differ from those seen with the second most common neurodegenerative disorder, Lewy Body Dementia (LBD), which while having substantial clinical and pathological overlap with AD, often shows additional clinical visuospatial (occipital) and parkinsonian symptomatology. FTD likely constitutes the third most-common cause of degenerative dementia. Clinical overlap can sometimes make it difficult to distinguish individual cases from AD. Genetic studies have shown that FTD, like AD, occurs in both familial and nonfamilial types, and a proportion of FTD cases arise from autosomal dominant genetic disorders due to mutations in the tau gene. Some recent formulations include in the family of frontal degenerative disorders other dementias with frontal symptomatology such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Lending support to such a grouping, neuropathological studies show a group of histologies, sometimes including PSP and CBD, to be the substrates for clinical FTD.     

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.     

You stole my food! Eating alterations in frontotemporal dementia

ABSTRACT

Patients with different types of dementia may exhibit pathological eating habits, including food fads, hyperphagia, or even ingestion of inanimate objects. Several findings reveal that such eating alterations are more common in patients with frontotemporal dementia (FTD) than other types of dementia. Moreover, eating alterations may differ between the two variants of the disease, namely the behavioral variant and semantic dementia (SD). In this review, we summarized evidences regarding four areas: eating and body weight alterations in FTD, the most common assessment methods, anatomical correlates of eating disorders, and finally, proposed underlying mechanisms. An increasing understanding of the factors that contribute to eating abnormalities may allow first, a better comprehension of the clinical features of the disease and second, shed light on the mechanism underlying eating behaviors in the normal population.     

Functional neuroimaging and presenting psychiatric features in frontotemporal dementia

BACKGROUND: Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD. OBJECTIVE: To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging. METHODS: 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion. RESULTS: The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. "Moria" or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion. CONCLUSIONS: Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non-verbal behaviour.     

Problems family caregivers encounter in home care of patients with frontotemporal lobar degeneration

Aim: Frontotemporal dementia (FTD) is a degenerative dementia in which primary degeneration of the frontal region of the brain occurs. Because of the behavioral symptoms, the care of FTD patients has numerous problems. However, little has been clarified with regard to the actual care situation, especially in a family care setting. The aim of the present study was to elucidate the caregiver burden and problems associated with the care of FTD patients in home care settings. Methods: Two patients were diagnosed with FTD on the basis of the Lund and Manchester group criteria at the clinic for outpatients of a hospital located in Aichi Prefecture, Japan. Semi‐structured interviews were conducted with the family caregivers of the FTD patients. The content of the interview covered the patient course and any problems encountered in the home setting regarding activities of daily living (ADL), behavioral disorders and cognitive function. Results: These FTD patients had abnormal eating behaviors such as cramming of food into one's mouth and the abnormal manner of eating. They had to be fed bit by bit with total caregiver assistance. They were also overactive, restless and distractable, which subsequently caused problems with ADL‐assistance including extreme uncooperativeness toward their caregivers. Other behavioral symptoms associated with FTD, e.g., stereotypic behavior, distractability and high impulsivity, were also considerably burdening to the caregivers. Conclusion: The behavioral symptoms peculiar to FTD pose huge problems and heavy burden to the family caregiver. More resources should be allocated to specific needs of the FTD patients and their families.     

Frontotemporal dementia, motor neuron disease and tauopathy: clinical and neuropathological study in a family

We report a familial disorder occurring in three patients that presented as frontotemporal dementia (FTD). A neuropathological study was performed in a 58-year-old patient, who developed FTD 2 years prior to the onset of motor neuron disease (MND), and died at age 62. Lesions indicative of associated MND were observed: neuronal loss in the anterior horns of the spinal cord, Bunina bodies, axonal spheroids, degeneration of the pyramidal tracts, and of FTD: decreased neuronal density and laminar microvacuolation of layers II and III in the frontal and temporal cortex. Ubiquitin-only-immunoreactive changes were found in the spinal cord and medulla, but were absent from the temporal and frontal cortex. There were also widespread deposits of various neuronal and glial inclusions containing abnormally phosphorylated tau protein, the Western blotting pattern of which was characterized by two major bands of 64 and 69 kDa. There were no abnormalities of the entire coding sequences of microtubule-associated protein tau (MAPT) and copper-zinc superoxide dismutase (SOD₁) genes. Our results suggest that FTD associated with MND can be caused by a larger spectrum of neuropathological lesions than commonly accepted.     

Altered speech-related cortical network in frontotemporal dementia

BackgroundIn healthy subjects (HS), transcranial magnetic stimulation (TMS) demonstrated an increase in motor-evoked potential (MEP) amplitudes during specific linguistic tasks. This finding indicates functional connections between speech-related cortical areas and the dominant primary motor cortex (M1).ObjectiveTo investigate M1 function with TMS and the speech-related cortical network with neuroimaging measures in frontotemporal dementia (FTD), including the non-fluent variant of primary progressive aphasia (nfv-PPA) and the behavioral variant of FTD (bv-FTD).MethodsM1 excitability changes during specific linguistc tasks were examined using TMS in 24 patients (15 with nfv-PPA and 9 with bv-FTD) and in 18 age-matched HS. In the same patients neuroimaging was used to assess changes in specific white matter (WM) bundles and grey matter (GM) regions involved in language processing, with diffusion tensor imaging (DTI) and voxel-based morphometry (VBM).ResultsDuring the linguistic task, M1 excitability increased in HS, whereas in FTD patients it did not. M1 excitability changes were comparable in nfv-PPA and bv-FTD. DTI revealed decreased fractional anisotropy in the superior and inferior longitudinal and uncinate fasciculi. Moreover, VBM disclosed GM volume loss in the left frontal operculum though not in the parietal operculum or precentral gyrus. Furthermore, WM and GM changes were comparable in nfv-PPA and bv-FTD. There was no correlation between neurophysiological and neuroimaging changes in FTD. Atrophy in the left frontal operculum correlated with linguistic dysfunction, assessed by semantic and phonemic fluency tests.ConclusionWe provide converging neurophysiological and neuroimaging evidence of abnormal speech-related cortical network activation in FTD.     

Neuropathological discrepancy between Japanese Pick’s disease without Pick bodies and frontal lobe degeneration type of frontotemporal dementia proposed by Lund and Manchester Group

The concept of frontotemporal dementia (FTD) proposed by the Lund and Manchester group is useful because it distinguishes dementia with frontal and anterior temporal involvement from Alzheimer‐type dementia. The classification and definition of FTD and related disorders, however, are controversial. One point of controversy is the neuropathology of the frontal lobe degeneration (FLD) type of FTD. The FLD type is described as having mild frontal and anterior temporal atrophy and no accompanying tau or ubiquitin pathology. We investigated cases of Japanese Pick’s disease without Pick bodies (PB), the majority of which are thought to correspond to FLD type, in order to clarify whether the nature of the degeneration in these cases could be distinguishable from that in Japanese Pick’s disease with PB, which corresponds approximately to the Pick type of the Lund and Manchester group. Except for the presence of tau‐pathology, no obvious differences were noted between Pick’s disease without PB (FLD type) and Pick’s disease with PB (Pick type) either on neuropathological examination of own cases or a questionnaire survey of Japanese neuropathologists. The reason for this discrepancy may be based on the role of heredity, namely, most Japanese cases of Pick’s disease are solitary, while the FTD cases of the Lund and Manchester group were reportedly accompanied by extensive familial history. There is a possibility that Japanese, British, and Swedish neuropathologists deal with heterogeneous groups of dementia characterized as FTD without tau or ubiquitin pathology.     

Stereotypical movements and frontotemporal dementia.

Stereotypical movements are characteristic of autism or mental retardation but can also occur in patients with dementia, particularly frontotemporal dementia (FTD). In this study, we administered the Abnormal Involuntary Movement Scale (AIMS) to 18 patients with FTD and to 18 patients with the most common form of dementia, Alzheimer's disease (AD). The AIMS scores were gathered at the initial presentation of patients who had not received antipsychotic medications. Compared to the AD patients, the FTD patients had significantly more stereotypical movements, including frequent rubbing behaviors and some self-injurious acts. All the FTD patients with stereotypical movements had compulsive-like behaviors, suggesting a similar pathophysiologic cause, and most had a decrease in their stereotypical movements with the administration of sertraline, a serotonin selective reuptake inhibitor.     

The Frontal Systems Behavior Scale discriminates frontotemporal dementia from Alzheimer’s disease

Frontotemporal dementia (FTD) is characterized by pronounced changes in affect, self-regulation, and social conduct. These behaviors can predate significant cognitive changes and can be the most disabling aspect of FTD, yet there are few scales designed to assess such changes. The Frontal Systems Behavior Scale (FrSBe) is a 46-item behavior rating scale that is intended to measure behavior associated with damage to the frontal systems of the brain, with subscales measuring Apathy, Disinhibition, and Executive Dysfunction. Thirty-four FTD patients and 34 matched patients with dementia of the Alzheimer’s type (DAT) were compared on the FrSBe in the present study. Both groups displayed increases in apathy and dysexecutive behaviors after the onset of dementia, but the FTD group exhibited significantly greater change in disinhibition. A discriminant analysis with just two scores from the FrSBe and a memory test correctly classified 81% of the patients into diagnostic group.     

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β₄₂ (Aβ₄₂), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD.MethodsWe retrospectively analyzed concentrations of MHPG, Aβ₄₂, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters.ResultsThe currently used combination of Aβ₄₂, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia.ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.     

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.     

Is motor neuron disease‐inclusion dementia a forme fruste of amyotrophic lateral sclerosis with dementia? An autopsy case further supporting the disease concept

We report the autopsy findings of a 62‐year‐old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin‐positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1‐subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin‐positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea‐like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease‐inclusion dementia (MND‐ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND‐ID live long enough, they may develop ALS.     

Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease, frontotemporal dementia and vascular dementia

OBJECTIVES: Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) are the three most common causes of young onset dementias. Most neuroimaging studies of these disorders have involved comparisons with normal controls. The aims of this study were to examine the clinical diagnostic value of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) (in combination and in isolation) in the differentiation of one form of dementia from another from amongst a group of AD, FTD and VaD. METHODS: T1 weighted MRI images and 99mTc-HMPAO SPECT images were obtained from consecutive patients with FTD (n=21), AD (n=23) and VaD (n=20) and rated visually by experienced neuroradiologists and nuclear medicine physicians. RESULTS: Asymmetrical atrophy was seen only in FTD. Frontotemporal dementia patients were the most atrophic whereas severe atrophy was rarely observed in VaD. Severe frontal atrophy (unilaterally or bilaterally) and/or asymmetrical atrophy on MRI is highly diagnostic (sensitivity 0.71, specificity 0.93, LR 10.24) of FTD from within a group of FTD and non-FTD (AD, VaD) patients. Mild or severe parietal atrophy with severe reduction in parietal regional cerebral blood flow on SPECT is diagnostic (sensitivity 0.71, specificity 0.76, LR 3.02) of AD from within a group of AD and non-AD (VaD, FTD) patients. CONCLUSION: Anatomical (MRI) and functional (SPECT) imaging provide different information and a combination of these modalities improves diagnostic specificity.     

Presenile non-Alzheimer dementia with motor neuron disease and laminar spongiform degeneration

We describe the clinicopathological findings in three autopsy cases of presenile dementia with motor neuron disease. These patients had a relatively rapid course involving dementia and muscle weakness with a distal pattern of atrophy in the upper extremities. Postmortem examination revealed features of motor neuron disease and spongiform cortical degeneration. The latter change was most marked in the second layer of the frontal or temporal cortex and included minimal to mild neuronal cell loss and mild to moderate gliosis. In this report we relate these patients' laminar spongiform degeneration to three other conditions; frontal lobe dementia, primary progressive aphasia and dementia lacking a distinctive histology. These three conditions and presenile dementia with motor neuron disease may fall within the spectrum of the non-Alzheimer type frontotemporal degenerative dementia.     

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.     

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer’s disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick’s disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family). Received: 8 November 1999 / Revised, accepted: 17 January 2000     

Determinants of quality of life in young onset dementia – results from a European multicenter assessment

ABSTRACT

Background: Promoting adaptation, improving well-being and maintaining an optimal quality of life (QOL) is an important aspect in dementia care. The purpose of this study was to identify determinants of QOL in young onset dementia, and to assess differences in QoL domains between people with Alzheimer's disease (AD) and frontotemporal dementia (FTD).

Methods: In total 135 persons with AD and 58 persons with FTD were included from two prospective cohort studies. QOL was assessed with the proxy reported quality of life in Alzheimer's disease questionnaire (QoL-AD). Possible determinants were explored using multiple linear regression and included sociodemographic variables, diagnosis, dementia severity, disease awareness, neuropsychiatric symptoms, met and unmet needs and hours of personal and instrumental care. Differences between QOL domains in people with AD and FTD were calculated using Mann-Whitney U tests.

Results: Lower QOL was associated with more depressive symptoms, lower disease awareness, and a higher amount of needs, both met and unmet. People with AD scored lower on the memory and higher on the friends' subscale. No differences were found for the other items.

Conclusion: This study demonstrates a unique set of determinants of QOL in AD and FTD. Interventions directed towards these specific factors may improve QOL.     

Two cases of frontotemporal dementia with predominant temporal lobe atrophy

Frontotemporal dementia (FTD) is a subtype of frontotemporal lobar degeneration, which also includes semantic dementia (SD) and progressive non‐fluent aphasia. Frontotemporal dementia is characterized by changes in personality and behavioral abnormalities, generally associated with predominant frontal lobe atrophy. Conversely, SD is typically characterized by Gogi (word meaning) aphasia based on semantic memory impairment and is associated with predominant temporal lobe atrophy. However, in the present cases, we diagnosed FTD on the basis of clinical symptoms, such as disinhibition, indifference, and stereotypy, without semantic memory impairment, even though neuroimaging showed predominant temporal lobe atrophy. We suggest that clinical symptoms are the most important cues for an accurate clinical diagnosis and there is no exclusive relationship between the syndrome and atrophy of the temporal lobes.     

Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.