Dementia in Motor Neuron Disease
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Patients with motor neuron disease (MND) are generally free of cognitive impairment, but evidence is growing to support an association between MND and frontal lobe or frontotemporal dementia (FTD).
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 the cerebral cortex beyond the motor regions. Evidence of impairment can clinically be seen in almost half of patients through direct neuropsychological testing, but frank FTD occurs in a limited percentage of patients. [1, 2, 3]
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 discovery of pathologic transactive response deoxyribonucleic acid (DNA) ̶ binding protein 43 (TDP-43) in ALS and FTD with ubiquitinated inclusions confirms that these are closely related conditions belonging to a new biochemical class of neurodegenerative diseases, the TDP-43 proteinopathies. [4, 5, 6, 7]
Complications in FTD/MND can include the following:
Progressive bulbar palsy results in dysphagia, the risk of aspiration pneumonia, and mutism
Muscular wasting and weakness may occur
Parkinsonism may develop in some patients
Dyspnea and hypoxic encephalopathy may be related positionally and can interfere with reclining for sleep
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 do patients with either FTD or MND alone. They are more likely to have a bulbar form of MND, which may help to explain its more aggressive course.
Treatment strategies for FTD may apply to FTD/MND, but this is not known for certain. Current treatments mainly are supportive and directed toward the features of MND.
Evaluate and treat sialorrhea, impaired breathing, swallowing, and mobility. There is no surgical treatment for FTD/MND, but consider gastrostomy tube feeding for patients with severe bulbar symptoms, severe dysphagia, and relatively mild dementia and limb weakness. Prior to gastrostomy, mechanically soft diets can be tried. [#TreatmentDiet]
Consider neuroprotective agents (eg, riluzole, gabapentin) or nutritional supplements (eg, creatine) to preserve muscle bulk, but note that their efficacy in FTD/MND is even more uncertain than it is in MND.
Depending on the patient’s occupation and level of cognitive and neurologic dysfunction, medical leave of absence or early retirement may be advisable.
For patient education information, see the Brain and Nervous System Center, as well as Dementia Overview, Dementia Medication Overview, and Dementia in Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease).
Worldwide, frontotemporal lobe dementia with motor neuron disease (FTD/MND) is a sporadic condition with an unknown etiology. It is characterized by pyramidal cell loss in the frontal and temporal lobes and degeneration of motor neurons in the hypoglossal nucleus and spinal motor neurons. Pyramidal neurons in the premotor cortex usually are preserved. [8]
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. [9] This is different from the neurofibrillary tangles of Alzheimer disease, dominant in layer II-III of the entorhinal cortex. This may provide a basis for clinical characterization of memory deficits of ALS, which may be distinct from those of Alzheimer disease.
TDP-43 has been identified as the major pathologic protein in sporadic ALS and has also been found in the most common pathologic subtype of FTD (ie, frontotemporal lobar degeneration with ubiquitinated inclusions). Data now suggest 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. [4, 5, 6, 7, 10, 11]
Signs and symptoms reflect frontal and temporal lobe dysfunction with lower motor neuron–type weakness, muscle atrophy, and fasciculations.
A minority of patients have a family history of FTD/MND, but this overlap syndrome may be related to other neurodegenerative overlap syndromes that include variable degrees of dementia, MND, and parkinsonism.
The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein-degradation pathways in the core of ALS pathogenesis. [12] The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Potential relevance has been shown regarding the pathobiology of more common MNDs such as ALS, providing an additional link between ALS and FTD. [13]
Two of the genes causing FTD alone (CHMP2B and GRN) are associated with a damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology. [14] Wang et al recently found relationship between sporadic forms of Alzheimer-type dementia and ALS that is linked to I2(PP2A) and the potential of I2(PP2A)-based therapeutics for these diseases. [15] .
Ubiquilin-2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to terminate disease. [16]
C9orf72 repeat expansion has been identified as an important genetic risk factor for both motor neuron disease and frontotemporal dementia. This has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. [17, 18]
Overall, the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes.
Frontal lobe dementia is the second or third most common type of degenerative dementia in autopsy series. The precise frequency with which frontotemporal lobe dementia with motor neuron disease (FTD/MND) occurs in autopsy or population studies is unknown (but low).
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). [19]
FTD/MND has been described in patients of Asian, European, and African descent. No data are available about incidence and prevalence among racial groups.
Men appear to be affected slightly more frequently than women, but this difference may not be significant. The mean age of onset in sporadic cases varies among series but overall is 55-65 years. Familial cases tend to be younger.
Frontotemporal lobe dementia with motor neuron disease (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, however, even those patients manifesting disinhibition and restlessness become increasingly apathetic.
Stereotypic behavior and repetitive rituals of hoarding, dressing, wandering, and toileting can be observed. In addition, 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. 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 involvement of the hypoglossal nucleus. Although there is significant memory impairment, 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 asymmetrical 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.
Consensus clinical criteria detailing core and supportive features for FTD syndromes have been published.
Patients with frontotemporal lobe dementia with motor neuron disease (FTD/MND) 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 24mo 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. [20] 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.
Conditions to consider in the differential diagnosis of frontotemporal lobe dementia with motor neuron disease (FTD/MND) include the following:
Alzheimer disease
ALS
Frontal and temporal lobe dementia
Frontal lobe syndromes
Pick disease
Vascular dementia
Dementia in Parkinson disease
Creutzfeldt-Jakob disease
Computed tomography (CT) scanning in patients with frontotemporal lobe dementia with motor neuron disease (FTD/MND) may show mild, generalized cerebral atrophy or asymmetrical frontotemporal atrophy.
Because it provides greater resolution than CT scanning does, magnetic resonance imaging (MRI) may reveal selective frontal and anterior temporal atrophy that cannot be appreciated on CT scanning.
Single-photon emission CT (SPECT) scanning often demonstrates reduced blood flow in an asymmetrical, frontotemporal pattern.
In a recent study, it has been shown that loss of gray matter volume in motor and extramotor regions of only ALS patients with FTD and not of ALS patients without FTD suggests distinct sites of predominant pathology. This may also provide some ideas about disease onset. Brain volumetric measures supplemented by histopathological correlations and other neuroimaging techniques, such as diffusion tensor imaging, may provide insight into ALS pathophysiology. [21]
A study reported that glucose hypometabolism on positron emission tomography (PET) scans in patients with dementia associated with MND affected only the frontal lobes, sparing the temporal lobes. [22] This contrasted with frontotemporal dementia, in which glucose hypometabolism is seen in the frontal lobes and temporal lobes. In Alzheimer disease, PET scans may reveal glucose hypometabolism in the parietal and temporal regions bilaterally.
Boyajian et al recommended magnetoencephalography (MEG) as a powerful new tool for researching the contribution of cortical dysfunction to motor disability, which can characterize the disease process. [23]
Early in the disease, frontotemporal lobe dementia with motor neuron disease (FTD/MND) preferentially affects frontal and temporal lobes, the hypoglossal nucleus, and the spinal motor neurons. The later and terminal stages reveal histologic evidence of widespread cortical involvement. In the frontal and temporal lobes, microscopic changes include loss of pyramidal cells, spongiform neuropil change, and astrocytic gliosis.
Ubiquitinated, tau-negative inclusions are present within the frontal cortex and the dentate gyrus of the hippocampus. Pick cells (inflated neurons) and Pick bodies (ubiquitin and tau-positive intracellular inclusions) are absent. Betz cells in the precentral gyrus usually are affected.
In approximately 50% of patients, neuronal loss and pigmentary incontinence in the substantia nigra and other pigmented brainstem neurons occur, even in patients without clinically overt parkinsonism. There can be marked hypoglossal and spinal motor neuron degeneration (although this is not essential for patients to progress to an anarthric state) and ubiquitinated tau-negative inclusions in the spinal neurons.
The following studies are also used in the evaluation of patients with frontotemporal lobe dementia with motor neuron disease (FTD/MND):
Typical blood studies
Thyroid function tests
Vitamin B-12 and folate levels
Venereal Disease Research Laboratory test
The electroencephalogram can remain normal even in the later stages of dementia, but often, mild dysrhythmic slowing occurs that is sometimes asymmetrical.
Electromyography may demonstrate widespread denervation in limb muscles. Early in the disease, especially in patients with a predominantly bulbar onset, findings may not fulfill the Lambert or El Escorial criteria for motor neuron disease.
No specific treatment is available for frontotemporal lobe dementia with motor neuron disease (FTD/MND). Treatments for MND, such as riluzole, do not appear to affect the course of the dementia-inducing illness. Riluzole is currently the only licensed medication for MND. Available data from therapeutic trials in MND do not show beneficial cognitive effects, although there are no specific contraindications in this context.
Gabapentin has been studied in trials as a disease-modifying agent in patients with MND but does not demonstrate specific cognitive-enhancing properties.
Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) are used to correct the cholinergic effect associated with Alzheimer disease. Although not studied specifically in FTD, anecdotal reports suggest they may increase irritability in patients with FTD.
Patients with FTD who have profound presynaptic serotonergic deficits and behavioral disturbances may respond to selective serotonin reuptake inhibitors.
Optimal symptomatic dopaminergic therapy should be offered to patients with overlap syndromes with idiopathic Parkinson disease and MND. On the other hand, selective dopamine blockers, such as olanzapine, may be useful in agitated patients; monitor for adverse effects, such as extrapyramidal syndromes.
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Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center
Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association
Disclosure: Nothing to disclose.
Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center
Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Joe Verghese, MD, MRCPI Associate Professor, Department of Neurology, Albert Einstein College of Medicine
Joe Verghese, MD, MRCPI is a member of the following medical societies: American Academy of Neurology and American Geriatrics Society
Disclosure: Nothing to disclose.
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