Motor Neuron Disease-inclusion Dementia Research Articles

Is motor neuron disease‐inclusion dementia aforme frusteof 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.

Démence fronto-temporale familiale avec inclusions marquées par l’anti-ubiquitine dans le tronc cérébral

Les démences fronto-temporales (DFT) forment un groupe hétérogène. Nous avons étudié une famille dont la mère et quatre enfants étaient atteints de DFT d’expression clinique typique, avec début précoce, avant 40 ans, par des troubles de la personnalité, et évolution prolongée, environ 30 ans, avec longue conservation de l’orientation spatiale, sans signe d’atteinte du motoneurone ni signes extrapyramidaux. L’étude neuropathologique d’un cas montra une atrophie massive prédominant au niveau des lobes frontaux. Dans les zones atrophiques, il existait une perte neuronale et un aspect spongieux des couches superficielles. Il n’y avait pas d’inclusion argentophile « de Pick », mais des inclusions marquées par l’anti-ubiquitine, mais non par l’anti-Tau, dans le fascia dentata. Dans le cytoplasme de certains neurones, dans les couches profondes du cortex mais surtout dans le tronc cérébral (réticulée magnocellulaire, noyaux du pont, noyaux moteurs, particulièrement noyau masticateur), de grandes inclusions argentophiles ovoïdes ou réniformes, peu denses, marquées seulement par l’anti-ubiquitine étaient observées. L’étude génétique mettait en évidence un Lod score positif non significatif avec des marqueurs flanquant le gène MAPτ, en l’absence de mutation décelable de ce gène. L’étude biochimique de la protéine Tau ne montrait pas d’anomalie qualitative. L’affection transmise dans la famille que nous avons étudiée paraît distincte aussi bien des DFT associées à une sclérose latérale amyotrophique (SLA) que des « taupathies ». Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPτ form a well-defined group. Definition and grouping of other types of FTD is still problematic. We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. The genetic study failed to detect any mutation in MAPτ; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic “Pick bodies“ were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. “Tangles“ were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis ), in the pes pontis , in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. In our opinion, “ubiquitinopathy” would be non-specific and “Motor Neuron Disease-Inclusion Dementia” (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.

Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in Dementia Lacking Distinctive Histopathology

The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study implies that DLDH is similar to motor neuron disease inclusion dementia. The high prevalence of HpScl may be the cause of some of the clinical features observed in patients with frontotemporal lobar degeneration.

Motor neuron disease group accompanied by inclusions of unidentified protein signaled by ubiquitin.

Peculiar tau-negative, ubiquitin-positive inclusions appear in dementia with ALS (ALS-D), the majority of lobar atrophy (Pick's disease) without Pick body and a small portion of ALS. Another common neuropathological lesion in these diseases is the motor neuron involvement with the degenerative processes. The lower motor neuron is predominantly involved in ALS and ALS-D the upper motor neuron is predominantly involved, but in varying degrees in a considerable number of patients with lobar atrophy that lack Pick bodies. There are, however, some points that have yet to be elucidated. The boundary between these diseases is not always clear and a significant number of cases are considered to be the transitional form. Lobar atrophy without Pick body seems to be a heterogeneous disease group. The nature of ubiquitin inclusions also needs to be clarified. Nevertheless, we postulate that these diseases are grouped with the concept of motor neuron disease-inclusion dementia.

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1. Motor neuron disease inclusion dementia (MNDID) On MRI, hyperintense signals are sometimes seen in the subcortical part of the precentral gyrus in MND patients, although their clinical significance is...

Las otras demencias: neuropatología de las demencias distintas a la enfermedad de Alzheimer

Alzheimer's disease (AD) is one of the most common causes of dementia, but requires neuropathological verification for a definitive diagnosis because there are a number of other neurodegenerative diseases that may present with dementia. Some of these disorders have considerable overlap both clinically and pathologically with AD, while others have distinct clinical and pathological profiles. Vascular dementia and dementia with Lewy bodies (DLB) have the greatest overlap with AD and considerable controversy still surrounds the exact contribution of the non AD pathology to the dementia syndrome. The frontotemporal dementias are loosely united by clinical presentation, but are pathologically heterogeneous and include Pick's disease, dementia lacking distinctive histopathology, motor neuron disease inclusion dementia and corticobasal degeneration (CBD). CBD can be difficult to distinguish from progressive supranuclear palsy, especially when the latter lacks the distinctive gaze palsy. Finally, Creutzfeldt Jakob disease (CJD) may be difficult to distinguish from AD when the symptoms progress at an atypically slow pace. Recently, a new variant of CJD (vCJD) that has been linked to bovine spongiform encephalopathy ('mad cow' disease) has heightened awareness of these prion protein disorders. The neuropathological criteria for the diagnosis of these non AD dementia disorders will be reviewed.

Frontotemporal lobar degeneration--tau as a pied piper?

Frontotemporal lobar degeneration (FTLD) is the second most-common form of cortical dementia in the presenium after Alzheimer disease. Clinically three disease entities can be distinguished: frontotemporal dementia, semantic dementia, and primary progressive aphasia. The underlying neuropathology can be classified into disorders with tau pathology (including Pick disease, corticobasal degeneration, progressive supranuclear palsy, and familial frontotemporal dementia with parkinsonism linked to chromosome 17 - FTDP-17), and into disorders that lack tau abnormalities (including dementia lacking distinctive histology and motor neuron disease inclusion dementia). The recent discovery of tau gene mutations in FTDP-17 brought tau to the center stage, but led to the erroneous trend of collectively grouping all forms of FTLD as tauopathies. However, clinicopathological and genetic studies strongly suggest that the majority of sporadic and familial FTLD cases are not associated with tau pathology and/or tau gene mutations. Furthermore, recent studies have linked several autosomal dominantly inherited familial frontotemporal dementia cases to a variety of gene loci on different chromosomes. Thus, this review is intended to summarize our current knowledge about the sporadic and familial FTLD disorders that lack tau pathology, and shall further strengthen the view that FTLD is heterogeneous, both in terms of clinicopathological phenotypes as well as genetic backgrounds.

La démence frontotemporale : aspects cliniques et morphologiques

Frontotemporal dementia (FTD) includes a heterogeneous group of sporadic and familial neuropsychiatric diseases. Together with dementia with Lewy bodies it is, after Alzheimer's disease, the second most common form of dementia in the presenile age. Unlike the incidence of Alzheimer's disease, which increases with age, frontotemporal dementia only rarely begins after the age of 75 and more often affects people in midlife. Based on consensus guidelines, three distinct clinical entities can be distinguished in frontotemporal dementia: frontotemporal dementia per se, primary progressive aphasia and semantic dementia. The core clinical phenotype of frontotemporal dementia per se consists of gradual and progressive changes in behaviour. The most common presentation is an early change in social behaviour and personal conduct, often associated with lack of inhibition, resulting in impulsive or inappropriate behaviour. In primary progressive aphasia, patients present with troubles in the expression of language, marked by problems using the correct word but with well-preserved understanding of word meaning. With progression of the disease, less and less language is used until the patient is virtually mute (non fluent aphasia). In semantic dementia, patients present with problems naming and understanding word meaning in the context of fluent, effortless and grammatically correct speech output (fluent aphasia). Both types of language disturbance occur in the setting of relative preservation of other cognitive domains, such as memory. All FTD patients have in common a circumscribed cortical atrophy of the frontal and/or the anterior temporal lobes although variations in the anatomical distribution of the pathology largely determine the associated clinical syndromes just mentioned. Pathologically, Pick's disease, corticobasal degeneration and familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) have been reported as the histological substrate of frontotemporal dementia. However, dementia of the frontal type and the motor neuron disease inclusion dementia (MNDID) are the most frequent neuropathological subtypes of frontotemporal dementia. Both are characterised by neuronal loss, astrocytic gliosis, laminar spongiosis affecting cortical laminae I-III and, in some cases, by an astrocytic gliosis and a cell loss in the striatum, the thalamus and the substantia nigra. Motor neuron disease inclusion dementia is further defined by the presence of characteristic ubiquitin-containing intracytoplasmic inclusions in granule cells of the dentate gyrus and in the cell somata and neurites of superficial neocortical neurons. By immunohistochemistry, these inclusions are found to react with anti-ubiquitin antibodies but not with antibodies to tau protein. However, the nature of the associated protein accumulating with ubiquitin in this disorder remains elusive. The recent finding of familial cases of frontotemporal dementia with ubiquitin-positive but tau-negative neuronal inclusions suggests that there might be a genetic background to this type of pathological process. In contrast to dementia of the frontal type and to motor neuron disease inclusion dementia, Pick's disease, corticobasal degeneration and FTDP-17 are characterised by abundant filamentous nerve cell inclusions made of the microtubule-associated protein tau.

Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia).

Frontotemporal dementia (FTD) with motor neuron disease means amyotrophic lateral sclerosis (ALS) with dementia. In the cerebrum of this condition, the medial cortex of the rostral temporal lobe is constantly and most remarkably involved. Another constant and quite characteristic lesion is neuronal loss localized to the CA1-subiculum transitional area at the level of the pes hippocampi. The rostral portion of the parahippocampal gyrus, and the amygdaloid nucleus are also involved. Ubiquitinated intracytoplasmic inclusions are seen in the dentate granule cells and parahippocampal gyrus neurons. Some cases of ALS without dementia show the identical temporal lobe degeneration as well as the cortical ubiquitinated inclusions, thus raising the possibility of overlooked dementia or premature death of the patients. Similarly, recently proposed motor neuron disease-inclusion dementia may be a forme fruste of ALS with dementia.