Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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The author offers an updated article of dementia associated with amyotrophic lateral sclerosis, including discussion of the consensus criteria for frontotemporal cognitive and behavioral syndromes in amyotrophic lateral sclerosis as well as updated information on the considerable neuropathological overlap between amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Additional updates highlight genetic and protein associations more recently described, including TDP-43, FUS, UBQLN2, and C9orf72, as well as avenues for clinical investigations and potential therapies to be pursued in light of these advances.
• The prevalence of dementia in amyotrophic lateral sclerosis is much higher than historically reported, with some evidence of cognitive or behavioral impairments not meeting criteria for the diagnosis of dementia in the majority of amyotrophic lateral sclerosis patients.
• The convergence of neuropathological and genetic evidence suggests that amyotrophic lateral sclerosis and frontotemporal dementia may represent a continuum of the same neurodegenerative process in many cases.
• A growing understanding of the protein neuropathology of both amyotrophic lateral sclerosis and frontotemporal dementia provides exciting opportunities for the development of disease-modifying therapies for this spectrum of neurodegenerative illnesses.
Nineteenth-century neurologists regarded dementia in patients with amyotrophic lateral sclerosis as either a second, independent neurologic process or an atypical presentation of amyotrophic lateral sclerosis (20). Two centuries later, it remains uncertain why only some amyotrophic lateral sclerosis patients become demented. Cognitive deficits in amyotrophic lateral sclerosis represent a wide spectrum from relatively mild frontal lobe dysfunction to fully manifested frontal lobe dementia (105). Although many names have been applied to this condition (50), this review will continue to refer to it as "dementia associated with amyotrophic lateral sclerosis," while also acknowledging contemporary classification schemes for clinical and molecular diagnosis.
Dementia and amyotrophic lateral sclerosis can present within other disorders. Guamanian amyotrophic lateral sclerosis associated with dementia seems to differ from dementia associated with sporadic or familial types of amyotrophic lateral sclerosis in etiology and pathology. In addition, clinical presentations of dementia associated with amyotrophic lateral sclerosis and the motor neuron variant of frontotemporal dementia overlap considerably. The motor neuron variant of frontotemporal dementia is classified as a pathological subtype of clinical frontal lobe dementia with its own diagnostic criteria (18; 49), whereas an international research conference on amyotrophic lateral sclerosis and frontotemporal dementia held in London, Canada in 2007 resulted in the publication of consensus criteria for the diagnosis of frontotemporal cognitive and behavioral syndromes in amyotrophic lateral sclerosis (102).
Cognitive and behavioral impairment associated with amyotrophic lateral sclerosis. The diagnosis of a dementia syndrome requires acquired, progressive impairment in at least 2 cognitive domains that is severe enough to cause social disability. Some patients with amyotrophic lateral sclerosis have cognitive impairment but do not progress to meet criteria for dementia. In particular, frontal lobe dysexecutive syndrome and attentional deficits may accompany the motor signs of amyotrophic lateral sclerosis in patients who never develop a memory disturbance or who become dependent on others because of their relentless motor disorder rather than their cognitive or behavioral changes. Impaired performance on the Wisconsin Card Sorting Test, Reitan's Trail Making Tests A and B, and the Stroop Interference Test may be indicative of a frontal dysexecutive syndrome. Word generation tests can be a useful screening tool for cognitive decline in amyotrophic lateral sclerosis patients (65) and are recommended for use in either the oral or written formats (03; 119; 120) by the current consensus criteria. Some patients may not show impairment on such tasks but, nevertheless, manifest personality changes, disinhibition, and obsessive-compulsive behaviors, which are behavioral manifestations of frontal and temporal lobe dysfunction. Informant measures such as the Neuropsychiatric Inventory (26) or the Frontal Behavioral Inventory (59) may be useful to elicit these symptoms in a structured interview. Language abnormalities in amyotrophic lateral sclerosis include both reduced word fluency and impaired confrontational naming, and both may be detected before dementia is diagnosed (02).
According to guidelines (102), patients with amyotrophic lateral sclerosis and associated cognitive or behavioral impairment should be classified according to the following schema:
(1) Patients meeting at least 2 non-overlapping supportive diagnostic features from either the Neary criteria (76) or Hodge’s criteria (48) for frontotemporal dementia shall be diagnosed ALSbi (amyotrophic lateral sclerosis behavioral impairment).
(2) Patients with evidence of cognitive impairment at or below the 5th percentile on at least 2 distinct tests of cognition deemed sensitive to executive functioning shall be diagnosed ALSci (amyotrophic lateral sclerosis cognitive impairment).
Population data are lacking. In 2012 Phukan and colleagues performed a prospective study of cognitive function in 160 Irish motor neuron disease patients residing in the community and found that 13.8% had frontotemporal dementia and 34.12% had cognitive impairment without dementia – these patients had a high frequency of language disability and memory dysfunction in comparison to controls; these abnormalities existing in patients with executive dysfunction (87). Cognitive impairment without executive dysfunction was seen in 14%. Almost 50% had no cognitive dysfunction.
A Korean study made inquiries of 318 motor neuron disease patients who were studied prospectively for 4 years from the time of diagnosis (80). About 50% were cognitively or behaviorally impaired and had more executive dysfunction. Patients with cognitive impairment or frontotemporal dementia had a poorer prognosis than motor neuron disease patients with normal cognition.
Little is known about cognitive impairment in Chinese patients with amyotrophic lateral sclerosis. One hundred and six Chinese patients from Beijing with sporadic amyotrophic lateral sclerosis were studied neuropsychologically and were classified into 4 groups: amyotrophic lateral sclerosis with normal cognition (approximately 80%), amyotrophic lateral sclerosis with executive cognitive impairment (approximately 11%), amyotrophic lateral sclerosis with nonexecutive cognitive impairment (approximately 5%), and amyotrophic lateral sclerosis with frontotemporal lobe degeneration (approximately 5%) (25). Executive cognitive impairment was greater in the nondemented amyotrophic lateral sclerosis groups than in healthy controls. Amyotrophic lateral sclerosis-frontotemporal dementia had more severe bulbar dysfunction.
A systematic review and metaanalysis suggested that cognitive impairment was found in about 30% of people with amyotrophic lateral sclerosis (11) – when present adversely affecting prognosis. Forty-four studies including 1287 patients and 1130 controls were studied and revealed that all cognitive domains except visuospatial functions showed impairment without motor impairment bias: fluency, language, social cognition, delayed verbal memory, and executive functions. In this study, diverging effect sizes could be explained with impairment bias. In this study, bulbar disease and mood state did not affect the results. The cognitive profile, on the basis of this analysis, suggests fluency, language, social cognition, executive function, and verbal memory compose the variable cognitive profile in nondemented amyotrophic lateral sclerosis subjects. The findings in relation to social cognition accentuate the relationship between frontal lobe dysfunction, frontotemporal lobe degeneration, and amyotrophic lateral sclerosis. This study emphasizes the importance of correcting for motor impairment when performing neuropsychological tests on patients with amyotrophic lateral sclerosis.
Dementia associated with amyotrophic lateral sclerosis. The pattern of dementia in cases of sporadic amyotrophic lateral sclerosis resembles frontotemporal dementia (105). In many cases, the behavioral alterations dominate over motor signs as a clinical feature. Dementia does not necessarily predate the onset of motor signs, but dementia sometimes precedes motor signs by several months to years (20; 77). Some patients develop dysarthria and dysphagia prior to the onset of dementia, and the incidence of dementia in the subgroup of patients with bulbar onset is particularly high (90).
Changes in personality and comportment are seen. Patients may display emotional disinhibition, lack of concern, apathy, and impulsiveness (109; 77; 48). Emotional lability was reported even in early cases (122), although this may in some instances be referable to a pseudobulbar state due to bilateral corticobulbar lesions rather than psychological dysfunction (72). Depression is common and is typically more severe than in age-matched controls (62). Neuropsychological testing demonstrates severe attention deficits and impaired judgment and insight (72; 85). Language presentations are variable (109; 110), and current consensus guidelines (102) suggest categorization of language impairment according to the Neary classification of progressive non-fluent aphasia and semantic dementia (76).
Progression of cognitive deficits does not correlate with the motor function decline (62). End-stage patients are mute and in a locked-in-like state, and it is difficult to determine their cognitive status; studies using event-related brain potentials demonstrated a variety of responses, from probably normal responses to no responses, consistent with severe cortical dysfunction (63). Visuospatial function and calculation are relatively preserved until late in the course of the illness but may be difficult to test if the patient's frontal dysexecutive function is prohibitive. Strong and colleagues prospectively studied cognitive decline in 8 amyotrophic lateral sclerosis patients (104); after 6 months, patients developed at least mild new deficits in oral and written word fluency, recognition memory for faces but not verbal material, and visual perception. Patients with bulbar amyotrophic lateral sclerosis declined more quickly with severe deficits in working and episodic memory, cognitive flexibility, and visuospatial processing within the 6-month period, paralleling the more rapid physical decline seen in these patients relative to non-bulbar amyotrophic lateral sclerosis. The cognitive changes could not be linked to depression in this study, although the patients developed other neuropsychiatric symptoms, such as agitation, anxiety, delusions, disinhibition, apathy, and irritability during the 6-month interval.
According to guidelines (102), patients with amyotrophic lateral sclerosis and associated dementia should be classified according to the following schema:
(1) Patients meeting either the Neary criteria (76) or Hodge’s criteria (48) for frontotemporal dementia shall be diagnosed ALS-FTD.
(2) Patients meeting criteria for dementia not typical of a frontotemporal lobar degeneration shall be diagnosed with ALS-dementia (ie, ALS-Alzheimer disease, ALS-vascular dementia, ALS-mixed dementia).
Amyotrophic lateral sclerosis is a clinical syndrome with a diverse phenotype involving motor and frontal neocortical neurons and implies molecular mechanisms propagating through the motor-frontal network (118; 44).
In 2017 the Strong diagnostic criteria were revised on the basis of an international workshop held in London, Canada in 2015. On the basis of increasing delineation of the neuropsychology of amyotrophic lateral sclerosis, it has become clear that there exists a panorama of neuropsychological observations with combinations of findings that might be discerned in about 50% of people with amyotrophic lateral sclerosis – this evidence of cognitive involvement deleteriously affecting survival. This new consensus proposes the notion of frontotemporal spectrum disorder of amyotrophic lateral sclerosis (ALS-FTLD) (101). This clinical heterogeneity is consistent with intricate molecular and stochastic processes affecting prion-like propagation, autophagy, vesicle trafficking, and RNA metabolism within the frontal-motor network (116; 38; Panegyres 2019).
Familial amyotrophic lateral sclerosis. Familial cases of amyotrophic lateral sclerosis demonstrate a similar clinical picture when dementia is involved, except that the dementia most often follows the onset of amyotrophic lateral sclerosis symptoms. Dementia has been reported in cases of juvenile familial amyotrophic lateral sclerosis where patients have survived into their third decade of life (82). However, it is unknown whether these patients have mutations in alsin or represent a separate genetic type of juvenile amyotrophic lateral sclerosis (46; 121).
Previous guidelines suggest that patients with familial amyotrophic lateral sclerosis and associated cognitive or behavioral changes or dementia should be classified according to the previously detailed schema, with the proviso that the familial component of the amyotrophic lateral sclerosis has confirmed genetic linkage or clinical evidence of autosomal dominant, autosomal recessive, or X-linked dominant inheritance pattern (102).
Motor neuron disease-like variant of frontotemporal dementia. Along with clinical features of frontotemporal dementia (disinhibition, change in mood or personality, loss of personal and social awareness, mental rigidity, hyperorality, stereotyped behaviors, impulsivity, reduction and stereotypy of speech, echolalia, late mutism, etc.), patients with associated motor neuron disease have earlier age at onset than is seen in other frontotemporal dementias and may exhibit both upper and lower motor neuron signs (49; 77).
According to guidelines (102), the entity FTD-MND-like will remain a neuropathological diagnosis in which the characteristic findings are those of frontotemporal lobar degeneration with associated evidence of motor neuron degeneration insufficient to be classified as amyotrophic lateral sclerosis.
All cases will end fatally, usually due to the natural course of the motor neuron disorder. Infectious complications are always likely. Supportive care is in order but differs according to the wishes of the patient and family. Recognizing the presence of a frontotemporal cognitive or behavioral syndrome in amyotrophic lateral sclerosis is prognostically important as it is a predictor of shorter survival time (81; 93; 32). Patients presenting with language variants rather than behavioral features may be more likely to have bulbar-onset, which portends a poorer prognosis (22).
A 74-year-old, right-handed woman with 7 years of education had initial symptoms of dysphonia, dysphagia, increasing respiratory difficulties, and fatigue. On neuropsychological evaluation 5 months into her illness, her affect was apathetic and restricted. She had little insight into her cognitive impairments. Speech was hypophonic, dysarthric, and non-fluent. Her responses were bradyphrenic and bradykinetic. Her assessment revealed mild to moderate impairment in most cognitive areas including:
• Orientation – oriented only to person, age, and year.
The patient died 1 year into the course of her illness. Autopsy of the brain and spinal cord confirmed the clinical diagnosis of amyotrophic lateral sclerosis. There was anterior horn motor neuron loss, accompanied by astrocytic proliferation and axonal swelling. Ubiquitin stains revealed rare dense cytoplasmic rounded granular inclusions. Extensive spongiosis and widespread tau immunoreactive glial cells were observed in the frontal lobes. Further neuronal loss appeared in the substantia nigra, periaqueductal grey, mamillary bodies, midline thalamic nuclei, and the hippocampal subiculum. Only rare neurofibrillary tangles and neuritic plaques were located. [Case courtesy of Strong and colleagues (103).]
The cause of cognitive and behavioral changes as well as dementia associated with amyotrophic lateral sclerosis is variable and related to genetic predispositions and the identified neuropathological substrates to be discussed further in the pathogenesis and pathophysiology section of this article. Although amyotrophic lateral sclerosis may co-exist with well-defined dementing illnesses such as Alzheimer disease, it does not in most instances appear to have linkage. At present, the majority of the cognitive and behavioral changes demonstrated by patients with amyotrophic lateral sclerosis are considered to be referable to the accumulation of TDP-43 neuropathology (39) or the abnormal accumulation of tau in a smaller but well-defined subset of patients (117).
Genetics. Genetic studies of patients with amyotrophic lateral sclerosis and dementia may provide an insight into the pathogenesis and pathophysiology of both the cognitive deficits and motor neuron degeneration. Amyotrophic lateral sclerosis is genetically heterogeneous, and several loci for autosomal dominant and recessive amyotrophic lateral sclerosis have been identified (67). Previously reported as the most common type of familial amyotrophic lateral sclerosis, mutations in the copper-zinc superoxide dismutase (SOD1) gene on chromosome 21 may be associated with a cognitive and behavioral syndrome characterized by apathy, anxiety, inattention, reduced verbal fluency, and hypersexuality (95; 69; 08).
The linkage to a locus on chromosome 17q21, which was later shown to be associated with frontotemporal dementia, was discovered in a pedigree whose phenotype was classified as disinhibition-dementia-parkinsonism-amyotrophy complex (117). Mutations in the microtubule associated protein tau gene have been later discovered as a cause of this type of dementia-amyotrophic lateral sclerosis complex (54; 89). Single cases of dementia in families with amyotrophic lateral sclerosis and mutations in ANG/VEGF on chromosome 14q11 (102) and VAPB on chromosome 20q13.33 have also been reported and require further study (79). A mutation in CHMP2B was initially described in a Danish cohort with autosomal dominant frontotemporal dementia and has subsequently been identified in patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis with frontotemporal dementia; the mutation may be associated with as much as 10% of lower motor neuron-predominant amyotrophic lateral sclerosis (23). Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, have also been reported to cause dominantly inherited, chromosome-X-linked amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/dementia. Novel ubiquilin 2 pathology in the spinal cords of amyotrophic lateral sclerosis cases and in the brains of amyotrophic lateral sclerosis dementia cases with or without UBQLN2 mutations has also been reported in association with this genetic discovery. Ubiquilin 2 is known to regulate the degradation of ubiquitinated proteins and preliminary work suggests that mutations in UBQLN2 lead to an impairment of protein degradation (28).
Additional loci on chromosome 9q21-q22 (51) and 9p13.2-21.3 (74) were initially identified in families with overlapping motor neuron disease and frontotemporal dementia, and the chromosome 9p linkage was confirmed by a genome-wide association replication study of patients with frontotemporal lobar degeneration and frontotemporal lobar degeneration and amyotrophic lateral sclerosis in 2 British cohorts (94). The discovery of the critical gene change as an expanded sequence of hexanucleotide repeats in C9orf72 was subsequently reported independently by 2 international research groups (27; 91). The genetic change affects a region outside of the normal protein coding portion of the gene and affects the non-coding RNA. Unaffected individuals may carry up to 30 DNA repeats in the gene, whereas affected patients with motor neuron disease or frontotemporal dementia may carry hundreds of repeats. Scientists have discovered that this genetic mutation may account for up to 12% of familial frontotemporal dementia, and as much as 22% of familial motor neuron disease, rendering the C9orf72 gene the most common genetic cause of both frontotemporal dementia and motor neuron disease identified to date. Clinically, motor neuron disease progression may be slower (97) and psychiatric symptoms may be more common in this genetic cohort of families presenting with frontotemporal dementia and amyotrophic lateral sclerosis (98). The role of the protein C9orf72 within neurons of the brain and spinal cord is not currently known and the mechanism of pathogenesis remains to be determined. Preliminary work with induced pluripotent stem cells suggests that compromised autophagy function may be involved (05).
Remarkably, although mutations in the TARDBP gene on chromosome 1p36.2 have been identified in patients with amyotrophic lateral sclerosis and the characteristically associated neuropathological inclusions representing the abnormal accumulation of TDP-43 have been identified in both amyotrophic lateral sclerosis and frontotemporal lobar degeneration, to date very few cognitive or behavioral phenotypes have emerged in patients with this genetic mutation (21). Conversely, although mutations in the PRGN gene on chromosome 17q.21.23 have been observed to account for as many as 5% of familial cases of frontotemporal dementia resulting in abnormal TDP-43 neuropathological inclusions, only a few pedigrees reported to date have overlapping motor neuron disease phenotypes (96; 100). Mutations in the FUS gene, an RNA-processing gene linked to chromosome 16q12 and functionally related to TDP-43, have been reported in approximately 3% of familial amyotrophic lateral sclerosis patients, with at least 2 cases presenting with frontotemporal dementia features (13; 17). Further highlighting the evolving, complicated pathological and genetic relationship between frontotemporal lobar degeneration and amyotrophic lateral sclerosis, FUS pathological inclusions have been reported in frontotemporal lobar degeneration to account for many of cases that were previously considered ubiquitin positive, TDP-43 and tau negative, but such cases have not been associated with FUS gene mutations (99).
There is a clinical and genetic spectrum of amyotrophic lateral sclerosis-frontotemporal dementia (07; 29; 19), mutations associated with amyotrophic lateral sclerosis-frontotemporal dementia (TBK1, C9orf72, TARDBP, FUS, CCNF, VCP, UBQLN2, CHCHDIO, SQSTM2), mutations with frontotemporal dementia (CHM2B, PGRN, MAPT), and those with amyotrophic lateral sclerosis only (SOD1, OPTN, PFN1) (09; 24; 55; 40). This array of genetic mutations implicates molecular mechanism involving protein homeostasis, the functions of RNA binding proteins, cytoskeletal kinetics, and the autophagy/lysomal machinery (47; 40).
The C9orf72 repeat expansion is the most frequent genetic cause of familial amyotrophic lateral sclerosis-frontotemporal dementia and a number of families have been reported in which mutations in other genes coexist in the same family, resulting in the concept of the oligogenic hypothesis where mutated alleles of causative, at-risk, and modifier genes give rise to disease (64). Giannoccaro and colleagues identified the p.V47A variant in the TYROBP gene in amyotrophic lateral sclerosis-frontotemporal dementia as well as other genetic variants: in their study if patients carried a double mutation there was an earlier age of onset, more likely to be a family history, and parkinsonism was more prevalent (41). In another study these authors described a pathogenic variant in the ITM2B gene associated with amyotrophic lateral sclerosis-frontotemporal dementia plus movement disorder, psychiatric problems, cognitive dysfunction, deafness, and optic atrophy (42). An intermediate length expansion has been identified in the ataxin 2 gene (ATXN2 polyQ) and an optineurin point mutation (OPTN p.Met 468 Arg) in 2 different families with amyotrophic lateral sclerosis-frontotemporal dementia and the C9orf72 hexanucleotide repeat expansion, providing further evidence that oligogenic inheritance may influence the phenotypic expression of C9orf72 (34).
Neuropathology. Aside from cases revealing pathological markers for Alzheimer disease, Creutzfeldt-Jakob disease, or Pick disease, patients with dementia associated with amyotrophic lateral sclerosis show gross frontal and temporal lobe atrophy. On closer inspection, neuronal cell loss in frontal and temporal cortex is more extensive than the usual depletion of Betz cells observed in amyotrophic lateral sclerosis without dementia (50; 35; 68; 86). In autopsied cases of familial amyotrophic lateral sclerosis, a pattern of predominantly frontotemporal neuronal degeneration, status spongiosis, and gliosis similar to dementia associated with sporadic amyotrophic lateral sclerosis is observed (52). Familial cases also show ubiquitin-positive inclusions in the temporal and frontal lobes (75; 58).
Affected areas show dropout of interneurons that immunolabel with calbindin D-28k but not those that label with parvalbumin (36); calbindin D-28k interneurons predominate in upper cortical layers, whereas parvalbumin interneurons are featured in deeper cortical layers. Because these studies did not compare demented to nondemented amyotrophic lateral sclerosis patients, it is not clear how much of a role the interneurons play in the dementing aspect of the syndrome. Their position in the superficial layers II and III of cortex may reflect damage to neuronal dendritic processes (86). Furthermore, cortical lesions are more prominent at the crests of gyri than in sulci (57). When compared with nondemented patients, the loss of the Betz cells in the primary motor cortex appears to be more severe in amyotrophic lateral sclerosis patients who are demented (111).
In 2006, TDP-43 (TAR DNA Binding Protein 43), a nuclear protein encoded by the TARDBP gene on chromosome 1, was identified as a major disease protein in amyotrophic lateral sclerosis as well as frontotemporal lobar degeneration with ubiquitinated inclusions and frontotemporal dementia with motor neuron disease (78), highlighting the potential for a common pathogenesis for these disorders, which may have considerable clinical overlap. In the majority of cases the TDP-43 protein co-localizes to inclusions previously identified with ubiquitin immunoreactivity (39). Evidence suggests that TDP-43 plays an essential role in dendritic branching, such that diminished neuronal connectivity may precede neuronal loss in TDP-43-associated amyotrophic lateral sclerosis and frontotemporal dementia (66).
The emotional disturbances seen in the dementia syndrome associated with amyotrophic lateral sclerosis focus interest on pathological changes in the limbic system. The basolateral nucleus of the amygdala; subiculum; nucleus accumbens; dorsomedial cortex of the anterior temporal horns; anterior cingulate; and orbital and insular gyri show degenerative changes in demented amyotrophic lateral sclerosis patients (57).
Degeneration of the substantia nigra is common in frontal lobe dementia cases and may be a marker for dementing cases of amyotrophic lateral sclerosis (50; 43; 68). The nucleus basalis of Meynert, locus ceruleus, and dorsal raphe appear unaffected (50; 68). Neurochemical investigations have disclosed no significant alterations in the major brain neurotransmitters, except for reductions in dopamine in the corpus striatum and substantia nigra in a case of amyotrophy-dementia with parkinsonism (43). Cholinergic activity, especially in the nucleus basalis, has been normal in several studies (50; 43).
MR spectroscopy has shown reduction of the N-acetylaspartate and creatine ratio in nondominant precentral motor gyrus in patients with amyotrophic lateral sclerosis, but there has been no clear correlation between this change and the degree of cognitive decline observed clinically (104).
More recent studies have emphasized the importance of clinical and pathological correlations of the dementias, including amyotrophic lateral sclerosis-frontotemporal dementia and the significance of proteomics, protein misfolding, and aggregation both in histopathological definition and molecular pathophysiology (31; 112). In patients with the linguistic presentation of nonfluent primary progressive aphasia and the semantic variant, 12% of these 139 primary progressive aphasia patients had amyotrophic lateral sclerosis – emphasizing that evidence of amyotrophic lateral sclerosis should be screened for in primary progressive aphasia; all of the primary progressive aphasia-amyotrophic lateral sclerosis patients had TDP pathology and half had mutations in recognized frontotemporal dementia/amyotrophic lateral sclerosis genes (107).
A fundamental problem remains that the majority of amyotrophic lateral sclerosis-frontotemporal dementia patients are sporadic and nongenetic, suggesting a role of stochastic processes involving DNA, RNA, and proteins in their pathogenesis (Panegyres 2019).
Estimates of the prevalence of dementia in amyotrophic lateral sclerosis range from 15% to 40% (65; 92), with a wider range of estimates, from 10% to 75%, for cognitive or behavioral impairments not meeting criteria for the diagnosis of dementia (88; 37). Historical estimates placed the frequency of dementia at 1% to 2% in sporadic amyotrophic lateral sclerosis (72; 85) and higher (15%) for familial amyotrophic lateral sclerosis (52).
Investigators are still debating whether dementia associated with amyotrophic lateral sclerosis is the equivalent of the motor neuron disease variant of frontotemporal dementia (76; 77). However, there is emerging evidence for the overlap of these 2 entities (12) based on convergence of clinical, neuropathological, and genetic evidence suggesting a continuum model of the diseases (39). Most investigators agree that the order of appearance (neurologic changes before cognitive impairment or vice versa) do not preclude classification of the dementia associated with amyotrophic lateral sclerosis as a frontotemporal dementia syndrome.
Until the pathogenesis and pathophysiology of these disorders are fully ascertained, there can be no definitive comments about prevention.
Once the molecular mechanisms have been elucidated it may be possible to use new technologies such as CRISPR and preimplantation genetic diagnoses to eradicate amyotrophic lateral sclerosis-frontotemporal dementia and other neurodegenerative conditions (115).
The differential diagnosis may include a dementia specifically resulting from neuropathological changes associated with amyotrophic lateral sclerosis or the co-occurrence of amyotrophic lateral sclerosis and another dementing illness. It may be difficult to distinguish the etiology of the dementia until one can make a pathologic diagnosis from brain biopsy or autopsy. Postmortem studies on patients with dementia associated with amyotrophic lateral sclerosis commonly reveal concomitant frontotemporal lobar degeneration, and less commonly Alzheimer disease, Creutzfeldt-Jakob disease, or Pick disease. Dementia has been reported rarely in spinal muscular atrophy (33).
Similar clinical dementia syndromes can be found with non-amyotrophic lateral sclerosis motor neuron disorders. Motor neuron involvement has been recognized in postencephalitic states and in forms of Creutzfeldt-Jakob disease. An association of these symptoms with pantothenate kinase-associated neurodegeneration has also been recognized (14; 84).
In obvious cases where there is ample evidence of both motor neuron involvement and cognitive or behavioral changes, both EMG and neurobehavioral screening evaluations will serve to confirm the joint presence of these deficits. Neurobehavioral screening should be performed on all patients diagnosed with amyotrophic lateral sclerosis and should always include tests of executive functioning. Current consensus recommendations (102) suggest that a screening assessment be completed that includes a measure of verbal fluency and a neurobehavioral assessment measure. The MMSE, a standard cognitive screening instrument, is not recommended. Diagnoses of ALSbi and ALS-FTD are permitted without a formal neuropsychological testing battery; however, more detailed neuropsychological testing is recommended in all cases with an abnormal brief screening exam and required when ALSci or ALS-dementia are diagnostic considerations. Premorbid level of function and deficits referable to motor symptomatology should be considered when interpreting neuropsychological test scores. In cases of frontotemporal dementia without evidence of motor neuron dysfunction (fasciculations, altered deep tendon reflexes, etc.), it may be useful to perform EMG testing for evidence of subclinical disease.
Although neuroimaging in both structural and functional modalities is promising with regard to reflection of early cognitive and behavioral abnormalities in patients with amyotrophic lateral sclerosis, they are currently deemed not yet suitable for clinical use as predictive tools (102). Structural neuroimaging studies on patients with amyotrophic lateral sclerosis reveal frontotemporal atrophy in patients with and without dementia (56; 61; 01). Unfortunately, in clinical practice, the rapidity of the progression of the illness may preclude identification of specific structural neuroimaging changes. In a more recent longitudinal study of 4 patients with ALS-FTD, there was a 1% annual rate of atrophy in the premotor, motor, and anterior parietal cortices compared to a 0.25% annual atrophy rate in the same regions in age-matched controls, suggesting that normalized methods of regional comparison may prove useful in detecting subtle atrophy previously attributed to individual variability (06).
In the realm of functional neuroimaging, PET scans from demented patients with amyotrophic lateral sclerosis identify a significant worsening of regional cerebral blood flow in bilateral frontal cortices, right temporal cortex, and bilateral cerebellar hemispheres, exceeding the reductions detected in nondemented patients with amyotrophic lateral sclerosis (109; 10). SPECT studies tend to correlate well with this pattern of dementia. Reduced isotope uptake in the frontal areas is consistently seen in those amyotrophic lateral sclerosis patients with dementia, whereas nondemented patients had only reduced uptake in the motor cortices (01; 108). Similar patterns of reduced uptake are demonstrated in patients with ALS-FTD and FTD compared to controls, involving the frontal, temporal, cingulate, and insular cortices, and supporting the continuum model of the 2 illnesses (45).
In the appropriate clinical or research setting, genetic counseling and commercially available genetic testing may be offered if there is a compelling family history of either amyotrophic lateral sclerosis or frontotemporal dementias, using World Federation of Neurology guidelines (115).
Current American Academy of Neurology guidelines for the standard of care in amyotrophic lateral sclerosis cite riluzole as "the only treatment that has been shown to prolong survival in amyotrophic lateral sclerosis" and recommend its administration as early in the course of illness as possible (71), but data from studies on amyotrophic lateral sclerosis focus on motor deterioration and time to respiratory failure instead of prevention or stabilization of dementia.
Other agents approved or under investigation for treating amyotrophic lateral sclerosis include glutamate antagonists, neurotrophic factors, protease inhibitors, and antioxidants.
In patients with frontotemporal dementia, selective serotonergic reuptake inhibitors such as sertraline HCl and paroxetine have shown efficacy for controlling agitation, mood disorders, and obsessive-compulsive behaviors (106; 04). Open-label trials of the NMDA-receptor antagonist memantine have demonstrated variable results in treating the behavioral symptoms of frontotemporal dementia (15; 30). Randomized, controlled clinical trials have failed to demonstrate a benefit of memantine in frontotemporal dementia (113; 16). Similar treatment strategies might be useful for dementia associated with amyotrophic lateral sclerosis, but the heterogeneous etiologies of this syndrome should dictate pharmacological trials. Therapies targeting the accumulation of TDP-43 are in the preclinical phase along with the development of appropriate animal models (114).
A patient with concomitant Alzheimer disease and amyotrophic lateral sclerosis might respond better to a cholinesterase inhibitor such as donepezil than to a selective serotonergic reuptake inhibitor, although cholinesterase inhibition has not been successful in treating patients with frontotemporal dementia (60). The cholinesterase inhibitor donepezil increased frontal behaviors in a small group of patients (70) whereas rivastigmine showed some benefit (73). However, larger more rigorous studies are required to investigate the role of neurotransmitter modulation in frontotemporal dementia (53). In general, treatment for both the motor deterioration and the dementia associated with amyotrophic lateral sclerosis is symptomatic.
Peter K Panegyres MD PhD
Dr. Panegyres, Director of Neurodegenerative Disorders Research, has no relevant financial relationships to disclose.See Profile
Howard S Kirshner MD
Dr. Kirshner of Vanderbilt University School of Medicine received fees from Biogen for consulting work.See Profile
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