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     

The new neuropathology of degenerative frontotemporal dementias

The clinical features and recent developments in the neuropathology of frontotemporal dementia are reviewed. The five main neurodegenerative disorders that underlie the clinical syndrome of frontotemporal dementia are distinguished using immunohistochemistry with antisera to ubiquitin and tau proteins. Motor neuron disease-type dementia is characterised by ubiquitin-immunoreactive intraneuronal inclusions in cortical layer II and the hippocampal dentate granule cells. A diagnosis of Alzheimer's disease changes is based upon the presence of neurofibrillary tangles, which immunostain with antibodies to tau and ubiquitin, and many associated neuritic plaques. Corticobasal degeneration is diagnosed by the presence of tau-immunoreactive, but ubiquitin-non-reactive intraneuronal inclusions in cortical layer II and the substantia nigra. Pick's disease is restricted to cases with tau- and ubiquitin-immunoreactive spherical cortical intraneuronal inclusions (Pick bodies), best seen in the hippocampal dentate gyrus and frontotemporal cortex. Dementia of frontal type is the preferred term for cases in which no intraneuronal inclusions are seen with antisera to tau and ubiquitin. A practical approach to the pathological diagnosis of frontotemporal dementia and the differential diagnosis of the five disorders using immunohistochemical studies is provided. Received: 7 August 1995 / Revised, accepted: 10 October 1995     

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.     

Dementia with motor neuron disease

Dementia with motor neuron disease has been described as a new clinicopathologic entity and more than 100 cases have been reported in Japan since 1964. The clinicopathologic criteria in the diagnosis of dementia with motor neuron disease are: (i) frontotemporal lobe‐type dementia with insidious onset, mostly in the presenile period; (ii) neurogenic muscular wasting during the course of the illness (amyotrophic lateral sclerosis‐ or SPMA‐like symptoms); (iii) duration from the onset of illness to death of 2–5 years (average, 30.6 months); (iv) both extrapyramidal symptoms and definite sensory deficits are present less commonly; (v) no characteristic abnormalities in the cerebrospinal fluid or electroencephalogram on screening; (vi) no known parental consanguinity or familial occurrence; and (vii) non‐specific, mild to slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei and spinal cord, and frequently in the substantia nigra. Dementia with motor neuron disease is characterized by ubiquitin‐immunoreactive intraneuronal inclusions in cortical layer II and hypocampal dentate granule cells.     

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.     

Ubiquitin-related cytoskeletal abnormality in frontotemporal dementia: immunohistochemical and immunoelectron microscope studies

Although reports of dementia lacking the distinctive non-Alzheimer-type histopathology have been increasing, the concept is still far from clear. It has become apparent that this population shows neuropathological heterogeneity, and some recent reports have proposed a classification or criteria for these disease conditions. Of the reported cases, frontotemporal dementia (FTD) of motor neuron disease is unique in that the neurons of the hippocampus and entorhinal cortex have ubiquitin-related abnormalities. Recently, a new ubiquitin-related abnormality, characterized by ubiquitinated inclusions in the neurites, has been found in some FTD cases. Using immunoelectron microscopy with immunogold particles, we have found that in these two disease conditions ubiquitinated inclusions consist of abnormal filaments of 10–15 nm in diameter. Our results support the speculation that there is a close relationship between ubiquitin and abnormal filaments in these two types of FTD, indicating that cytoskeletal-related disorders may underlie certain types of FTD. Received: 30 October 1996 / Revised, accepted: 15 January 1997     

The topographic distribution of brain atrophy in frontal lobe dementia

Summary The topographic distribution of brain atrophy was quantified by image analysis of fixed brain slices from ten patients dying with dementia of frontal type (DFT) and from six other patients dying with dementia of frontal type with motor neurone disease (DFT+MND). In both groups the atrophy was maximal within frontal, anterior temporal and anterior parietal regions of cortex, although other structures such as the amygdala, caudate nucleus, thalamus and hippocampus were also affected. The magnitude of the atrophy was much greater, in all affected regions, in DFT alone than in DFT+MND. Grey and white matter were affected equally in DFT alone although in DFT+MND a preferential white matter involvement was noted. No differences in the topographic distribution of the atrophy was observed in cases of DFT showing a spongiform degeneration of the cortex compared to those showing a gliotic degeneration with, or without, Pick cells and Pick bodies.Supported by a studentship (to PWS) from the Zochonis Foundation     

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.     

Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS

We present the case of a patient who had clinical frontal lobe dementia without apparent motor neurone disease (MND), with pathologic findings not typical of any single currently classified frontotemporal degeneration (FTD). At autopsy, the brain had frontal and temporal atrophy with neuronal loss, gliosis, and superficial spongiosis, typical of all FTDs. There were at least three different morphologic types of intracytoplasmic neuronal inclusions in a variety of brain and brainstem regions, including the hippocampal dentate gyrus and pyramidal neurones, the neocortex (in particular, the motor cortex), basal ganglia, thalamus, subthalamic nucleus, basis pontis, and inferior olivary nuclei. Inclusions had the morphologies of Pick-like bodies, pleomorphic inclusions, and hyaline conglomerate (HC)-like inclusions. None of these were positive with tau immunostains. Pick-like bodies in the dentate gyrus were labelled with ubiquitin. The pleomorphic inclusions in the neocortex and dentate gyrus and the HC-like inclusions in the motor and parietal cortex were strongly positive with immunostains for neurofilament. We discuss the differential diagnosis and compare this case with those disorders to which it is most similar. In particular, we compare the unique neurofilament-positive inclusions to the inclusions of FTD-MND, to Pick bodies, and to the basophilic and HC inclusions that are occasionally seen in amytrophic lateral sclerosis (ALS). Although FTD-MND may be found in ALS, the findings in this case may have additional implications for a link between FTD and ALS.     

An autopsy case of frontotemporal dementia with severe dysarthria and motor neuron disease showing numerous basophilic inclusions

We report a clinicopathological study of a patient suffering from frontotemporal dementia (FTD) with severe dysarthria and concomitant motor neuron disease (MND). The patient was a 52‐year‐old woman with almost simultaneous emergence of severe dysarthria and FTD. The severe dysarthria subsequently evolved into anterior opercular syndrome. Motor neuron signs then emerged, and the patient developed akinetic mutism approximately 2 years after the onset of the disease. The patient died of pneumonia after a 7‐year clinical illness. Pathologically, severe and widespread degeneration in the frontal and temporal lobes, including the anterior opercular area, limbic system, basal ganglia, spinal cord and cerebellum, and frequent ubiquitin‐ and tau‐negative basophilic inclusions were observed. The pyramidal tracts and anterior horns of the cervical cord also showed marked degeneration. Cases showing basophilic inclusions reported so far have been divided into two groups: early onset FTD and MND with basophilic inclusions. Our case presented clinicopathological features of both FTD and MND, which suggests that cases showing basophilic inclusions may constitute a clinicopathological entity of FTD/MND.