Clinical features of pathologic subtypes of behavioral--variant frontotemporal dementia

OBJECTIVE: To identify clinical features in behavioral-variant frontotemporal dementia that may help predict tau-positive pathology. METHODS: Clinical and historical features of patients with pathologically confirmed tau-positive and tau-negative frontotemporal lobar degeneration from 1970 to 2006 were retrospectively reviewed in a blinded fashion. The initial clinical features of those patients who eventually met consensus criteria for frontotemporal dementia were examined using univariate and cluster analyses to explore characteristics that may be associated with tau pathology. RESULTS: Fifty-six patients (24 tau-positive cases) were included in the analysis. There was no difference in demographics between the tau-positive and tau-negative cases. Univariate analysis showed that poor planning and/or judgment was more commonly associated with tau-positive pathology (P = .03). Cluster analysis using behavioral characteristics identified 2 groups of patients: cluster 1 contained mainly tau-positive cases (57%) and cluster 2 was mostly tau-negative cases (71%). Poor planning and/or judgment was a common presenting sign in the first group (P < .001), while the second group was more likely to present with impaired regulation of personal conduct (P < .001) and a decline in personal hygiene (P = .005). CONCLUSIONS: Poor planning and/or judgment was associated with behavioral-variant frontotemporal dementia patients who had tau-positive pathology. The constellation of impaired personal conduct and a paucity of dysexecutive symptoms identified tau-negative patients.     

Clinical subtypes of frontotemporal dementia

Three distinctive clinical presentations can occur in frontotemporal dementia (FTD): disinhibited, apathetic and stereotypic subtypes. Each one shows a specific pattern of clinical, neuropsychological and neuroimaging findings, besides manifesting the core features of this form of dementia. We report three clinical cases, each one an example of a subtype of FTD, that were evaluated by neuropsychological and neuroimaging methods. Even the reported cases being a prototype of a specific subgroup, they can share some features with the others subtypes. According to this, patients with predominantly disinhibited or stereotypic behavior can also show apathy, in much the same way as predominantly apathetic or disinhibited patients can manifest stereotypic ritualistic behavior. The final stage of FTD is generally dominated by apathetic behavior.     

Clinical manifestation of frontotemporal dementia

Frontotemporal dementia is a degenerative disease, usually of presenile onset, frequently with positive family history, whose main clinical features are early social and personal behavioral disturbances, cognitive defects mainly in attention, language and executive functions, personality disorders and blunt, unconcerned and subdepressive affect. Anatomic and functional neuroimaging shows atrophy and functional defects in anterior brain regions, and the EEG is persistently normal. Although frontotemporal dementia has been confounded with Alzheimer's disease for long time, it can be identified on clinical grounds in order to perform new therapeutic trials.     

Clinical presentation of prodromal frontotemporal dementia

BACKGROUND: Misrecognition of symptoms in the early stages of frontotemporal dementia (FTD) frequently contributes to diagnostic delay. Three frameworks have been proposed for the clinical identification of prodromal FTD: (1) cognitive profiling, (2) the presence of behavioral/psychiatric symptoms in the absence of memory complaints, and (3) a combined approach of cognitive, behavioral, and neuroimaging features. OBJECTIVE: To evaluate current conceptual frameworks for the clinical recognition of prodromal FTD with current empirical evidence. METHOD: We performed a comprehensive PsychINFO and MEDLINE database search to identify articles investigating the prodromal symptoms of FTD. CONCLUSIONS: The 3 frameworks capture important aspects of the clinical picture of prodromal FTD but require further refinement. The prodromal stage of FTD is characterized by both cognitive and behavioral features. Diagnostic accuracy will likely be improved by considering a combination of cognitive and behavioral features, because some features overlap with prodromes for Alzheimer's disease and vascular dementia.     

Clinical and molecular aspects of frontotemporal dementia

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.     

额颞叶痴呆患者的临床特征与早期诊断

目的:探讨额颞叶痴呆患者的临床特征,为早期诊断提供依据. 方法:回顾性分析16例额颞叶痴呆患者的临床特点. 结果:额颞叶痴呆早期的首发症状以人格改变(75％)、精神行为症状(12.5％)、语言障碍(25％)或(伴)记忆力下降(50％)等为主.伴随认知功能的逐步下降,患者会逐渐出现各种非特异的症状表现如淡漠、失眠、注意力不集中、异常或刻板行为、易激惹、口欲亢进、脱抑制及收藏癖.额颞叶痴呆的首次诊断符合率总体在50％左右. 结论:额颞叶痴呆患者症状丰富且无特异性,早期诊断需要综合考虑,特别要警惕痴呆患者的首发症状.     

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.     

Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation

OBJECTIVE: To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10(+16) mutation. METHODS: Retrospective chart reviews of family members with FTD belonging to nine tau 10(+16) mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. RESULTS: The median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. CONCLUSIONS: All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors.     

Core features of frontotemporal dementia recapitulated in progranulin knockout mice

Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn−/−). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn−/− mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn−/− mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn−/− mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.     

Clinical entity of frontotemporal dementia with motor neuron disease

Non‐Alzheimer‐type dementias occur in association with a variety of pathological conditions that include a group of diseases characterized by atrophy of the frontal and temporal lobes. Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U). The vast majority of FTLD‐U is now referred to as FTLD‐TDP, following the recent discovery of TAR DNA‐binding protein of 43 kDa (TDP‐43) as the major constituent of the ubiquitin‐positive inclusions. FTLD‐TDP, but not Pick's disease with Pick bodies, is often associated with motor neuron disease (MND). MND is a group of diseases in which the central nervous system lesions were long believed to be confined to the motor neuron system. In other words, MND was not considered to be associated with other neurological symptoms such as dementia. Nevertheless, more than 200 FTD cases associated with clinical MND have been reported in Japan since 1964. Neuropathologically, MND in such FTD cases was essentially similar to MND in cases without dementia. The combination of FTD and MND was so characteristic that we considered these cases comprise a unique clinicopathological subgroup of FTD. FTD with MND and the classical MND without dementia share the occurrence of ubiquitinated TDP‐43‐positive inclusions, a finding that could be a key to unlock the pathological backgrounds of both diseases.     

Neuroimaging of frontotemporal dementia

With the development of neuroimaging, frontal lobe atrophy has been demonstrated with increased frequency, first with structural studies (computed tomography and magnetic resonance imaging), then with functional images (Single photon emission computed tomography and Positron emission tomography).     

Clinical features and survival of 3R and 4R tauopathies presenting as behavioral variant frontotemporal dementia

We compared the clinical characteristics of 3 repeat (3R) and 4 repeat (4R) tau-positive cases (tauopathies) presenting as behavior variant frontotemporal dementia (bv-FTD). We identified and retrospectively reviewed demographics and clinical features of patients with pathologically confirmed tau-positive frontotemporal lobar degeneration in a blinded fashion. Those presenting as bv-FTD were divided according to their tau isoform, 3R versus 4R, and compared with age-matched and sex-matched control patients with 4R tauopathies but presenting clinical syndromes other than bv-FTD. Twenty-four cases with tau-positive bv-FTD and 18 4R tau-positive controls were included in the study. Patients with 4R tauopathies had significantly shorter disease duration than patients with 3R tauopathy (median, 6.5 y vs. 9.5 y; P<0.05), despite similar age of disease onset and regardless of whether bv-FTD was the presenting clinical syndrome. Among bv-FTD cases, those with 4R tauopathies were more likely to display behavioral underactivity than those with 3R tauopathy (P=0.03), although 3R and 4R tauopathy patients shared many similar clinical features. In summary, survival in 4R tauopathies seemed independent of the presenting clinical phenotype, and there may be subtle clinical differences between bv-FTD patients with 3R and 4R tauopathies.     

Neuropathology of frontotemporal dementia

The syndrome of progressive fronto-temporal dementia represents the clinical expression of several pathological processes, mostly degenerative, preferentially involving the frontal and temporal lobes. These processes include dementia with Pick bodies, cortico-basal degeneration, dementia with ITSNU (Inclusions Tau and Synuclein Negative, Ubiquitinated), also known as dementia of motorneuron disease type, dementia with basophilic inclusion bodies, and dementia lacking specific histopathology, and in addition all variants linked to mutations in the tau gene, located in chromosome 17. The term "Pick complex" encompasses these processes and their clinical manifestations, which in addition to fronto-temporal dementia include primary progressive aphasia and apraxic-motor syndromes. The pathologic processes are better discriminated by histopathology than distribution of atrophy, but the latter is the main determinant of the clinical presentation.     

家族性额颞叶痴呆合并肌萎缩侧索硬化综合征一个家系报道

目的家族性额颞叶痴呆合并肌萎缩侧索硬化(FTD/ALS)综合征是罕见一种神经变性病,本文报道1个FTD/ALS家系,并分析先证者的临床和神经影像学特征。方法收集FTD/ALS家系1个,对其先证者进行病史询问、神经心理评估、体格检查、磁共振(MRI)检查、肌电图(EMG)、单光子电子计算机扫描(SPECT)检查和基因检查。结果该家系3代中共有9位患者,先证者主要表现为言语不利、反应迟钝、右上肢萎缩无力。先证者头颅MRI显示额颞叶为主的脑萎缩,SPECT结果提示颞叶、额叶及基底核区葡萄糖代谢不均匀减低,EMG提示广泛神经源性损害。结论家族性FTD/ALS家系表现为FTD和ALS的组合,脑葡萄糖代谢SPECT及EMG有助于FTD/ALS诊断。     

Neuroimaging in frontotemporal dementia

Abstract

The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are associated with atrophy of the frontal and temporal lobes, and present clinically with impairments of behaviour or language. Three main subtypes are described, behavioural variant FTD (bvFTD) and two subtypes of the language presentation (known as primary progressive aphasia or PPA) called semantic variant of PPA and non-fluent variant of PPA. Most imaging studies of FTD have used volumetric T1 magnetic resonance imaging (MRI) or positron emissions tomography imaging to identify patterns of grey matter atrophy or hypometabolism in these different subtypes, but more recently newer imaging techniques have been used to help define abnormalities in structural connectivity (white matter tract integrity using diffusion tensor imaging), functional connectivity (resting state networks using resting state functional MRI) and perfusion (using arterial spin labelling perfusion MRI) in FTD. These techniques have the potential to improve the differential diagnosis of FTD from other disorders and to provide more informative imaging signatures of FTD syndromes.     

Misdemeanor in frontotemporal dementia

The nature and prevalence of misdemeanor in patients with dementia due to frontotemporal lobar degeneration has been described in a few case reports and in two small U.S. studies. Our clinical impression suggests that antisocial and aggressive behaviour are relatively frequent in this patient population. The objective of the present study was to verify this observation. For this purpose we developed a standardized questionnaire on misdemeanor in Frontotemporal Dementia. Using this instrument caregivers of 30 patients with Frontotemporal Dementia (FTD), 11 patients with Semantic dementia (SD) and 33 patients with Alzheimer-type dementia (AD) were interviewed. The interview included questions about theft, burglary, damaging other peoples' belongings, verbal or physical offence, bodily harm, drug abuse and use of weapons. Questions about the frequency of criminal behaviour, the amount of damages and consequences if applicable completed the questionnaire. Misdemeanor was found in half of the patients with FTD (15 out of 30) and in 7 out of 11 patients with SD, but only in one out of 33 patients with AD. The most frequent type of inappropriate behaviour was theft (13 patients), particularly shoplifting. 8 patients with FTD, 1 patient with SD and 1 patient with AD entered someone else's house without permission. 10 patients with FTD and 3 patients with SD but none of the patients with AD had physically threatened spouses, relatives or strangers. In one case another person was hurt.