Dementia in Motor Neuron Disease 

Motor neuron disease (MND), as the name suggests, is a pure motor disorder without any significant evidence of sensory symptoms, extraocular movement disturbances, bladder and bowel dysfunction, or cognitive impairment. Cognitive impairment in amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Evidence of impairment can clinically be seen in almost half of patients through direct neuropsychological testing, but frank frontotemporal dementia (FTD) occurs in a limited percentage of patients.

Patients with MND are generally free of cognitive impairment, but evidence is growing to support an association between MND and frontal lobe or FTD. Some propose that frontotemporal lobe dementia with motor neuron disease (FTD/MND) is nosologically distinct; others suggest that it is part of a spectrum of diseases encompassing classic MND at one end and FTD at the other. The recent discovery of pathological transactive response DNA-binding protein 43 (TDP-43) in both ALS and FTD with ubiquitinated inclusions confirms that these are closely related conditions within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.

Pyramidal cell loss in frontal and temporal lobes and degeneration of motor neurons in the hypoglossal nucleus and spinal motor neurons characterize FTD/MND. Pyramidal neurons in the premotor cortex usually are preserved.

Takeda et al have shown that ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II-III of the transentorhinal cortex (TEC) – molecular dentate gyrus (DG) projection and subiculum is specific to ALS.^[1] This is different from the neurofibrillary tangles of Alzheimer disease (AD), dominant in layer II-III of the entorhinal cortex. This may provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of Alzheimer disease.

TDP-43 was recently identified as the major pathological protein in sporadic ALS and in the most common pathological subtype of FTD (ie, frontotemporal lobar degeneration with ubiquitinated inclusions). Data now suggests that delocalization, accumulation, and ubiquitination of TDP-43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS.

Signs and symptoms reflect frontal and temporal lobe dysfunction with lower motor neuron – type weakness, muscle atrophy, and fasciculations.

Frequency

United States

Frontal lobe dementia is the second or third most common type of degenerative dementia in autopsy series. The precise frequency of the subgroup of FTD patients with FTD/MND in autopsy or population studies is unknown (but rare).

International

In a Scandinavian autopsy series, dementia was reported in 2-6% of patients with MND. The relative frequency of FTD/MND in all patients with dementia appears similar in the United States and Japan. Certain populations (eg, Chamorro Indians of Guam, indigenous residents of the Kii peninsula) have a disproportionately higher incidence and prevalence of overlap degenerative syndromes (MND, dementia, parkinsonism).

Mortality/Morbidity

• Progressive dementia with symptoms of executive dysfunction, personality change, and motor weakness leads to severe morbidity.
• Death usually occurs within 3 years of onset from inanition, pulmonary failure, and aspiration.
• Patients with FTD/MND generally follow a more rapid course than patients with either FTD or MND alone. They are more likely to have a bulbar form of MND, which may help explain its more aggressive course.
• Based on the cohort study by Josephs et al, Creutzfeldt-Jakob disease (CJD) remains the most likely cause of a rapidly progressive neurodegenerative dementia. The frontotemporal lobar degeneration with motor neuron degeneration, diffuse Lewy body disease, tauopathies, and Alzheimer disease are other less common causes of a rapidly progressive dementia.

Race

FTD/MND has been described in patients of Asian, European, and African descent. No data are available about incidence and prevalence among racial groups.

Sex

Men appear to be affected slightly more frequently than women, but this difference may not be significant.

Age

The mean age of onset in sporadic cases varies among series but overall is 55-65 years. Familial cases tend to be younger.