eMedicine Specialties > Neurology > Behavioral Neurology and Dementia

Dementia in Motor Neuron Disease

Author: Jasvinder Chawla, MBBS, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Associate Professor and Director, Neurology Residency Training Program, Loyola University Medical Center
Contributor Information and Disclosures

Updated: Jan 20, 2010

Introduction

Background

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.

Pathophysiology

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.

Clinical

History

• FTD/MND usually presents as a change in personality with deterioration in social conduct.
  • Initial behavioral changes vary but include abulia, apathy, and reduced spontaneity and/or initiation.
  • Some patients become strikingly disinhibited, overactive, and frankly inappropriate with emotional lability.
• With disease progression, even those patients manifesting disinhibition and restlessness become increasingly apathetic.
• Stereotypic behavior and repetitive rituals of hoarding, dressing, wandering, and toileting can be observed.
• Patients may overeat, exhibit hyperoral tendencies, and develop food fads (although this is more exceptional); some patients may hold food in their mouth for prolonged periods without swallowing.
• Dynamic spontaneous speech output progressively declines, resulting in anarthria and mutism. Visuospatial skills are relatively spared throughout illness, but there is significant memory impairment.
  • A subset of patients presents with rapidly progressive aphasia.
  • Despite progression to anarthria, autopsy studies show that anarthria can occur in the absence of significant hypoglossal nucleus involvement.
  • Memory also is impaired, but this is not as distinguishing as the frontal lobe or language features.
  • Posterior cortical functions (eg, visuospatial skills) are preserved and/or spared until the preterminal stages.
  • The clinical pattern reflects the topographic pattern of atrophy, often visible radiographically, with asymmetric frontotemporal atrophy.
  • If asymmetrically worse in the left (language-dominant) hemisphere, aphasia is a likely and prominent clinical feature.
• Throughout the course of the disease, signs and symptoms of MND also progress.
  • Cognitive changes often precede signs of MND.
  • Limb weakness and dysphagia eventually become disabling, although some patients have a primarily bulbar pattern of weakness with relative sparing of limb strength.
• Recently, consensus clinical criteria detailing core and supportive features for FTD syndromes were published.

Physical

• Patients usually perform poorly on tests of frontal lobe function (ie, Wisconsin card sorting, picture sequencing, verbal fluency tests). Memory is impaired, but less consistently in the mild stages.
• Clinical signs of MND usually follow or accompany dementia onset. MND signs include bulbar weakness with dysarthria and dysphagia, limb weakness, muscle wasting and fasciculations, and, of greatest concern, dyspnea.
• Akinesia and rigidity are uncommon in this disorder but more common in patients with a longer interval between onset of dementia and neurologic signs (more than 24 mo in a Japanese series). This may reflect, in part, the variable involvement of the substantia nigra and other pigmented brainstem nuclei that are observed in roughly 50% of patients at autopsy. This, in turn, may vary between populations (more common in Chamorro Indians).
• Moon et al have shown that slow vertical saccades are common in FTD/MND.² This may require additional studies in the future to confirm the involvement of the burst neurons in the dorsal midbrain in patients with FTD/MND.
  
  

Causes

• Worldwide, FTD/MND is sporadic with unknown etiology.
• A minority of patients has a family history, but this overlap syndrome may be related to other neurodegenerative overlap syndromes that include variable degrees of dementia, MND, and parkinsonism.
• The genes causing most cases of ALS are still unknown. Familial cases are linked to a mutated region of chromosome 17, which contains the tau gene. Mutations in 2 genes with related functions were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus on chromosome 16 and the TARDBP gene at the ALS10 locus on chromosome 1.
• The discovery of mutations in the DNA/RNA-binding proteins transactive response DNA-binding protein 43 (TDP-43) in familial ALS has shed some light on the disease pathogenesis.

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