Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of presenile dementia patients with motor neuron disease

Summary Ubiquitin-positive intraneuronal inclusions were found in the extramotor cortices of ten presenile dementia patients with motor neuron disease. There were inclusions in the hippocampal granular cells and in the small neurons of the superficial layers of the temporal and frontal cortices. Bunina bodies were present in the anterior horn cells in all cases. These results suggest that ubiquitin-related cytoskeletal abnormalities are common in cerebral non-motor small neurons in these patients.     

Ubiquitin-positive neuronal and tau 2-positive glial inclusions in frontotemporal dementia of motor neuron type

Attempts at classification of fronto-temporal dementias have not yet been completely successful. We report ten cases of sporadic fronto-temporal dementia (FTD) with ubiquitin-positive neuronal inclusions in cortex or in motor neurons in brain stem or spinal cord, which may contribute to the classification of FTD. Marked variation in clinical presentation as well as in pathological findings was the rule in all cases. Dementia was a prominent feature. Only one case had clinical features suggestive of motor neuron disease. Three of four younger onset cases displayed an especially severe atrophy of the temporal lobes, the basal ganglia and the substantia nigra. This contrasted with the other seven cases in which the fronto-temporal atrophy and changes in basal ganglia and substantia nigra were variable and sometimes mild. In addition to the presence of ubiquitin-reactive, but tau-and silver impregnation-negative neuronal inclusions, all cases demonstrated tau 2-positive glial inclusions, similar to those recently reported in three motor neuron disease cases with dementia. The glial inclusions were not visible with antibody to tau 1. Reaction with antibody to alpha-synuclein was invariably negative. If the combination of ubiquitin-positive neuronal and tau 2-positive glial inclusions is found to be consistently present in FTD of motor neuron type, this feature will provide a firmer basis for this diagnosis than previously available.     

Thalamic dementia and motor neuron disease

A 46-year-old woman developed a progressive neurologic disorder over the course of 30 months which was characterized by profound dementia complicated by a motor neuron disorder that became evident 10 months prior to death. Postmortem examination of the nervous system disclosed extensive neuronal loss and gliosis of the thalamus, predominantly involving the dorsomedial nuclei, as well as severe degeneration of the corticospinal tracts, spinal anterior horns, and hypoglossal nuclei. The disease could not be transmitted to experimental animals by intracerebral inoculation of the patient's brain tissue. This case represents a unique dementing disorder, possibly familial, with associated motor neuron disease.     

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.     

123I-IMP-SPECT finding of a case of presenile dementia with motor neuron disease--comparison between Alzheimer's disease, Pick's disease and presenile dementia with motor neuron disease

Cross-sectional X-CT and 123I-IMP-SPECT studies comparing patients with presenile dementia with motor neuron disease (52-year-old, female), with Alzheimer's disease (51-year-old, male) and Pick's disease (49-year-old, male), have found a pattern of reductions in regional cerebral blood flow; the most severe reductions have been in fronto-temporal regions in cases of Pick's disease and presenile dementia with motor neuron disease. 123I-IMP-SPECT in a patient with presenile dementia with motor neuron disease differed significantly from uptake in a case with Alzheimer's disease. Although these findings should be evaluated as part of a prospective longitudinal study with X-CT and 123I-IMP-SPECT, it could be suggested that the development of these diseases has different pathophysiologies.     

Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum

One of the characteristic pathologic changes in classic motor neuron disease (MND) is the presence of ubiquitin-immunoreactive (ub-ir) inclusions in the cytoplasm of lower motor neurons. In addition, cases of MND with dementia (MND-d) also have ub-ir neuronal cytoplasmic inclusions and dystrophic neurites in extramotor neocortex and hippocampus. Although this extramotor pathology is a highly sensitive marker for dementia in MND, similar changes are found in a subset of patients with frontotemporal dementia (FTD) with no motor symptoms (FTD-MND type). The purpose of this study is to more fully describe and compare the pattern of ub-ir pathology in these 3 conditions. We performed ubiquitin immunohistochemistry on postmortem tissue, representing a wide range of neuroanatomic structures, in cases of classic MND (n = 20), MND-d (n = 15), and FTD-MND type (n = 15). We found the variety of morphologies and the anatomic distribution of ub-ir pathology to be greater than previously documented. Moreover, the degree of overlap suggests that MND, MND-d, and FTD-MND type represent a spectrum of clinical disease with a common pathologic substrate. The only finding restricted to a specific subgroup of patients was the presence of ub-ir neuronal intranuclear inclusions in some cases of familial FTD.     

Semantic dementia combined with motor neuron disease

Up to 20% of patients with behavioural variants of frontotemporal dementia (FTD) also have motor neuron disease (MND); conversely, this comorbidity is rare in patients with language variants of FTD. A few patients have been reported with semantic dementia (SD) combined with MND. However, these patients demonstrated the clinical features of MND in the advanced stage. We report a patient with SD who also demonstrated MND symptoms in an earlier stage of the disease. A 61-year-old man visited our memory disorder clinic as a result of language disturbance and dysarthria of 8 months duration and facial recognition impairment of 3 months duration. Neuropsychological tests revealed anomic aphasia, prosopagnosia, and decreased semantic fluency. A brain MRI revealed significant atrophies localized in both anterior temporal lobes with a greater prominence on the right side. Clinical examination and electrophysiological studies confirmed a diagnosis of MND 17 months after the onset of the disease.     

Rapidly progressive aphasic dementia and motor neuron disease

Articulatory and language impairment heralded rapidly progressive motor neuron disease in 7 patients aged 54 to 77 years. One patient had a family history of a similar disorder. Severe nonfluent aphasia developed in all 7 patients and 4 were anarthric within a year. Other cognitive domains were impaired, yet 2 patients lived alone until 1 month before their deaths. Four died within 2 years. Abnormalities were found on electromyography, computed tomography, magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography. Neuropathological examination in 3 patients showed bilateral hemispheric atrophy with neuronal loss and gliosis predominantly of superficial cortical layers. Pigmented and hypoglossal nuclei were relatively preserved. At all spinal levels there was degeneration of corticospinal tracts and loss of anterior horn cells with gliosis. Rapidly progressive aphasic dementia and motor neuron disease are a distinctive clinical entity whose nosology is poorly understood.     

Frontal lobe dementia and motor neuron disease.

Four patients are described, in whom a profound and rapidly progressive dementia occurred in association with clinical features of motor neuron disease. The pattern of dementia indicated impaired frontal lobe function, confirmed by reduced tracer uptake in the frontal lobes on single photon emission computed tomography (SPECT). Pathological examination of the brains of two patients revealed frontal-lobe atrophy, with mild gliosis and spongiform change. The spinal cord changes were consistent with motor neuron disease. The clinical picture and pathological findings resembled those of dementia of frontal-lobe type and were distinct from those of Alzheimer's disease. The findings have implications for the understanding of the spectrum of non-Alzheimer forms of primary degenerative dementia.     

Ubiquitin‐positive tau‐negative intraneuronal inclusions in dementia with motor neuron disease

We first reported ubiquitin‐positive tau‐negative intraneuronal inclusions in the hippocampal granular cell layer and entorhinal cortices in patients with amyotrophic lateral sclerosis (ALS). We then found that those inclusions occur frequently in patients with presenile dementia and motor neuron disease. The ultrastructure of the inclusions consists mainly of granules with a few filaments. In 2006, TDP‐43 was identified as a major component of the inclusions specific for frontotemporal lobar degeneration and ALS. Here, we review the current knowledge regarding ubiquitin‐positive tau‐negative intraneuronal inclusions.     

Swelling of neuronal processes in motor neuron disease

We investigated serial sections of the anterior horns of the lower lumbar cord by a modified Bielschowsky's silver impregnation, in a case of sporadic lower motor neuron disease. We paid special attention to any direct connection between the swellings of neuronal processes and the perikarya. Focal swellings of neuronal processes were occasionally directly connected with the perikarya; some had morphologic peculiarities of axons, and others originated in dendrites.     

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.     

Sporadic motor neuron disease with Lewy body-like hyaline inclusions

Summary Lewy body-like hyaline inclusions were immunocytochemically and electron microscopically investigated in a patient with sporadic motor neuron disease. The hyaline inclusions were chiefly observed within the perikarya of both normal-looking and chromatolytic anterior horn cells in the lumbar spinal cord, but some were detected in the axons and dendrites. Usually, a single inclusion was found in the perikaryon, but in rare cases two or more were observed. Immunocytochemically, these inclusions were intensely immunostained with anti-ubiquitin anti-body. Ultrastructurally, the hyaline inclusions were chiefly composed of randomly arranged linear structures associated with ribosome-like granules, varying from compactly arranged linear densities to more loosely packed ones. They contained scattered vesicles of various sizes and occasionally a focal accumulation of randomly arranged 10-nm neurofilaments or 13–25-nm filamentous structures.     

Right temporal variant frontotemporal dementia with motor neuron disease

Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including diffusion tensor imaging in one patient, and FDG positron emission tomography revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in two patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer’s disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.     

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.     

Lewy body-like hyaline inclusions in sporadic motor neuron disease are ubiquitinated

Summary Round eosinophilic hyaline inclusion bodies with halos in the somata of anterior horn cells from a case of sporadic lower motor neuron disease (MND) were intensely immunostained with the monoclonal anti-ubiquitin antibody (DF2). A few similar, DF2-positive inclusions were also observed in the nerve cell processes of anterior horn cells or in the neuropil. Most inclusions showed intense homogeneous staining of the entire inclusion, whereas a few had intense staining of their periphery with no or pale staining of the central areas. Other DF2-positive structures in the somata of anterior horn cells included cytoplasmic granular structures, eosinophilic thread-like or reticular structures, and small eosinophilic profiles different from Bunina bodies. The DF2-staining intensity of Bunina bodies and spheroids did not exceed the background level. These results suggest that ubiquitination is associated with a pathological process of anterior horn cell degeneration in this MND case.