Dementia associated with amyotrophic lateral sclerosis …

Peter K Panegyres MD PhD PhD FRACP

Neurobehavioral & Cognitive Disorders

Updated 08.11.2024
Released 07.20.1994
Expires For CME 08.11.2027

Dementia associated with amyotrophic lateral sclerosis

Author: Peter K Panegyres MD PhD PhD FRACP

See Contributor Disclosures

Editor: Howard S Kirshner MD

Dementia associated with amyotrophic lateral sclerosis

In This Article

Quick Link

Introduction

Overview

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.

Key points

	• 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.

Historical note and terminology

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 (33). 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 (165). Although many names have been applied to this condition (78), 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 (30; 77), 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 (162).

Clinical manifestations

Presentation and course

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 (100) and are recommended for use in either the oral or written formats (04; 182; 183) 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 (41) or the Frontal Behavioral Inventory (91) 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 (03).

According to guidelines (162), 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 (118) or Hodge’s criteria (76) 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 (137). 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 (124). 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%) (40). Executive cognitive impairment was greater in the nondemented amyotrophic lateral sclerosis groups than in healthy controls. ALS-FTD 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 (20) – 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 (165). 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 (33; 119). 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 (141).

Changes in personality and comportment are seen. Patients may display emotional disinhibition, lack of concern, apathy, and impulsiveness (170; 119; 76). Emotional lability was reported even in early cases (186), although this may in some instances be referable to a pseudobulbar state due to bilateral corticobulbar lesions rather than psychological dysfunction (114). Pseudobulbar affect with pathological laughter and crying may be seen. This phenomenon is most likely due to pathology involving the cerebro-ponto-cerebellar pathways and is a disinhibition or release effect. This distressing syndrome might respond to a combination of dextromethorphan/quinidine (Nuedexta) and selective serotonin reuptake inhibitors. Depression is common and is typically more severe than in age-matched controls (94). Neuropsychological testing demonstrates severe attention deficits and impaired judgment and insight (114; 134). Language presentations are variable (170; 172), and current consensus guidelines (162) suggest categorization of language impairment according to the Neary classification of progressive non-fluent aphasia and semantic dementia (118).

Progression of cognitive deficits does not correlate with the motor function decline (94). 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 (98). 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 (164); 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 (162), patients with amyotrophic lateral sclerosis and associated dementia should be classified according to the following schema:

(1) Patients meeting either the Neary criteria (118) or Hodge’s criteria (76) 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 (181; 69).

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) (161). 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 (179; 58; 128; 129).

Cognitive differences have been emphasized in cognition and behavior between patients with behavioral variant frontotemporal dementia, frontotemporal amyotrophic lateral sclerosis patients, and those with C9orf72 (151).

CSF neurofilament light (NfL) may predict disease progression in amyotrophic lateral sclerosis and, therefore, in amyotrophic lateral sclerosis frontotemporal dementia (48). Motor cortical excitability might predict cognitive phenotypes in amyotrophic lateral sclerosis (06). NfL, a marker of axonal pathology, shows that NfL is increased in amyotrophic lateral sclerosis and most of the other neurodegenerative diseases, elevation in neurofilament light correlated with disease progression, and a poorer prognosis, and studies suggest that long-term kinetics in blood might help in monitoring the gene mutations and the natural history of ALS-FTD (176).

In 3-Tesla MRI scanning, changes in cortical thickness and increased cortical diffusivity may be a biomarker of extra-motor cortical neurodegeneration in ALS-FTD (84). The studies of Hakkinen and colleagues support selective patterns of atrophy in genetic frontotemporal dementia and amyotrophic lateral sclerosis (74).

A metaanalysis showed that frontal, medial, and caudate circuits in behavioral and frontotemporal dementia are also found in amyotrophic lateral sclerosis patients without dementia, the grey matter particularly involving the frontal limbic circuitry, the anterior insula, and anterior cingulate regions (104). Intrusion errors may occur during verbal fluency tasks in patients with amyotrophic lateral sclerosis, suggesting this may be a marker of cognitive change (136).

In patients with amyotrophic lateral sclerosis, 7 Tesla fMRI reveals changes in long-range functional connectivity between the superior sensory and motor cortex, the precentral gyrus, and the bilateral cerebellar lobule VI. This is of interest as cerebellar lobule VI is a transition zone between anterior motor networks and the posterior nonmotor networks in the cerebellum, cerebellar lobule VI having function in complex motor and cognitive processing tasks (15).

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 (126). However, it is unknown whether these patients have mutations in alsin or represent a separate genetic type of juvenile amyotrophic lateral sclerosis (73; 184).

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 (162).

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 (77; 119).

According to guidelines (162), 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.

ALS-FTD may represent a disease spectrum. By utilizing mathematical modelling of MRI connectomic information, disordered frontotemporal and parietal networks, and focal structural damage within the sensorimotor-basal ganglia may be seen (36).

The cognitive profiles of amyotrophic lateral sclerosis patients differ in functional connectivity measured in the resting state, depending on the clinical presentation of predominantly motor involvement versus cognitive shifting (171).

Prognosis and complications

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 (125; 146; 50). Patients presenting with language variants rather than behavioral features may be more likely to have bulbar-onset, which portends a poorer prognosis (37).

Retrospective analysis of 625 patients revealed that a poor prognosis was associated with amyotrophic lateral sclerosis and frontotemporal dementia versus amyotrophic lateral sclerosis, shorter time to diagnosis and higher age at symptom onset with rapid decline for a person with a high amyotrophic lateral sclerosis functional rating scale sum score, and if the individual has chronic obstructive pulmonary disease (144).

The Edinburgh Cognitive and Behavioral ALS Screen was found to be useful to determine if patients with amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia were portending a poorer prognosis (19; 185).

Studies of the clinical heterogeneity of ALS-FTD indicate those with amyotrophic lateral sclerosis have predominant frontoparietal involvement, whereas those with ALS-FTD behavioral variant frontotemporal dementia have more frontal, cingulate, amygdala, insula, thalamic, hippocampal, and temporal lobe involvement, suggesting there are distinct atrophic profiles across the ALS-FTD spectrum with more involvement of the motor cortex and insula in those with ALS-FTD. Cortical involvement might explain the origin of some of the behavioral difficulties (07). Pathological expansion in the C9orf72 gene is associated with accelerated decline of respiratory function and reduced survival in amyotrophic lateral sclerosis (112).

Clinical vignette

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.
• Memory – a retrieval deficit on a simplified multiple trial of 10 pictures of objects (ie, patients had failure of retrieval of information and not encoding).
• Attention and information processing speed.
• Executive skills, as tested with the Trail Making Test, Part B; Neurobehavioral Cognitive Status Examination similarities and judgment subtests; phonemic fluency was more affected than semantic fluency.
• Visuospatial ability – poor clock drawing and block design.
• Language – anomia, impaired repetition and comprehension.

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 (163).]

Clinical diagnosis and management remains challenging (109).

Biological basis

Etiology and pathogenesis

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 (62) or the abnormal accumulation of tau in a smaller but well-defined subset of patients (180).

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 (105). 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 (150; 108; 16).

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 (180). Mutations in the microtubule associated protein tau gene have been later discovered as a cause of this type of dementia-amyotrophic lateral sclerosis complex (83; 140). Single cases of dementia in families with amyotrophic lateral sclerosis and mutations in ANG/VEGF on chromosome 14q11 (162) and VAPB on chromosome 20q13.33 have also been reported and require further study (121). 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 (38). 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 (43).

Additional loci on chromosome 9q21-q22 (79) and 9p13.2-21.3 (116) 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 (149). 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 (42; 143). 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 (154) and psychiatric symptoms may be more common in this genetic cohort of families presenting with frontotemporal dementia and amyotrophic lateral sclerosis (157). 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 (10).

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 (35). 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 (153; 159). 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 (24; 29). 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 (158).

There is a clinical and genetic spectrum of amyotrophic lateral sclerosis-frontotemporal dementia (14; 44; 31), 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) (17; 39; 86; 63). This array of genetic mutations implicates molecular mechanism involving protein homeostasis, the functions of RNA binding proteins, cytoskeletal kinetics, and the autophagy/lysomal machinery (75; 63).

The known genes causing frontotemporal dementia/motor neurone disease are listed in Table 1 along with their functions: autophagy, vesicular trafficking, RNA metabolism, mitochondrial function, apoptosis, ubiquitination, mitophagy, innate immunity, transcription, chaperone protein, microtubule function, cytoskeletal integrity, axonal transport, and stress granule formation. The frequencies of these gene mutations in populations of ALS-FTD patients is unknown, but C9orf72, TD4-43, and FUS are the most common, and other gene mutations are not (05; 70).

The C9orf72 hexanucleotide repeat expansion in Exon 1 is the most common cause of ALS-FTD and is not detected by Sanger sequencing. This DNA expansion is first searched for; if not detected, next generation sequencing on ALS-FTD panel is performed.

Table 1. Genes causing ALS + FTD and their functions

Gene	Name	Functions
C9orf72	Chromosome 9 open reading frame 72	Autophagy/vesicular trafficking
TDP-43	TAR DNA-binding Protein 43	RNA metabolism
FUS	Fused in Sarcoma	RNA metabolism
CHCHD10	Coiled-coil-helix-coiled-coil-helix Domain containing protein 10	Mitochondrial metabolism Apoptosis
UBQLN2	Ubiquilin 2	Ubiquitin-proteosome system Autophagy
TBK1	Tank-Binding Kinase 1	Autophagy Mitophagy Innate immune signalling
VCP	Valosin Containing Peptide	Ubiquitin binding
SQSTM1	Sequestosome 1	Apoptosis Autophagy Transcription regulation
CYLD	Cytochrome Lysine 63 Deubiquitinase	Autophagosome
SIGMAR1	SIGMA-1 receptor	Chaperone protein
TUBA4A	Tubulin Alpha 4A microtubule protein	Microtubule protein Cytoskeleton integrity Axonal transport
TIA1	T-cell Intracellular Antigen 1 binding protein	RNA binding protein Stress granule formation
CCNF	Cyclin F, member FBOX proteins	Ubiquitin proteosomal pathway

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 (99). 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 (65). 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 (66). 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 (54).

A large Australian family with frontotemporal dementia-motor neurone disease was shown to have the cytochrome lysine 63 deubiquitinase (CYLD) gene mutation as the cause (47); there was increased glial cytochrome CYLD immunoreactivity. Mice expressing this mutation also increased cytoplasmic localization of TDP-43 and shortened axons. In vitro studies reveal inhibition of NF-kB cell single transition molecule resulting in reduced phagosome fusion to lysosomes, a key process in autophagy. That is, this mutation leads to a loss of autophagosome function resulting in protein accumulation and cellular dysfunction. CYLD interacts with 3 other genes and proteins important in autophagosome function TBK1, optineurin, and sequestosome-1. This contributes to impaired autophagy and neurodegeneration. CYLD is a protease that removes ubiquitin from proteins and, therefore, regulates protein activity and functions as a tumor suppressor gene. CYLD mutation has also been identified in Chinese populations (71). A rare mutation in the cytoplasmic dynein 1 heavy chain gene has been associated with ALS-FTD (111) and is an endoplasmic reticulum ATPase—an ATPase associated with diverse cellular activities, with functions in ubiquitination and protein degradation, autophagy, lysosome clearance, and mitochondrial quality control. Mutations in this gene lead to amyotrophic lateral sclerosis with TDP-43 mislocalization from the nucleus into the cytoplasm (152). Patients with SOD1 mutations have been shown to have increased metabolism in the motor cortex compared to sporadic amyotrophic lateral sclerosis, suggesting that there may be different mechanisms (32). Studies suggest that 30% of patients with ALS-FTD have genetic pathogenic mutations or variants (147).

Machine learning studies suggest polygenic risks factors contribute to cognitive function in amyotrophic lateral sclerosis and might be useful in frontotemporal dementia, in that cognitive decline and cortical thinning from motor neuronal loss might be related to polygenic risk score (138). The genetics of ALS-FTD show significant overlap (05; 142).

Neurophysiology. Physiological mechanisms operate in the pathophysiology of ALS-FTD. Studies of C9orf72 repeat expansion mutations in ALS-FTD indicate hyperexcitability, both increase in excitatory signals and reduced inhibition, synaptic vesicle disruption, impaired plasticity, morphological deficits, glutamate excitotoxicity, and reduced synaptic transition with general increased excitability of surrounding neuronal structures (132). Transmagnetic stimulation is the best technique to explore cortical hyperexcitability in ALS-FTD (61; 160).

Mechanisms of neurophysiological impairments in the cortex and lower motor neurons in C9ORF72RE amyotrophic lateral sclerosis

In humans, upper motor neurons (blue) descend from the motor cortex and project onto the brainstem and spinal cord via the corticospinal tract. These corticospinal neurons form a monosynaptic pathway (in primates and humans) th...

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 (78; 55; 106; 135). 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 (81). Familial cases also show ubiquitin-positive inclusions in the temporal and frontal lobes (117; 90).

Affected areas show dropout of interneurons that immunolabel with calbindin D-28k but not those that label with parvalbumin (56); 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 (135). Furthermore, cortical lesions are more prominent at the crests of gyri than in sulci (88). 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 (173).

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 (120), 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 (62). 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 (103).

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 (88).

Degeneration of the substantia nigra is common in frontal lobe dementia cases and may be a marker for dementing cases of amyotrophic lateral sclerosis (78; 67; 106). The nucleus basalis of Meynert, locus ceruleus, and dorsal raphe appear unaffected (78; 106). 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 (67). Cholinergic activity, especially in the nucleus basalis, has been normal in several studies (78; 67).

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 (164).

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 (49; 174). 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 (168).

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 (128; 129).

Chemical biology. Amyotrophic lateral sclerosis-frontotemporal dementia in many situations is unified by the loss of TDP-43 from the nucleus of neurons in the brain and spinal cord and its translocation into the cytoplasm. TDP-43 functions to repress inclusion of cryptic exons during RNA splicing. When TDP-43 is depleted, this function is lost. Cryptic splicing targets include STM2, UNC13A, and others (08). UNC13A is important in ALS-FTD as a risk factor. Gene variants make this gene more susceptible to cryptic exon inclusion. Cryptic splicing events suggest novel therapeutic targets for ALS-FTD. The study of ALS-FTD emphasized the importance of autophagy and RNA homeostasis (80). Autophagy is the multi-target removal of malfunctioning cellular components with many layers of regulation including protein degradation and RNA catabolism. ALS-FTD proteins are of importance in the clearance of stress granules. Genes such as TDP-43, sequestosome-1, optineurin, TBK-1, C9orf72, SMN, VCP, VAP, SPG11, CHMP2B, ALS2, Sigma-1, CCNF, GRN, and ubiquitin 2 are involved in the regulation of these mechanisms. DNA damage response and effective DNA protein repair is also considered one of the important mechanisms in frontotemporal dementia amyotrophic lateral sclerosis with the proteins involved in DNA damage and repair being affected in ALS-FTD such as TAR TDP-43, FUS, C9orf72, SOD1, SETX, VCP, CCNF, and NEK1 (96). The 4C2G expansion found in C9orf72 mutations gives rise to dipeptide repeat polypeptides (DPRs), which are neurotoxic. The dipeptide repeat polypeptides interfere with tethering of the endoplasmic reticulum to the mitochondria. This tethering is mediated by the VAPB-PTPIP51 tethering proteins, which the dipeptide repeat polypeptides disrupt. This disruption of the tethering gives rise to an increase in the glycogen synthase kinase beta gene, a negative regulator of VAPB-PTPIP51, which further impairs the endoplasmic reticulum and mitochondria tethering leading to neurodegeneration (68). Cyclophilin A known as a peptidylprolyl isomerase A (PPIA) is a foldase and molecular chaperone. PPIA knockout mice have neurodegeneration like frontotemporal dementia with TDP motor neurone changes. Reduction in PPIA leads to an increase in the GTP binding nucleoprotein RAN, and this causes mislocation of TDP-43. Therefore, reductions in PPIA affect TDP-43 autoregulation, decrease TDP-43 synaptic function, and impair synaptic plasticity; PPIA is reduced in patients with ALS-FTD (131). Inflammation is thought important in ALS-FTD as experiments with induced pluripotent stem cells (iPS) reveal that cytokines, chemokines, growth factors, and extracellular matrix molecules interfere with TDP-43 and other neuropathological processes in ALS-FTD (102). ALS-FTD both have evidence of chronic inflammation mediated by microglia and astrocytes. Immune signaling kinases have been shown to be abnormal in ALS-FTD including TBK-1, RIPK-1, 3, RAK1, and EPHA4; this led to clinical trials for immune kinase inhibitors in ALS-FTD (60). Protein synthesis modulation is a possible therapeutic intervention in ALS-FTD; therapies that restore protein imbalance, but not affect translation activity of cells is a desired goal. The mechanisms of protein folding and unfolding, accumulation, and mislocalization are shared between amyotrophic lateral sclerosis and frontotemporal dementia, with a complex interaction between the endoplasmic reticulum and elongation factors, which increase expression of chaperone proteins which, in turn, repress translation, to restore protein homeostasis, that is proteostasis. In ALS-FTD, and all neurodegenerative disorders, there is unbalanced protein overload; therefore, modulation of protein translation without affecting the normal translational activity of cells is a potential therapeutic approach. This therapy approach includes regulation of activation initiation of elongation factors, inhibition of unfolded protein response activation, and induced chaperone expression (see Table 2) (34).

Chemical biology in ALS-FTD

The interaction between dipeptide repeat polypeptides (DPRs), tethering of mitochondria to the endoplasmic reticulum by the VAPB-PTPIP51 tethering proteins, calcium and glycogen synthase beta gene (GSK-3b), resulting in impaire...

Table 2. Potential molecular mechanisms ALS-FTD

1. TDP 43 – cryptic exons – RNA splicing
2. Autophagy – RNA homeostasis
3. DNA damage response + defective DNA repair
4. 4C2G à DPR peptides
5. Cyclophilin (PPIA)
6. Neuroinflammation
7. Immune signalling kinases
8. Unbalanced protein overload
9. Impaired protein synthesis
10. miRNAs
11. DPR – gain of function
12. FUS ¯ protein transport Fragments Golgi/ER stress ¯ Golgi trafficking
13. Polyphenols
14. TDP inflammatory mechanisms
15. T cell activation
16. Parvalbumin interneuron loss
17. G3BP1 / mRNA stability - stress granules
18. Universal gene pathways
	• Innate immune genes • Cytoskeletal genes • RNA processing genes • Mitochondrial electron transfer genes
19. Stathmin 2 – TDP
20. Liquid-liquid phase separation

MicroRNAs (miRNAs) are single-stranded noncoding RNA less than 22 nucleotides in length. They recognize sequences in 3 prime untranslated regions of target mRNA and induce mRNA degradation or inhibit translation. miRNA dysregulation in neurodegenerative disease is known in Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, Huntington disease, frontotemporal dementia, macular degeneration, multiple sclerosis, and ALS-FTD. Expression of miRNAs depends on the diagnosis and the state of the disease. The most robust and microRNA markers in serum and CSF have been increased miR-233-3P and reductions in miR-15A-5P. These markers help to distinguish frontotemporal dementia from normal subjects. Cortical tissue mi132-3P in the frontal and temporal regions is helpful in distinguishing frontotemporal dementia from normal. Strong miRNA in behavioral variant frontotemporal dementia is found in blood serum and CSF including mi233-3P, mi22-3P, miR15A-5P, miR124, and CSF. These micro-MRI are thought important in neurodegeneration, and changes in TDP-43 and other mechanisms of the molecular cascade in amyotrophic lateral sclerosis/frontotemporal dementia interact through miRNAs to affect translation (107). Experimental models of C9orf72 mutations in Drosophila revealed reduced transcription, decreased function, and also gain of function with repetitive sense and antisense RNA, with the reduction of DPR polypeptides, which cause toxicity, with the gain-of-function affecting RNA molecules, and the DPR toxicity compromising endoplasmic reticulum stability leading to neurodegeneration (155). In ALS-FTD, TDP-43 mislocalizes to the cytoplasm from the nucleus. Mutant FUS reduces protein transport in the cell and fragments the Golgi apparatus causing endoplasmic reticulum stress with reduced Golgi trafficking contributing to neurotoxicity, along with the FUS mutant protein impeding DNA repair. Disulfide isomerase (PDI) is protective against FUS in vitro models, suggesting a therapeutic target (130). Phenols such as flavanone and non-flavanone molecules have been successfully used in experimental models of ALS-FTD and might be a future therapy (123). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are important in ALS-FTD; hnRNP are family of RNA-binding proteins. In frontotemporal dementia-amyotrophic lateral sclerosis, pre-mRNA splicing regulation, cryptic exon expression, stress expansion assembly and DNA damage response, functions mediated by hnRNPs, are disrupted, especially hnpA1 (13). TDP43 is a member of this hnRNP family and is mislocated into the cytoplasm and has an effect on ubiquitination of protein aggregates. TDP also has immune and inflammatory functions. TDP-43 can increase inflammation, which can increase neurodegeneration. TDP-associated genes are linked with immunity and inflammation; TDP proteins initiate immune inflammation pathways; TDP is involved in immune pathway; and TDP is implicated in acute and chronic inflammatory processes (13; 28). Amyotrophic lateral sclerosis patients have increased intrathecal T cell activation (148). Mislocalization of FUS and TDP-43 into cytoplasm are prominent pathophysiological mechanisms, and a rapid in vitro test to quantify mislocalization has been developed (127). Localization of TDP from the nucleus to the cytoplasm is associated with cell stress signaling abnormalities and stress granule dynamics; stress granule assembly is also affected, causing increased cellular vulnerability to death. The mRNA G3BP1 molecule is a RAS-GAPSH3 domain binding protein I and is critical in stress granule assembly. TDP-43 stabilizes G3BP1 through mRNA transcription. When TDP-43 is reduced, G3PB1 concentration is low, contributing to neurodegeneration; in ALS-FTD, G3PB1 transcripts are low and in experimental models of TDP-43 mutations. Therefore, mutations that cause disruption of TDP-43 can destabilize G3BP1, leading to impaired stress granule formation and neurodegeneration (156). G3BP1 MRNA stability is affected by TDP-43 depletion, leading to loss of function and disease. The 4G2C noncoding mutation, C9orf72, gives rise to dipeptide repeat polymers of protein and arginine. These derail protein folding by sequestering molecular chaperones leading to neurodegeneration and inhibit folding catalyzed by PPIA (12). The TDP-43 “knock in” mouse shows parvalbumin interneuron loss and impaired neurogenesis, which might be relevant to the pathophysiology of ALS-FTD (101). Glial cell dysfunction has been identified in C9orf72 mutations in microglia and astrocytes, with loss and gain of function. The C9orf72 mutation is associated with gliosis, TDP-43 aggregation, and toxic gain of function mRNA, leading to dipeptide release and non-ATG RAN translation (64). Four micro mRNAs in the plasma represent a molecular signature for ALS-FTD, particularly mi 349-5p, miR 345-5p, mi 200C-3p, and mi 10a-3p (95). TDP-43 oligomers and their interactions may be important in ALS-FTD (113). Measurement of serum protein levels suggests impaired calcium and immune dysregulation in frontotemporal dementia-amyotrophic lateral sclerosis (89). Findings of differential gene expression data from a number of different studies in the human central nervous system show there are shared gene expressions between ALS-FTD, Lewy Body disease, and Alzheimer disease, with these gene expressions driving the pathophysiology of these diverse proteinopathies. The principal genes identified in 2600 studies are innate immunity genes, cytoskeletal genes, and RNA processing genes with downregulation of mitochondrial electron transfer genes. Also, genes involving neural inflammation, phagocytosis, are increased along with mitochondrial oxidative phosphorylation, lysosomal function, and ubiquitin-proteasome pathways. This suggests that in the pathophysiology of neurodegenerative disorders there are shared pathophysiological pathways (122). Interestingly, reduced telomere length has not been related to amyotrophic lateral sclerosis and might not be relevant to ALS-FTD, but further studies are required (59). Pathogenic Huntington repeat expansions have been identified in frontotemporal dementia and amyotrophic lateral sclerosis; their significance is unclear, but they might reflect spontaneous mutations (45). Studies of the UNC13A polymorphism suggests vesicle maturation during exocytosis, and neurotransmitter release might be affected in ALS-FTD (167). Immune activation in C9orf72 expansions is associated with increased cytokine activation, stimulation of innate inflammatory mechanisms, and intracellular receptors that elicit inflammation response to cellular stress, indicating the importance that immunology might have in ALS-FTD (132). Stathmin 2 (STMN2) is a microtubular associated protein that is important in axonal development and repair. STMN2 promotes microtubular stability necessary for axonal length and regeneration. STMN2 is regulated by TDP-43. Evidence reveals that reduced nuclear TDP-43 function results in impaired splicing of the gene encoding STMN2, leading to reduced production of a truncated protein resulting in axonal degeneration. Reduction in TDP-43 in the nucleus and its translocation to the cytoplasm caused impaired splicing of STMN2 and truncated STMN2 proteins causing axonal degeneration, a finding linking changes in TDP to axonal pathology (21).

There has been increasing interest in the liquid-liquid phase separation (LLPS) of protein and nucleic acid scaffolds in the biogenesis of membraneless organelles. These organelles marshal biochemical reactions and allow the expression of genotype-->phenotype. Liquid-liquid phase separation are important physiologically and pathologically. Liquid-liquid phase separation of important protein and nucleic acids can result in disease. Liquid-liquid phase separation can condense RNA-binding proteins like TDP-43, FUS, hnRNP A1, tau, HTT-PolyQ C9orf72, and others, which have prion-like domains that form self-replicating fibrils that result in disease, promising novel therapeutic interventions involving phase boundary interactions, material properties of condensed phases such as viscoelasticity reversibility of exchange within the dynamics of molecular movement, and fiber formation (51).

Regulating and targeting liquid phase separation

Three modes of action currently link phase separation to pathology with the potential to serve as pathways for intervention. (A) The phase boundary, a metric for the propensity to phase-separate, is defined by the saturation co...

Diagnostic workup

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 (162) 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 (162). Structural neuroimaging studies on patients with amyotrophic lateral sclerosis reveal frontotemporal atrophy in patients with and without dementia (87; 93; 02). 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 (11).

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 (170; 18). 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 (02; 169). 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 (72).

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 (178).

Management

The following have all been approved by the FDA for the treatment of amyotrophic lateral sclerosis: riluzole, a glutamate antagonist; Edaravone, an antioxidant; a combination of phenylbutyrate/taurursodiol (Relyvrio) thought to prevent neuronal death by stabilizing mitochondria; and the endoplasmic reticulum. Nuedexta is an approved treatment for pseudobulbar affect.

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 (166; 09). Open-label trials of the NMDA-receptor antagonist memantine have demonstrated variable results in treating the behavioral symptoms of frontotemporal dementia (26; 46). Randomized, controlled clinical trials have failed to demonstrate a benefit of memantine in frontotemporal dementia (175; 27). 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 (177).

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 (92). The cholinesterase inhibitor donepezil increased frontal behaviors in a small group of patients (110) whereas rivastigmine showed some benefit (115). However, larger more rigorous studies are required to investigate the role of neurotransmitter modulation in frontotemporal dementia (82). In general, treatment for both the motor deterioration and the dementia associated with amyotrophic lateral sclerosis is symptomatic.

Experimental models suggest that antisense oligonucleotides silencing FUS expression may be a therapeutic approach in amyotrophic lateral sclerosis and also ALS-FTD (97). Medications targeting proteostasis might be useful in ALS-FTD, and one example is trehalose, which has been shown to inhibit protein misfolding (52). Monoaminergic dysfunction might suggest treatment possibilities for frontotemporal dementia-amyotrophic lateral sclerosis, but not kynurenine genetic pathways (85).

Media

References

01: Ababneh NA, Scaber J, Flynn R, et al. Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair. Hum Mol Genet 2020;29(13):2200-17. PMID 32504093
02: Abe K, Fujimura H, Toyooka K, Sakoda S, Yorifuji S, Yanagihara T. Cognitive function in amyotrophic lateral sclerosis. J Neurol Sci 1997;148(1):95-100. PMID 9125395
03: Abrahams S, Goldstein LH, Simmons A, et al. Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance study. Brain 2004;127:1507-17. PMID 15163610
04: Abrahams S, Leigh PN, Harvwy A, Vythelingum GN, Grise D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia 2000;38:734-47. PMID 10689049
05: Abramzon YA, Fratta P, Traynor B, Chia R. The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia. Front Neurosci 2020;14:42. PMID 32116499
06: Agarwal S, Highton-Williamson E, Caga J, et al. Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis. Sci Rep 2021;11(1):2172. PMID 33500476
07: Ahmed RM, Bocchetta M, Todd EG, et al. Tackling clinical heterogeneity across the amyotrophic lateral sclerosis–frontotemporal dementia spectrum using a transdiagnostic approach. Brain Commun 2021;3(4):fcab257. PMID 34805999
08: Akiyama T, Koike Y, Petrucelli L, Gitler AD. Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: towards therapeutic targets and biomarkers. Clin Transl Med 2022;12(5):e818. PMID 35567447
09: Allain H, Bentue-Ferrer D, Tribut O, Merienne M, Belliard S. Drug therapy of frontotemporal dementia. Hum Psychopharmacol 2003;18(3):221-5. PMID 12672175
10: Almeida S, Gascon E, Tran H, et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuopathol 2013;126(3):385-99.
11: Avants B, Khan A, McCluskey L, Elman L, Grossman M. Longitudinal cortical atrophy in amyotrophic lateral sclerosis with frontotemporal dementia. Arch Neurol 2009;66:138-9. PMID 19139315
12: Babu M, Favretto F, de Opakua AI, Rankovic M, Becker S, Zweckstetter M. Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis. Nat Commun 2021;12(1):3396. PMID 34099711
13: Bampton A, Gittings LM, Fratta P, Lashley T, Gatt A. The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis. Acta Neuropathol 2020;140(5):599-623. PMID 32748079
14: Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet 2015;386(10004):1672-82. PMID 26595641
15: Barry RL, Babu S, Anteraper SA, et al. Ultra-high field (7T) functional magnetic resonance imaging in amyotrophic lateral sclerosis: a pilot study. Neuroimage Clin 2021;30:102648. PMID 33872993
16: Battistini S, Giannini F, Greco G, et al. SOD1 mutations in amyotrophic lateral sclerosis: results from a multi-centre Italian study. J Neurol 2005;252:782-8. PMID 15789135
17: Baumer D, Talbot K, Turner MR. Advances in motor neuron disease. J R Soc Med 2014;107(1):14-21. PMID 24399773
18: Beall DP, Martin D, Chin BB. Decreased bilateral frontal lobe perfusion in dementia of amyotrophic lateral sclerosis. Clin Nucl Med 1998;23:855-6. PMID 9858308
19: Beeldman E, Govaarts R, de Visser M, et al. Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen. J Neurol 2021;268(7):2533-40. PMID 33547953
20: Beeldman E, Raaphorst J, Klein Twennaar M, de Visser M, Schmand BA, de Haan RJ. The cognitive profile of ALS: a systematic review and meta-analysis update. J Neurol Neruosurg Psychiatry 2016;87(6):611-9. PMID 26283685
21: Benarroch E. What is the role of stathmin-2 in axonal biology and degeneration? Neurology 2021;97(7):330-3. PMID 34400561
22: Benatar M, Wuu J, McHutchison C, et al. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain 2022;145(1):27-44. PMID 34677606
23: Bigio EH, Lipton AM, White CL 3rd, Dickson DW, Hirano A. Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS. Neuropathol Appl Neurobiol 2003;29:239-53. PMID 12787321
24: Blair IP, Williams KL, Warraich ST, et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry 2010;81(6):639-45. PMID 19965854
25: Bots GT, Staal A. Amyotrophic lateral sclerosis-dementia complex, neuroaxonal dystrophy, and Hallervorden-Spatz disease. Neurology 1973;23:35-9. PMID 4734498
26: Boxer AL, Boeve BF. Frontotemporal dementia treatment: current symptomatic therapies and implications of recent genetic, biochemical, and neuroimaging studies. Alzheimer Dis Assoc Disord 2007;21:S79-87. PMID 18090429
27: Boxer AL, Knopman DS, Kaufer DI, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013;12(2):149-56. PMID 23290598
28: Bright F, Chan G, van Hummel A, Ittner L, Ke YD. TDP-43 and inflammation: implications for amyotrophic lateral sclerosis and frontotemporal dementia. Int J Mol Sci 2021;22(15):7781. PMID 34360544
29: Broustal O, Camuzat A, Guillot-Noël L, et al. FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis. J Alzheimers Dis 2010;22(3):765-9. PMID 21158017
30: Brun A, Gustafson L, Passant U. A new kind of degenerative dementia. Localization, rather than type is significant in frontal lobe dementia. Lakartidningen 1994;91(50):4751-7. PMID 7830428
31: Burrell JR, Halliday GM, Kril JJ, et al. The frontotemporal dementia-motor neuron disease continuum. Lancet 2016;388(10047):919-31. PMID 26987909
32: Canosa A, Calvo A, Moglia C, et al. Amyotrophic lateral sclerosis with SOD1 mutations shows distinct brain metabolic changes. Eur J Nucl Med Mol Imaging 2022;49(7):2242-50. PMID 35076740
33: Cavalleri F, De Renzi E. Amyotrophic lateral sclerosis with dementia. Acta Neurol Scand 1994;89:391-4. PMID 8085439
34: Charif SE, Vassallu F, Salvanal L, Igaz LM. Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia. Neural Regen Res 2022;17(7):1423-30. PMID 34916412
35: Chio A, Calvo A, Moglia S, et al. Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations. Arch Neurol 2010;67(8):1002-9. PMID 20697052
36: Cividini C, Basaia S, Spinelli EG, et al. amyotrophic lateral sclerosis–frontotemporal dementia: shared and divergent neural correlates across the clinical spectrum. Neurology. 2022; 98(4): e402–15. PMID 34853179
37: Coon EA, Sorenson EJ, Whitwell JL, Knopman DS, Josephs KA. Predicting survival in frontotemporal dementia with motor neuron disease. Neurology 2011;76(22):1886-93. PMID 21624986
38: Cox LE, Ferraiuolo L, Goodall EF, et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLos One 2010;5(3):e9872. PMID 20352044
39: Crook A, Williams K, Adams L, Blair I, Rowe DB. Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations. Amyotroph Lateral Scler Frontotemporal Degener 2017;18(7-8):475-85. PMID 28585888
40: Cui B, Cui L, Gao J, et al. Cognitive impairment in Chinese patients with sporadic amyotrophic lateral sclerosis. PLoS One 2015;10(9):e0237921. PMID 26367133
41: Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308-14. PMID 7991117
42: DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC Hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011,72(2):245-56. PMID 21944778
43: Deng HX, Chen W, Hong ST, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011;477(7363):211-5. PMID 21857683
44: Devenney E, Vucic S, Hodges JR, Kiernan MC. Motor neuron disease-frontotemporal dementia: a clinical continuum. Expert Rev Neurother 2015;15(5):509-22. PMID 25865485
45: Dewan R, Chia R, Ding J, et al. Pathogenic Huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 2021;109(3):448–60.e4. PMID 33242422
46: Diehl-Schmid J, Forstl H, Perneczky R, et al. A 6 month open label study of memantine in patients with frontotemporal dementia. Int J Geriatr Psychiatry 2008;23:754-9. PMID 18213609
47: Dobson-Stone C, Hallupp M, Shahheydari H, et al. CYLD is a causative gene for frontotemporal dementia – amyotrophic lateral sclerosis. Brain 2020;143(3):783-99. PMID 32185393
48: Dreger M, Steinbach R, Gaur N, et al. Cerebrospinal fluid neurofilament light chain (NfL) predicts disease aggressiveness in amyotrophic lateral sclerosis: An application of the D50 disease progression model. Front Neurosci 2021;15:651651. PMID 33889072
49: Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 2017;13(8):457-76. PMID 28708131
50: Elamin M, Phukan J, Bede P, et al. Executive dysfunction is a negative prognostic factor in patients with ALS without dementia. Neurology 2011;76(14):1263-8. PMID 21464431
51: Elbaum-Garfinkle S. Matter over mind: liquid phase separation and neurodegeneration. J Biol Chem 2019;294(18):7160-8. PMID 30914480
52: Elliott E, Bailey O, Waldron FM, Hardingham GE, Chandran S, Gregory JM. Therapeutic targeting of proteostasis in amyotrophic lateral sclerosis: A systematic review and meta-analysis of preclinical research. Front Neurosci 2020;14:511. PMID 32523508
53: Evans C, Bacon E. Rapid neurocognitive decline in spinal muscular atrophy. Neuropsychol Rev 2000:22-5.
54: Farhan SMK, Gendron TF, Petrucelli L, Hegele RA, Strong MJ. OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia. Am J Med Genet B Neuropsychiatr Genet 2018;177(1):75-85. PMID 29080331
55: Ferrer I, Riog C, Espino A, Peiro G, Guiu XM. Dementia of frontal lobe type and motor neuron disease. A Golgi study of the frontal cortex. J Neurol Neurosurg Psychiatry 1991;54:932-4. PMID 1744652
56: Ferrer I, Tunon T, Serrano MT, et al. Calbindin D-28k and parvalbumin immunoreactivity in the frontal cortex in patients with frontal lobe dementia of non-Alzheimer type associated with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1993;56(3):257-61. PMID 8459241
57: Frank B, Haas J, Heinze HJ, Stark E, Munte TF. Relation of neuropsychological and magnetic resonance findings in amyotrophic lateral sclerosis: evidence for subgroups. Clin Neurol Neurosurg 1997;99:79-86. PMID 9213049
58: Gao FB, Almeida S, Lopez-Gonzalez R. Dysregulated molecular pathways in amyotrophic lateral sclerosis–frontotemporal dementia spectrum disorder. EMBO J 2017;36(20):2931-50. PMID 28916614
59: Gao Y, Wang T, Yu X, International FTD-Genomics Consortium (IFGC), Zhao H, Zeng P. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis. Sci Rep 2020;10(1):12184. PMID 32699404
60: Garcia-Garcia R, Martin-Herrero L, Blanca-Pariente B, Perez-Cabello J, Roodveldt C. Immune signaling kinases in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Int J Mol Sci 2021;22(24):13280. PMID 34948077
61: Geevasinga N, Van den Bos M, Menonn P, Vucic S. Utility of transcranial magnetic simulation in studying upper motor neuron dysfunction in amyotrophic lateral sclerosis. Brain Sci 2021;11(7):906. PMID 34356140
62: Geser F, Martinez-Lage M, Kwong L, Lee V, Trojanowski J. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 2009;256(8):1205-14. PMID 19271105
63: Ghasemi M, Brown RH. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb Perspect Med 2018;8(5):a024125. PMID 28270533
64: Ghasemi M, Keyhanian K, Douthwright C. Glial cell dysfunction in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia. Cells 2021;10(2):249. PMID 33525244
65: Giannoccaro MP, Bartoletti-Stella A, Piras S, et al. Multiple variants in families with amyotrophic lateral sclerosis and frontotemporal dementia related to C9orf72 repeat expansion: further observations on their oligogenic nature. J Neurol 2017;264(7):1426-33. PMID 28620717
66: Giannoccaro MP, Bartoletti-Stella A, Piras S, et al. The first historically reported Italian family with FTD/ALS teaches a lesson on C9orf72 RE: clinical heterogeneity and oligogenic inheritance. J Alzheimers Dis 2018;62(2):687-97. PMID 29480190
67: Gilbert JJ, Kish SJ, Chang LJ, Morito C, Shannak K, Hornykiewicz O. Dementia, parkinsonism, and motor neuron disease: neurochemical and neuropathological correlates. Ann Neurol 1988;24:688-91. PMID 2904794
68: Gomez-Suaga P, Morotz M, Markovinovic A, et al. Disruption of ER‐mitochondria tethering and signalling in C9orf72‐associated amyotrophic lateral sclerosis and frontotemporal dementia. Aging Cell 2022;21(2):e13549. PMID 35026048
69: Grad LI, Rouleau GA, Ravits J, Cashman NR. Clinical spectrum of amyotrophic lateral sclerosis (ALS). Cold Spring Harb Perspect Med 2017;7(8). PMID 28003278
70: Gregory JM, Fagegaltier D, Phatnani H, Harms MB. Genetics of amyotrophic lateral sclerosis. Current Genetic Med Reps 2020;8:121-31.
71: Gu X, Chen Y, Wei Q, et al. Rare CYLD Variants in Chinese patients with amyotrophic lateral sclerosis. Front Genet 2021;12:740052. PMID 34868212
72: Guedj E, Le Ber I, Lacomblez L, et al. Brain SPECT perfusion of frontotemporal dementia associated with motor neuron disease. Neurology 2007;69:488-90. PMID 17664410
73: Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genet 2001;29(2):166-73. PMID 11586298
74: Hakkinen S, Chu SA, Lee SE. Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis. Neurobiol Dis 2020;145:105063. PMID 32890771
75: Hardy J, Rogaeva E. Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not. Exp Neurol 2014;262(Pt B):75-83. PMID 24246281
76: Hodges JR, Miller B. The classification, genetics, and neuropathology of frontotemporal dementia. Introduction to the special topic papers: part 1. Neurocase 2001;7:31-5. PMID 11239074
77: Hooten WM, Lyketsos CG. Frontotemporal dementia: a clinicopathological review of four postmortem studies. J Neuropsychiatry Clin Neurosci 1996;8:10-9. PMID 8845692
78: Horoupian DS, Thal L, Katzman R, et al. Dementia and motor neuron disease: morphometric, biochemical and Golgi studies. Ann Neurol 1984;16(3):305-13. PMID 6148912
79: Hosler BA, Siddique T, Sapp PC, et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000;284(13):1664-9. PMID 11015796
80: Houghton OH, Mizielinska S, Gomez-Suaga P. The interplay between autophagy and RNA homeostasis: Implications for amyotrophic lateral sclerosis and frontotemporal dementia. Front Cell Dev Biol 2022;10:838402. PMID 35573690
81: Hudson A. Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain 1981;104:217-47. PMID 7016254
82: Huey ED, Putnam MAS, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 2006;66(1):17-22. PMID 16401839
83: Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702-5. PMID 9641683
84: Illan-Gala I, Montal V, Pegueroles J, et al. Cortical microstructure in the amyotrophic lateral sclerosis–frontotemporal dementia continuum. Neurology 2020;95(18):e2565-76. PMID 32913016
85: Janssens J, Vermeiren Y, van Faassen M, van der Ley Claude, Kema IP, De Deyn PP. Monoaminergic and kynurenergic characterization of frontotemporal dementia and amyotrophic lateral sclerosis in cerebrospinal fluid and serum. Neurochem Res 2020;45(5):1191-201. PMID 32130630
86: Ji AL, Zhang X, Chen WW, Huang WJ. Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. J Med Genet 2017;54(3):145-54. PMID 28087719
87: Kato S, Hayashi H, Yagishita A. Involvement of the frontotemporal lobe and limbic system in amyotrophic lateral sclerosis: as assessed by serial computed tomography and magnetic resonance imaging. J Neurol Sci 1993;116:52-8. PMID 8509805
88: Kato S, Oda M, Hayashi H, Kawata A, Shimizu T. Participation of the limbic system and its associated areas in the dementia of amyotrophic lateral sclerosis. J Neurol Sci 1994;126(1):62-9. PMID 7836949
89: Katzeff JS, Bright F, Lo K, et al. Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation. Sci Rep 2020;10(1):13741. PMID 32792518
90: Kawashima T, Dohura K, Kikutchi H, Iwaki T. Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent-shaped ubiquinated intraneuronal inclusions in the parahippocampal gyrus and amygdale, but not in the neostriatum. Acta Neuropathol 2001;102:467-72. PMID 11699560
91: Kertesz A, Davidson W, Fox H. Frontal behavioural inventory: diagnostic criteria for frontal lobe dementia. Can J Neruol Sci 1997;24:29-36.
92: Kertesz A, Morlog D, Light M, et al. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord 2008;25:178-85. PMID 18196898
93: Kew JJ, Goldstein LH, Leigh PN, et al. The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. Brain 1993;116(Pt 6):1399-423. PMID 8293278
94: Kilani M, Micallef J, Soubrouillard C, et al. A longitudinal study of the evolution of cognitive function and affective state in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:46-54. PMID 15204024
95: Kmetzsch V, Anquetil V, Saracino D, et al. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2021;92(5):485-93. PMID 33239440
96: Konopka A, Atkin JD. DNA Damage, Defective DNA repair, and neurodegeneration in amyotrophic lateral sclerosis. Front Aging Neurosci 2022;14:786420. PMID 35572138
97: Korobeynikov VA, Lyaschenko AK, Bianco-Redondo B, Jafar-Nejad P, Shneider NA. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med 2022;28(1):104-16. PMID 35075293
98: Kotchoubey B, Lang S, Winter S, Birbaumer N. Cognitive processing in completely paralyzed patients with amyotrophic lateral sclerosis. Eur J Neurol 2003;10:551-8. PMID 12940838
99: Lattante S, Ciura S, Rouleau GA, Kabashi E. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet 2015;31(5):263-73. PMID 25869998
100: Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal. Neurology 2003;60(7):1094-7. PMID 12682312
101: Lin Z, Kim E, Ahmed M, et al. MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia. Brain Commun 2021;3(2):fcab114. PMID 34136812
102: Liu E, Karpf L, Bohl D. Neuroinflammation in amyotrophic lateral sclerosis and frontotemporal dementia and the interest of induced pluripotent stem cells to study immune cells interactions with neurons. Front Mol Neurosci 2021;14:767041. PMID 34970118
103: Lu Y, Ferris J, Gao FB. Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2009;2(1):30. PMID 19781077
104: Luo C, Hu N, Xiao Y, Zhang W, Gong Q, Lui S. Comparison of gray matter atrophy in behavioral variant frontal temporal dementia and amyotrophic lateral sclerosis: a coordinate-based meta-analysis. Front Aging Neurosci 2020;12:14. PMID 32116647
105: Majoor-Krakauer D, Willems PJ, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet 2003;63(2):83-101. PMID 12630951
106: Mann DM, South PW, Snowden JS, Neary D. Dementia of frontal lobe type: neuropathology and immunohistochemistry. J Neurol Neurosurg Psychiatry 1993;56:605-14. PMID 8509772
107: Martinez B, Peplow PV. MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis. Neural Regen Res 2022;17(7):1412–22. PMID 34916411
108: Mase G, Ros S, Gemma A, et al. ALS with variable phenotypes in a six-generation family caused by leu144phe mutation in SOD1 gene. J Neurol Sci 2001;191:11-8. PMID 11676987
109: Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 2020;27(10):1918-29. PMID 32526057
110: Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychistry 2007;15(1):84-7. PMID 17194818
111: Mentis AA, Vlachakis D, Papakonstantinou E, et al. A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum. Cold Spring Harb Mol Case Stud 2022;8(2):a006096. PMID 34535505
112: Miltenberger-Miltenyi, Conceicao VA, Gromiche M, et al. Pathologic expansion in the C9orf72 gene is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis. Ann Med 2021;53(Suppl 1):S6. PMID 29661924
113: Montalbano M, McAllen S, Lo Cascio F, et al. TDP-43 and tau oligomers in Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Neurobiol Dis 2020;146:105130. PMID 33065281
114: Montgomery GK, Erickson LM. Neuropsychological perspectives in amyotrophic lateral sclerosis. Neurol Clin 1987;5:61-81. PMID 3104753
115: Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004;21(14):931-7. PMID 15554751
116: Morita M, Al-Chalabi A, Andersen PM, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006;66:839-44. PMID 16421333
117: Nakano I. Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia). Neuropathology 2000;20:68-75. PMID 10935441
118: Neary D, Mann DM, Snowden JS. Frontotemporal dementia with motor neuron disease. Chapter in Pick’s disease and Pick complex. Kertesz A and Munoz DG, editors. New York: Wiley Liss, 1998:145-58.
119: Neary D, Snowden JS, Mann DM. Cognitive change in motor neurone disease/amyotrophic lateral sclerosis. J Neurol Sci 2000;180:15-20. PMID 11090859
120: Neumann M, Sampathu DM, Kwong LK, et al. Ubiquinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314: 130-33. PMID 17023659
121: Nishimura AL, Mitne-Neto M, Silva NC, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004;75:822-31. PMID 15372378
122: Noori A, Mezlini AM, Hyman T, Serrano-Pozo A, Das S. Differential gene expression data from the human central nervous system across Alzheimer's disease, Lewy body diseases, and the amyotrophic lateral sclerosis and frontotemporal dementia spectrum. Data Brief 2021;35:106863. PMID 33665258
123: Novak V, Rogelj B, Zupuski V. Therapeutic potential of polyphenols in amyotrophic lateral sclerosis and frontotemporal dementia. Antioxidants (Basel) 2021;10(8):1328. PMID 34439576
124: Oh SI, Park A, Kim HJ, et al. Spectrum of cognitive impairment in Korean ALS patients without known genetic mutations. PLoS One 2014;9(2):e87163. PMID 24498297
125: Olney RK, Murphy J, Forshew D, et al. The effects of executive and behavioural dysfunction on the course of ALS. Neurology 2005;65:1774-7. PMID 16344521
126: Otero Siliceo E, Arriada-Mendicoa N, Balderrama J. Juvenile familial amyotrophic lateral sclerosis: four cases with long survival. Dev Med Child Neurol 1998;40:425-8. PMID 9652786
127: Oyston LJ, Ubiparipovic S, Fitzpatrick L, et al. Rapid in vitro quantification of TDP-43 and FUS mislocalisation for screening of gene variants implicated in frontotemporal dementia and amyotrophic lateral sclerosis. Sci Rep 2021;11(1):14881. PMID 34290285
128: Panegyres PK. Stochastic considerations into the origins of sporadic adult onset neurodegenerative disorders. Accessed February 2020. Available at: www.omicsonline.org. J Alzheimers Dis Parkinsonism 2019;9(4):473.
129: Panegyres PK. Stochasticity, entropy and neurodegeneration. Brain Sci 2022;12(2):226. PMID 35203989
130: Parakh S, Perri ER, Vidal M, et al. Protein disulphide isomerase (PDI) is protective against amyotrophic lateral sclerosis (ALS)-related mutant Fused in Sarcoma (FUS) in in vitro models. Sci Rep 2021;11(1):17557. PMID 34475430
131: Pasetto L, Grassano M, Pozzi S, et al. Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia. Brain 2021;144(12):3710-26. PMID 34972208
132: Pasniceanu IS, Atwal MS, Souza CDS, Ferraiuolo L, Livesey MR. Emerging mechanisms underpinning neurophysiological impairments in C9ORF72 repeat expansion-mediated amyotrophic lateral sclerosis/frontotemporal dementia. Front Cell Neurosci 2021;15:784833. PMID 34975412
133: Panegyres PK, Armari E, Shelly R. Creutzfeldt-Jakob disease presenting with amyotrophy: a case report. J Med Case Rep 2013;7(1):218. PMID 23971649
134: Peavy GM, Herzog AG, Rubin NP, Mesulam MM. Neuropsychological aspects of dementia of motor neuron disease: a report of two cases. Neurology 1992;42:1004-8. PMID 1579222
135: Pellissier JF, Baeta AM, Figarella-Branger D. Neuropathology of the cortex in amyotrophic lateral sclerosis with dementia. Adv Neurol 1995;68:139-41. PMID 8787223
136: Perez M, Amayra I, Lazaro E, et al. Intrusion errors during verbal fluency task in amyotrophic lateral sclerosis. PLoS One 2020;15(5):e0233349. PMID 32469951
137: Phukan J, Elamin M, Bede P, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 2012;83(1):102-8. PMID 21836033
138: Placek K, Benatar B, Wuu J, et al. Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis. EMBO Mol Med 2021;13(1):e12595. PMID 33270986
139: Poloni M, Capitani E, Mazzini L, Ceroni M. Neuropsychological measures in amyotrophic lateral sclerosis and their relationship with CT scan assessed cerebral atrophy. Acta Neurol Scand 1986;74:257-60. PMID 3811831
140: Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43(6):815-25. PMID 9629852
141: Portet F, Cadilhac C, Touchon J, Camu W. Cognitive impairment in motor neuron disease with bulbar onset. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:23-9. PMID 11465929
142: Ranganathan R, Haque S, Coley K, Shepheard S, Cooper-Knock J, Kirby J. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci 2020;14:684. PMID 32733193
143: Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257-68. PMID 21944779
144: Requardt MV, Gorlich D, Grehl T, Boentert M. Clinical determinants of disease progression in amyotrophic lateral sclerosis: A retrospective cohort study. J Clin Med 2021;10(8):1623. PMID 33921250
145: Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Shulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 2005;65:586-90. PMID 16116120
146: Roberson ED, Hesse JH, Rose KD, et al. Frontotemporal dementia progresses to death faster than Alzheimer’s disease. Neurology 2005;65:719-25. PMID 16157905
147: Roggenbuck J, Rich KA, Vicini L, et al. Amyotrophic lateral sclerosis genetic access program: Paving the way for genetic characterization of ALS in the clinic. Neurol Genet 2021;7(5):e615. PMID 34386583
148: Rolfes L, Schulte-Mecklenbeck A, Schreiber S, et al. Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation. Brain Commun 2021;3(3):fcab157. PMID 34405141
149: Rollison S, Mead S, Snowden J, et al. Frontotemporal lobar degeneration genome wide association study replication confirms a risk locus shared with amyotrophic lateral sclerosis. Neurobiol Aging 2011;32(4):758.e1-7.
150: Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362(6415):59-62. PMID 8446170
151: Saxon JA, Thompson JC, Harris JM, et al. Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2020;91(12):1304-11. PMID 33055142
152: Scarian E, Fiamingo G, Diamanti L, et al. The role of VCP mutations in the spectrum of amyotrophic lateral sclerosis—frontotemporal dementia. Front Neurol 2022;13:841394. PMID 35273561
153: Schymick JC, Yang Y, Andersen PM, et al. Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatr 2007;78:754-6. PMID 17371905
154: Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology 2012;79(10):1002-11. PMID 22875087
155: Sharpe JL, Harper NS, Garner DR, West RJH. Modeling C9orf72-related frontotemporal dementia and amyotrophic lateral sclerosis in drosophila. Front Cell Neurosci 2021;15:770937. PMID 34744635
156: Sidibé H, Khalfallah Y, Xiao S, et al. TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia. Brain 2021;144(11):3461-76. PMID 34115105
157: Snowden JS, Harris J, Richardson A, et al. Frontotemporal dementia with amyotrophic lateral sclerosis: a clinical comparison of patients with and without repeat expansions in C9orf72. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(3):172-6. PMID 23421625
158: Snowden JS, Hu Q, Rollinson S, et al. The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol 2011;122(1):99-110. PMID 21424531
159: Spina S, Murrell JR, Huey ED, et al. Clinicopathological features of frontotemporal dementia with progranulin sequence variation. Neurology 2007;68:820-7. PMID 17202431
160: Stetkarova I, Ehler E. Diagnostics of amyotrophic lateral sclerosis: up to date. Diagnostics (Basel) 2021;11(2):231. PMID 33546386
161: Strong MJ, Abrahams S, Goldstein LH, et al. Amyotrophic lateral sclerosis – frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 2017;18(3-4):153-74. PMID 28054827
162: Strong MJ, Grace GM, Freedman M, et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009;10(3):131-46. PMID 19462523
163: Strong MJ, Grace GM, Orange JB, Leeper HA. Cognition, language, and speech in amyotrophic lateral sclerosis: a review. J Clin Exp Neuropsychol 1996;18:291-303. PMID 8780963
164: Strong MJ, Grace GM, Orange JB, Leeper HA, Menon RS, Aere C. A prospective study of cognitive impairment in ALS. Neurology 1999;53:1665-70. PMID 10563610
165: Strong MJ, Lomen-Hoerth CL, Caselli RJ, Bigio EH, Yang W. Cognitive impairment, frontotemporal dementia, and the motor neuron disease. Ann Neurol 2003;54(Suppl 5):S20-3. PMID 12833364
166: Swartz JR, Miller BL, Lesser IM, Darby AL. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry 1997;58:212-6. PMID 9184615
167: Tan HHG, Westeneng HJ, van der Burgh HK, et al. The distinct traits of the UNC13A polymorphism in amyotrophic lateral sclerosis. Ann Neurol 2020;88(4):796-806. PMID 32627229
168: Tan RH, Guennewig B, Dobson-Stone C, et al. The underacknowledged PPA-ALS: a unique clicicopathologic subtype with strong heritability. Neurology 2019;92(12):e1354-66. PMID 30770429
169: Tanaka M, Ichiba T, Kondo S, Hirai S, Okamoto K. Cerebral blood flow and oxygen metabolism in patients with progressive dementia and amyotrophic lateral sclerosis. Neurol Res 2003;25:351-6. PMID 12870260
170: Tanaka M, Kondo S, Hirai S, Sun X, Yamagishi T, Okamoto K. Cerebral blood flow and oxygen metabolism in progressive dementia associated with amyotrophic lateral sclerosis. J Neurol Sci 1993;120:22-8. PMID 8289076
171: Temp AGM, Dyrba M, Buttner C, et al. Cognitive profiles of amyotrophic lateral sclerosis differ in resting-state functional connectivity: An fMRI study. Front Neurosci 2021;15:682100. PMID 34248485
172: Tsuchiya K, Ozawa E, Fukushima J, et al. Rapidly progressive aphasia and motor neuron disease: a clinical, radiological, and pathological study of an autopsy case with circumscribed lobar atrophy. Acta Neuropathologica 2000;99(1):81-7. PMID 10651032
173: Tsuchiya T, Ikeda K, Mimura M, et al. Constant involvement of the Betz cells and pyramidal tract in amyotrophic lateral sclerosis with dementia: a clinicopathological study of eight autopsy cases. Acta Neuropathol 2002;104:249-59. PMID 12172910
174: Umoh ME, Dammer EB, Dai J, et al. A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol Med 2018;10(1):48-62. PMID 29191947
175: Vercelletto M, Boutoleau-Bretonniere C, Volteau C, et al. Memantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis 2011;23(4):749-59. PMID 21157021
176: Verde F, Otto M, Silani V. Neurofilament light chain as biomarker for amyotrophic lateral sclerosis and frontotemporal dementia. Front Neurosci 2021;15:679199. PMID 34234641
177: Vossel KA, Miller BL. New approaches to the treatment of frontotemporal lobar degeneration. Curr Opin Neurol 2008;21:708-16. PMID 18989117
178: Wedderburn S, Panegyres PK, Andrew S, et al. Predictive gene testing for Huntington disease and other neurodegenerative disorders. Int Med J 2013;43(12):1272-9. PMID 23654213
179: Weishaupt JH, Hyman T, Dikic I. Common molecular pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Trends in Mol Med 2016;22(9):769-83. PMID 27498188
180: Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. Am J Hum Genet 1994;55:1159-65. PMID 7977375
181: Woolley SC, Strong MJ. Frontotemporal dysfunction and dementia in amyotrophic lateral sclerosis. Neurol Clin 2015;33(4):787-805. PMID 26515622
182: Wooley-Levine S, Moore D, Katz J. What is the best verbal bedside tool to screen for cognitive impairment in ALS. Amyotroph lateral Scler 2007a;8:101.
183: Wooley-Levine S, York M, Haring K, et al. Development of a cognitive behavioural screen for use with ALS patients: preliminary data. Amyotroph Lateral Scler 2007b;8:102.
184: Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet 2001;29(2):160-5. PMID 11586297
185: Ye S, Jin P, Chen L, Zhang N, Fan D. Prognosis of amyotrophic lateral sclerosis with cognitive and behavioural changes based on a sixty-month longitudinal follow-up. PLoS One 2021;16(8):e0253279. PMID 34379621
186: Ziegler LH. Psychotic and emotional phenomenon associated with amyotrophic lateral sclerosis. Arch Neurol Psychiatry 1930;24:930-6.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Peter K Panegyres MD PhD PhD FRACP

Dr. Panegyres, Director of Neurodegenerative Disorders Research, has no relevant financial relationships to disclose.
See Profile

Editor

Howard S Kirshner MD

Dr. Kirshner of Vanderbilt University School of Medicine has no relevant financial relationships to disclose.
See Profile

Former Authors

James Voci MD (original author), Tiffany W Chow MD, Peter Hedera MD, and Brandy R Matthews MD

Patient Profile

Age range of presentation: 19 to 65+ years
Sex preponderance: female>male, >1:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Anterior horn cell/motor neuron disease–other: 355.29

Dementia due to or associated with conditions classified elsewhere: 294.1

Frontal lobe dementia: 290.10
ICD-10: Motor neuron disease: G12.2

Dementia in other specified diseases classified elsewhere: F02.8

Unspecified dementia: F03
OMIM: Amyotrophic lateral sclerosis 1: #105400

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Dementia associated with amyotrophic lateral sclerosis

Associated Disorders

Alzheimer disease
Creutzfeldt-Jakob disease
Familial amyotrophic lateral sclerosis
Frontotemporal dementia
Frontotemporal lobar degeneration
- Pick disease

Differential Diagnosis

Alzheimer disease
Creutzfeldt-Jakob disease
frontotemporal lobar degeneration
Pick disease
spinal muscular atrophy
- postencephalitic states
- pantothenate kinase-associated neurodegeneration

Also Relevant

ALS-like disorders of the Western Pacific
Amyotrophic lateral sclerosis
Frontotemporal dementia

Clinical Categories

Patient Handouts

Web References

Guidelines

Alerts and Advisories

AAN: Treatment of Amyotrophic Lateral Sclerosis with Riluzole

Dementia associated with amyotrophic lateral sclerosis …

Dementia associated with amyotrophic lateral sclerosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Genes causing ALS + FTD and their functions

Table 2. Potential molecular mechanisms ALS-FTD

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Congenital muscular dystrophy: merosin deficient form

Leigh syndrome

Acid sphingomyelinase deficiency

Neurogenetics and genetic and genomic testing

Developmental delay in children: evaluation and management

Pathogenesis and pathology of tauopathies

Porphyria

Asymptomatic hyperCKemia

Dementia associated with amyotrophic lateral sclerosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Genes causing ALS + FTD and their functions

Table 2. Potential molecular mechanisms ALS-FTD

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Congenital muscular dystrophy: merosin deficient form

Leigh syndrome

Acid sphingomyelinase deficiency

Neurogenetics and genetic and genomic testing

Developmental delay in children: evaluation and management

Pathogenesis and pathology of tauopathies

Porphyria

Asymptomatic hyperCKemia

This is an article preview.
Start a Free Account
to access the full version.