Motor Neurone Disease-inclusion Dementia

doi:10.1006/neur.1996.0046

Neurodegeneration

Volume 5, Issue 4, December 1996, Pages 339-350

Neurodegeneration

https://doi.org/10.1006/neur.1996.0046 Get rights and content

Abstract

We describe nine patients, five women and four men (age at death 58–83 years), who developed isolated progressive frontotemporal dementia over 4 to 12 years. These cases represent nine of the 385 (2.3%) cases from a series of autopsy cases of dementia in a large teaching hospital. One had a mother with a history of frontotemporal dementia and marked frontal lobe atrophy. Another had multiple affected family members with frontotemporal dementia, motor neurone disease or both. None of the nine had clinical evidence of either an upper or lower motor neurone disorder. In each case neuropathological examination revealed cortical pathology identical to that described previously as typical of dementia associated with motor neurone disease. There was variable macroscopic atrophy and neuronal loss in the frontal and temporal lobes. All cases had cortical microvacuolation, in seven limited to cortical layer II, and transcortical in two. There was variable cortical and subcortical gliosis. Intraneuronal ubiquitin-immunoreactive inclusions, characteristic of the extra-motor involvement of motor neurone disease, were found in the hippocampal dentate granule cells and residual neurones in layer II of the frontotemporal cortex of all cases. Similar inclusions were also seen in the nucleus ambiguus of three cases. The hypoglossal nuclei showed no neuronal loss, gliosis or ubiquitin-immunoreactive inclusions. Ubiquitin-immunoreactive dystrophic neurites were detected within affected cortex, being most conspicuous in layer II in areas containing microvacuolation. Dystrophic neurites were not detected in subcortical structures. Spinal cords were unavailable for examination because of limited autopsy consent. The finding of intraneuronal ubiquitin-immunoreactive inclusions characteristic of motor neurone disease in patients with frontotemporal dementia, without clinical or pathological evidence of motor system degeneration, extends the clinical spectrum of diseases associated with such inclusions. We propose the term motor neurone disease-inclusion dementia (MNDID) for these cases.

References (0)

Cited by (213)

Posttranslational modifications of TDP-43
2022, TDP-43 and Neurodegeneration: From Bench to Bedside
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder that is characterized by the degeneration of upper and lower motor neurons resulting in muscle weakness and paralysis. Frontotemporal dementia (FTD) is the second most common form of dementia after Alzheimer's in individuals under the age of 65, and is characterized by shrinkage within the frontal and temporal lobes of the brain, inducing behavioral changes and language dysfunction. Although ALS and FTD have different phenotypes and affect different parts of the central nervous system, there is strong clinical association between the disorders, with a subset of cases showing both cognitive and motor deficits. Frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa (TDP-43)-positive inclusions is a major pathological subtype of FTD that shares a similar molecular phenotype with the majority of ALS cases, whereby the nuclear RNA-binding protein TDP-43 accumulates in large cytoplasmic aggregates in affected neurons. It is hypothesized that aberrant TDP-43 aggregation may cause disease through a toxic loss of function, affecting the regulation of mRNAs implicated in neuronal function, or through a toxic gain of function whereby the presence of the aggregates themselves induces apoptotic signaling pathways. Aberrant TDP-43 aggregates are associated with specific posttranslational modifications (PTMs), the three dominant ones being ubiquitination, phosphorylation, and C-terminal fragmentation. Recent studies have implicated oxidative stress–induced cysteine oxidation and lysine acetylation in impairing TDP-43's capacity to bind its target mRNAs. This chapter will review the literature pertaining to these PTMs, discussing both toxic loss-of-function and gain-of-function mechanisms.
Dementias and the Frontal Lobes
2017, Executive Functions in Health and Disease
Dementing diseases with predominant frontal and frontostriatal involvement are often characterized by early progressive behavioral and executive symptoms. This phenomenon is seen not only in individuals with frontotemporal lobar degeneration but also in patients with early-onset Alzheimer’s disease, vascular dementia, and dementias associated with movement disorders. The assessment of executive deficits in patients with dementia is challenging, especially in the context of more general decline. Thus, scores on tasks aimed to assess executive function need to be interpreted only in light of full cognitive and language profile as well as qualitative observations, whereas behavioral assessment should be based both on clinician’s observations and the interview with the patient’s caregiver. This chapter characterizes the most common dementing diseases that may affect frontal lobe function. Particular attention has been paid to behavior, affect, and executive function. Some implications for assessment of frontal lobe function have been also discussed.
Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants
2015, Neurologic Clinics
Multiple brain pathologies in dementia are common
2010, European Geriatric Medicine
Multiple pathological processes are common in those with dementia and can affect clinical presentations. This study defined the extent of multiple pathological processes at autopsy in a well-characterized dementia clinic population and determined their impact on cognitive deficits. Forty-five cases from the Canadian Collaborative Cohort of Related Dementia (ACCORD) were prospectively assigned one primary clinical diagnosis and up to one secondary clinical diagnosis. Neuropathological examination followed a uniform protocol including mandatory semiquantitative assessment of a wide range of pathological changes. Multiple significant pathologies were identified in 21 cases (46.7%) including 19 cases with two cases with three pathological diagnoses. The pathological diagnoses in these mixed cases included Alzheimer disease (AD) (n = 18), dementia with Lewy Bodies (DLB) (n = 9, eight also with AD), frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) (n = 10, eight with coexisting AD), cerebrovascular disease (CVD) (n = 5, three cases with coexisting AD) and progressive supranuclear palsy (PSP) (n = 1, also with CVD and FTLD-TDP). Only two cases with multiple pathological diagnoses were all recognized in the clinical diagnoses. Additional pathology of uncertain significance in 24 cases included vascular lesions, argyrophilic grains and hippocampal sclerosis. Patients with multiple pathologies were older and their baseline MMSE score higher at presentation.
The neural basis of semantic memory: Evidence from semantic dementia
2009, Neurobiology of Aging
Citation Excerpt :
In terms of neuropathology, most SD cases (72%) conform to a single subtype of FTD, with intra-neuronal deposits containing the protein ubiquitin (Davies et al., 2005). Such deposits are also described in motor neuron disease (MND) and are sometimes termed MND inclusions (Jackson et al., 1996). Patient with clinical features of FTD (typically behavioural disturbance and reduced fluency of speech) with signs of MND are increasingly recognized, and may be labelled ‘FTD–MND’ (Lomen-Hoerth et al., 2002, 2003; Neary et al., 1990; Rakowicz and Hodges, 1998).
Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD–MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD–MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD–MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD–MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions.
Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43): its journey of more than 100 years
2022, Journal of Neurology

View all citing articles on Scopus

View full text

Regular ArticleMotor Neurone Disease-inclusion Dementia

Abstract

Regular Article
Motor Neurone Disease-inclusion Dementia