Neurobehavioral & Cognitive Disorders
Mental status examination
Jun. 17, 2026
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Dementia associated with amyotrophic lateral sclerosis …
- Updated 01.06.2026
- Released 07.20.1994
- Expires For CME 01.06.2029
Dementia associated with amyotrophic lateral sclerosis
Introduction
Overview
The author offers an updated article on dementia associated with amyotrophic lateral sclerosis, including a 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
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• 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. | |
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• 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. | |
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• 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 (43). 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 (220). Although many names have been applied to this condition (100), 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 (39; 99), 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 (217).
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 two 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 (133) and are recommended for use in either the oral or written formats (05; 242; 243) by the 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 (53) or the Frontal Behavioral Inventory (116) 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 (04).
According to guidelines (217), patients with amyotrophic lateral sclerosis and associated cognitive or behavioral impairment should be classified according to the following schema:
(1) Patients meeting at least two non-overlapping supportive diagnostic features from either the Neary criteria (156) or Hodge’s criteria (98) for frontotemporal dementia shall be diagnosed with ALSbi (amyotrophic lateral sclerosis behavioral impairment).
(2) Patients with evidence of cognitive impairment at or below the 5th percentile on at least two distinct tests of cognition deemed sensitive to executive functioning shall be diagnosed with 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 (180). 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 (162). 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 four 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%) (52). 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 meta-analysis suggested that cognitive impairment was found in about 30% of people with amyotrophic lateral sclerosis (26), when present, adversely affecting prognosis. Forty-four studies, including 1287 patients and 1130 controls, were reviewed 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 by 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 (220). 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 (43; 157). 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 (186).
Changes in personality and comportment are seen. Patients may display emotional disinhibition, lack of concern, apathy, and impulsiveness (225; 157; 98). Emotional lability was reported even in early cases (249), although this may in some instances be referable to a pseudobulbar state due to bilateral corticobulbar lesions rather than psychological dysfunction (152). 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 (119). Neuropsychological testing demonstrates severe attention deficits and impaired judgment and insight (152; 177). Language presentations are variable (225; 228), and consensus guidelines (217) suggest categorization of language impairment according to the Neary classification of progressive non-fluent aphasia and semantic dementia (156).
Progression of cognitive deficits does not correlate with the motor function decline (119). 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 (126). 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 eight patients with amyotrophic lateral sclerosis (219); 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 (217), patients with amyotrophic lateral sclerosis and associated dementia should be classified according to the following schema:
(1) Patients meeting either the Neary criteria (156) or Hodge’s criteria (98) for frontotemporal dementia shall be diagnosed with 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 (241; 89).
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 consensus proposes the notion of frontotemporal spectrum disorder of amyotrophic lateral sclerosis (ALS-FTLD) (216). 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 (239; 72; 168; 170).
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 (197).
CSF neurofilament light (NfL) may predict disease progression in amyotrophic lateral sclerosis and, therefore, in amyotrophic lateral sclerosis frontotemporal dementia (61). Motor cortical excitability might predict cognitive phenotypes in amyotrophic lateral sclerosis (07). 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 (236).
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 (107). The studies of Hakkinen and colleagues support selective patterns of atrophy in genetic frontotemporal dementia and amyotrophic lateral sclerosis (94).
A meta-analysis showed that frontal, medial, and caudate circuits in behavioral and frontotemporal dementia are also found in patients with amyotrophic lateral sclerosis without dementia, in the grey matter, particularly involving the frontal limbic circuitry, the anterior insula, and anterior cingulate regions (137). Intrusion errors may occur during verbal fluency tasks in patients with amyotrophic lateral sclerosis, suggesting this may be a marker of cognitive change (179).
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 (20).
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 (165). However, it is unknown whether these patients have mutations in alsin or represent a separate genetic type of juvenile amyotrophic lateral sclerosis (93; 246).
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 (217).
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 (99; 157).
According to guidelines (217), 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 (47).
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 (226).
More recent studies have emphasized that frontotemporal dementia and motor neuron disease are on a continuum. Studies suggest that motor unit number index, transcranial magnetic stimulation, electrical impedance myography, and advancements in measuring fluid-based biomarkers, including neurofilament light and micromRNAs, might be useful in the study of phenoconverters, as well as assessment of the p75 neurotrophin receptor (106).
The Miami Framework also suggests overlap of ALS-FTD and some extrapyramidal syndromes. The so-called Miami Framework attempts to integrate manifestations of ALS-FTD extrapyramidal syndromes into a continuum, from silent to prodromal to clinically manifest. Moving away from traditional diagnostic approaches for these patients and instead using biomarkers and clinical phenomenology may help to better understand these complex patient groups (28).
Machine learning and artificial intelligence may accelerate biomarker discovery, particularly for synaptic markers, such as the neuronal pentraxin 2 (NPTX2) and neuronal pentraxin receptor (NPTXR). Synaptic biomarkers provide insight into the ALS-FTD spectrum and cognitive decline (127).
More recent neuropathological studies show impairment in inhibitory neurons containing parvalbumin, calbindin, and GABA-A, with reduced expression of inhibitory genes and decreased intracortical inhibition neurons in both amyotrophic lateral sclerosis and frontotemporal dementia (134). This provides a pathological framework for the role of increased neuronal excitability and an imbalance between excitatory and inhibitory influences and impaired functional connectivity in frontotemporal dementia and amyotrophic lateral sclerosis. These studies offer a refreshing therapeutic approach and posit inhibitory neurons as a therapeutic option in ALS-FTD.
Studies emphasize that cerebellar dysfunction in ALS-FTD is under-recognized, implicate the spinocerebellar tract pathology and pathways, especially in patients with C9orf72 mutations, and suggest a cerebral and cerebellar disconnection. These studies highlight that cerebellar abnormalities, dysfunction in cerebellar projections, and pathology involving cerebral and cerebellar networks probably contribute to differences in the phenotypes of frontotemporal dementia. Cerebellar network abnormalities should be carefully considered in ALS-FTD, and some neuropsychological and motor presentations may not be solely attributable to cortical involvement (121).
Clinical and pathological studies have indicated that frontotemporal lobar degeneration occurs in 35.5% of neuropathologically confirmed motor neuron disease. The spectrum of frontotemporal lobar dementia is highly heterogeneous, without any specific patterns or subgroups, suggesting that biomarkers are needed to help characterize the relationship between FTLD and motor neuron disease (42).
A study of 800 Italian patients showed that 50% with amyotrophic lateral sclerosis are not demented but might have subtle behavioral difficulties, and people with worse motor function have more abnormal behaviors, including executive dysfunction, language difficulties, impaired memory, and apathy (183).
Long-term MRI studies of individuals with asymptomatic C9orf72 mutations revealed distinctive atrophy patterns many years before symptom onset; these distinctive patterns of atrophy can predict phenoconversion to amyotrophic lateral sclerosis versus ALS-FTD (232).
A meta-analysis has shown that patients with amyotrophic lateral sclerosis and frontotemporal dementia had elevated neurofilament light in their blood and other fluids, such as CSF, but neurofilament light is not very useful as a diagnostic aid in patients with frontotemporal dementia (235).
A study of postmortem ALS-FTD tissue has shown that the leptin receptor mRNA was increased in the superior frontal gyrus in frontotemporal dementia and within the primary motor cortex and lumbar spinal cord in amyotrophic lateral sclerosis. Insulin receptor mRNA was elevated in the superior frontal gyrus and insula cortex in frontotemporal dementia cases. Neuropeptide Y protein was diminished in the primary motor cortex of the lumbar spinal cord in patients with amyotrophic lateral sclerosis. These findings indicate that metabolic hormones undergo complex changes in ALS-FTD, which might contribute to appetite fluctuations, well-recognized clinical manifestations in frontotemporal dementia (15).
Neuropsychology defines amyotrophic lateral sclerosis as a disorder in a continuum from pure motor to ALS-FTD. Cognition and behavior vary across the continuum, with 50% of people with amyotrophic lateral sclerosis being normal. Fifteen percent meet the criteria for ALS-FTD; the remaining 35% are in the middle of the spectrum, with mild or no focal impairments. The cognitive impairments include verbal fluency, executive dysfunction, and impaired social behavior, with apathy as a prominent behavioral change. The range and degree of cognitive and behavioral alterations predict cerebral hypofunction, as indicated by brain imaging and postmortem analysis. Neuropsychology has defined cognition and behavior as components of the spectrum of amyotrophic lateral sclerosis and has given rise to standardized assessment techniques used in research and clinical care. This helps to quantify changes in clinical trials, with neuropsychology being a biomarker for preclinical stages (03).
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 (163; 191; 64). Patients presenting with language variants rather than behavioral features may be more likely to have bulbar-onset, which portends a poorer prognosis (49).
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 (189).
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 (25; 247).
Studies of the clinical heterogeneity of ALS-FTD indicate that 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 (08). Pathological expansion in the C9orf72 gene is associated with accelerated decline of respiratory function and reduced survival in amyotrophic lateral sclerosis (149).
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:
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• Orientation – oriented only to person, age, and year. |
The patient died 1 year into the course of her illness. Autopsy of the brain and spinal cord confirmed the clinical diagnosis of amyotrophic lateral sclerosis. There was anterior horn motor neuron loss, accompanied by astrocytic proliferation and axonal swelling. Ubiquitin stains revealed rare dense cytoplasmic rounded granular inclusions. Extensive spongiosis and widespread tau-immunoreactive glial cells were observed in the frontal lobes. Further neuronal loss appeared in the substantia nigra, periaqueductal grey, mamillary bodies, midline thalamic nuclei, and the hippocampal subiculum. Only rare neurofibrillary tangles and neuritic plaques were located. [Case courtesy of Strong and colleagues (218).]
Clinical diagnosis and management remain challenging (143).
Biological basis
Etiology and pathogenesis
Cryo-electron microscopy has allowed us to define neurodegenerative processes by the aggregation of filamentous proteins in the central nervous system. The genetics of these neurodegenerative disorders indicate protein assembly as a fundamental mechanism. Cryo-electron microscopy has also enabled the identification of these protein filaments in the brains of patients with neurodegenerative processes. It seems that all neurodegenerative disorders, including frontotemporal dementia, motor neuron disease with DNA-binding protein TDP-43 in ALS-FTD, and other neurodegenerative disorders, are characterized by this self-aggregation of proteins as amyloid filaments (199; 14).
Approximately 10% to 15% of patients with ALS-FTD have involvement of both the frontotemporal regions of the brain and the motor system. Such patients’ disease presentation has been related to expansion of the intron of C9orf72, along with inclusions of TDP-43 in the brain and other genes with similar effects--namely, VCP, FUS, SQSTM1, TBK1, and CHCHD1. These genes have similar functions in RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Whole-genome-wide association studies have identified several genes--namely CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, and DNAJC7. Other genetic risk factors and modifiers have been found by genome-wide association studies. These genes are found in association with known genes implicated in pathogenesis, suggesting interaction of digenetic or polygenetic models of inheritance with epistatic interactions and mechanisms. They are implicated not only in the ALS-FTD spectrum, but also in Alzheimer disease, ataxia, and parkinsonism (120).
About 50 genes have been implicated in amyotrophic lateral sclerosis, and these genes have diverse functions involving neuroinflammation, glutamate excitotoxicity, and mitochondrial dysfunction. These observations have led to treatments for amyotrophic lateral sclerosis that have relevance to the ALS-FTD spectrum (36).
Short tandem repeats (STRs or microsatellites) are repetitive segments of DNA that are two to six nucleotides in length and represent 3% of the human genome. STRs may be pathogenic. A study of 100 patients discovered that about 18% of patients with amyotrophic lateral sclerosis and frontotemporal dementia had at least one STR allele considered to be pathogenic or probably pathogenic for another neurodegenerative disorder; STR expansions were identified in C9orf72, ATXN1 (spinocerebellar ataxia type 1 or SCA1), ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington disease), DMPK (myotonic dystrophy type 1 or DM1), CNBP (DM2), and Fragile X. This finding raises fascinating questions on the relationship between genes and neurodegenerative processes where an autosomal dominant gene and STR expansions in other neurodegenerative disease-causing genes were identified in amyotrophic lateral sclerosis and frontotemporal dementia cases. These STRs possibly cause disease by loss of gene function, the formation of repeat-containing RNA segments, polyglutamine aggregation, and repeat-associated non-AUG translation of toxic peptides. The pathological outcome is dependent on the location of the STR in relation to the gene, the nucleotide makeup, and the number of repeated motifs (97). This discovery of the role of STRs is compatible with biological systems that evolve randomly with time (so-called stochastic processes) and compatible with theories of the evolution of neurodegenerative processes (169; 170; 171).
Genetics. A study of carriers of the APOE4 genotype, which is related to Alzheimer disease, using the Global Neurodegeneration Proteomics Consortium SomaScan dataset on CSF and plasma (with a machine-learning proteome profiling approach) identified an APOE4 proteomic signature shared with Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson disease dementia, and Parkinson disease. This characteristic was composed of pro-inflammatory immune and infection pathways of immune cells, including monocytes, T cells, and natural killer cells and was identified in the prefrontal cortex proteome using the Accelerating Medicines Partnership for Alzheimer disease at the University of Pennsylvania Proteomics Study. The APOE phenotype was independent of neurodegenerative pathology and included TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia, Abeta/Tau in Alzheimer disease, gliosis for all diseases, and alpha synuclein in Parkinson disease and Parkinson disease dementia. This proteomic change is consistent across APOE4 carriers and clinical and lifestyle factors. This APOE4 characteristic causes a bio-susceptibility but does not predict the neurodegenerative process, indicating gene-environment interactions and identifying a conserved APOE pro-inflammatory immune signature irrespective and unrelated to the type of neurodegenerative process. This insight supports the stochastic theory of neurodegenerative disorders and now makes APOE4 a predisposition to neurodegenerative disorders in general, with its effect on the immune system and microglial function (208).
Genetic studies of patients with amyotrophic lateral sclerosis and dementia may provide 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 (138). 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 (196; 142; 21).
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 (240). Mutations in the microtubule-associated protein tau gene have been later discovered as a cause of this type of dementia-amyotrophic lateral sclerosis complex (105; 185). Single cases of dementia in families with amyotrophic lateral sclerosis and mutations in ANG/VEGF on chromosome 14q11 (217) and VAPB on chromosome 20q13.33 have also been reported and require further study (159). 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 (50). Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, have also been reported to cause dominantly inherited, 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 (56).
Additional loci on chromosome 9q21-q22 (101) and 9p13.2-21.3 (154) 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 two British cohorts (195). The discovery of the critical gene change as an expanded sequence of hexanucleotide repeats in C9orf72 was subsequently reported independently by two international research groups (54; 188). 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 (203), and psychiatric symptoms may be more common in this genetic cohort of families presenting with frontotemporal dementia and amyotrophic lateral sclerosis (211). The role of the protein C9orf72 within neurons of the brain and spinal cord is not 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 (11).
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 (46). 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 (200; 214). 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 two cases presenting with frontotemporal dementia features (32; 38). 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 cases that were previously considered ubiquitin positive, TDP-43 and tau negative, but such cases have not been associated with FUS gene mutations (212).
There is a clinical and genetic spectrum of amyotrophic lateral sclerosis-frontotemporal dementia (19; 57; 40), 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) (22; 51; 109; 80). This array of genetic mutations implicates a molecular mechanism involving protein homeostasis, the functions of RNA-binding proteins, cytoskeletal kinetics, and the autophagy or lysosomal machinery (95; 80).
The known genes causing frontotemporal dementia or motor neuron 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 patients with ALS-FTD are unknown, but C9orf72, TD4-43, and FUS are the most common (06; 90). Table 2 shows rare causative genes for amyotrophic lateral sclerosis and frontotemporal dementia.
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 the ALS-FTD panel is performed.
Table 1. Well-Known Genes Causing ALS and FTD and Their Functions
|
Gene |
Name |
Functions |
|
C9orf72 |
Chromosome 9 open reading frame 72 |
Autophagy or 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 |
|
UBQLN2 |
Ubiquilin 2 |
Ubiquitin-proteosome system |
|
TBK1 |
Tank-Binding Kinase 1 |
Autophagy |
|
VCP |
Valosin Containing Peptide |
Ubiquitin binding |
|
SQSTM1 |
Sequestosome 1 |
Apoptosis |
|
CYLD |
Cytochrome lysine 63 deubiquitinase |
Autophagosome |
|
SIGMAR1 |
SIGMA-1 receptor |
Chaperone protein |
|
TUBA4A |
Tubulin Alpha 4A microtubule protein |
Microtubule protein |
|
TIA1 |
T-cell Intracellular Antigen 1 binding protein |
RNA-binding protein |
|
CCNF |
Cyclin F, member FBOX proteins |
Ubiquitin proteosomal pathway |
Table 2. Rare Causative Genes for ALS and FTD
|
Gene (OMIM number) |
Protein |
Associated clinical diagnosis or feature |
|
RNA/DNA binding proteins (involved in pre-mRNA processing, metabolism, and transport) | ||
|
hnRNPA1 (*164017) and hnRNPA2B1 (*600124) |
Heterogeneous nuclear ribonuclear protein A1 and A2B1 |
ALS; inclusion body myopathy with early onset Paget disease with or without frontotemporal dementia |
|
MATR3 (*164015) |
Matrin 3 |
ALS with or without cognitive impairment or dementia; distal myopathy |
|
ANG (*105850) |
Angiogenin |
Frequent bulbar onset ALS; co-existing parkinsonism with FTD |
|
Genes that encode for structural proteins (cytoskeleton proteins) | ||
|
TUBA4A (*191110) |
Tubulin-alpha 4A (alpha tubulin) |
ALS with or without FTD |
|
ANXA11 (*602572) |
Annexin A11 |
Later-onset ALS (average 67 years); inclusion body myopathy and brain white matter abnormality |
|
PRPH (*170710) |
Peripherin |
ALS |
|
DCTN1 (*601143) |
Dynactin 1 |
Distal motor neuronopathy with vocal paresis |
|
PFN1 (*176610) |
Profilin 1 |
ALS |
|
KIF5a (*602821) |
KIF5a (kinesin family member 5A) |
Also implicated in HSP-10, CMT |
|
Loss-of-function mutations in genes encoding proteins important for protein degradation or autophagy pathways | ||
|
CHMP2B (*609512) |
Charged multivesicular body protein 2B |
FTD with or without ALS |
|
VAPB/VAMP (*605704) |
Synatobrevin-associated protein B/vesicle associated membrane protein |
Lower motor neuronopathy |
|
| ||
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 (128). 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 (82). 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 (83). 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 two 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 (68).
C9orf72 repeat mutations produce dipeptide-repeat proteins (62). Dipeptides are produced by non-AUG translation--protein synthesis in eukaryotes usually begins at ribosome methionine residues (AUG), but non-AUG codons like CUG or GUG induce proteoforms with altered functions. The repeats glycine-arginine, proline-arginine, and glycine-alanine form neuronal inclusions that possess aggregates of the peptides. These dipeptide repeats bind with Annexin 11 and other oligomers. These oligomers are toxic, regardless of their repeat length (30). It has been suggested that the dipeptide repeats disrupt the native condensation of RNA-binding proteins with RNA, leading to toxicity (62). Cellular stress can interfere with RNA binding, impair condensation, and result in toxicity (233).
The hexanucleotide repeat expansions of the C9orf72 mutation, ie, RNA HRE = hexanucleotide repeat expansions r(G4C2)n, can form toxic RNA foci, which sequester RNA-binding proteins and impair RNA processing. The crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex, lays the foundation for understanding the mechanism of neurologic toxicity and therapeutic possibilities (78). The r(G4C2)2 can fold into distinct structures involving parallel or antiparallel topology of the G-quadruplex (77).
These hexanucleotide repeat RNAs co-localize with nuclear speckles, causing a phase separation and impairing granule dynamics. The nuclear speckled scaffold protein serine/arginine repetitive matrix 2 (SRRM2), important for mRNA splicing, is sequestered into poly-GR cytoplasmic inclusions in the C9orf72 ALS-FTD patients in postmortem tissues. These increases in nuclear speckles cause dysfunction. Impaired nuclear speckle integrity leads to exon skipping, intron retention, and neuronal toxicity. These observations emphasize that RNA splicing abnormalities lead to impaired nuclear speckle formation and disease (244). Disruption of nuclear speckle integrity through this mechanism enhances RNA missplicing, exon skipping, intron retention, and neuronal death, ie, impaired nuclear speckling function, and may be a biomarker for neurodegeneration in frontotemporal dementia and motor neuron disease. The pathogenic mechanisms of r(G4C2)2 in C9orf72 are at the level of structural and functional aspects of DNA, transcription of RNA, hRNA foci via phase separation, cytoplasmic accumulation of toxic dipeptide repeats, quadruplex structures altering C9orf72 function, and RNA binding proteins, revealing the bewildering complexity of hexanucleotide r(G4C2)2 ALS-FTD (78).
A study of single-cell transcriptomics (scRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9orf72 patients revealed alterations of gene expression, with the greatest changes in the upper and deeper layers of excitatory neurons, as well as in astrocytes. In neurons, the changes reflect proteostasis, metabolism, and protein expression pathways, alongside decreased function in astrocytes. These changes suggest activation and structural remodeling. Patients with ALS-FTD had fewer neuronal nuclei in the frontal cortex and increased expression of multiple genes within glial cells (129).
The protein TANK-binding kinase 1 (TBK1) gene causes FTD-ALS along with C9orf72. TBK1 is phosphorylated in response to C9orf72 aggregation and sequestered into inclusions, resulting in reduced TBK1 activity and leading to neurodegeneration. Dipeptide aggregation toxicity is augmented in these phenotypes, increasing TDP-43 pathology and causing endosomal augmentation. The disrupted endosomal pathway increases TDP-43 aggregation, suggesting that the interaction between TDP-43 and TBK1 is important in the pathogenesis of some forms of FTD-ALS (204). The C9orf72 dipeptide repeat sequesters TBK1 into inclusions, limiting its function with downstream effects on the endolysosomal pathway, thereby aggravating TBK1 function, which disrupts the endolysosomal pathway again and increases TDP-43 aggregation.
It has been shown in patient-derived induced pluripotent stem cells from postmortem brain tissue of patients with frontotemporal dementia that N6-methyladenosine (m6A), the most important regulator of mRNA methylation, is downregulated. Global m6A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, particularly in genes involved with synaptic activity and neuronal function. This modification in the C9orf72 intron sequence upstream of the expanded repeats enhances RNA decay via the nuclear reader YTH domain-containing protein (YTHDC1), a nuclear protein involved in splice site selection that localizes to YT bodies. Antisense RNA repeats can also be regulated through m6A. The decrease in m6A leads to repeat RNAs and polydipeptides that cause disease; increasing m6A methylation reduces RNA repeat levels and dipeptides and enhances cell survival, suggesting a therapeutic mechanism (130).
Through CRISPR interference screening of human-derived neurons, a receptor-type tyrosine-protein phosphatase S (PTP delta) has been found to be a strong modifier of poly-GR, that is, arginine-rich, dipeptide toxicity. Reducing PTP delta increases neuronal survival by increasing the protein phosphatidylinositol 3-phosphatase (P13P) with restored endosome and lysosome function. Knockdown of PTP delta or its inhibition rescues endolysosomal defects and improves the survival of C9orf72 ALS-FTD patient-derived neurons. The decreased PTP delta diminishes arginine-rich toxicity and rescues pathological and behavioral phenotypes in mice. This highlights an important role for phosphatidylinositol-3-phosphate endolysosomal defects caused by arginine-rich dipeptide repeats and suggests a therapeutic approach to ALS-FTD (248). That is, dipeptide repeat proteins in both sense and antisense forms can be modified by PTP delta by reducing disease phenotypes and toxicity caused by the repeats after elevating P13P and reducing PTP delta.
A large Australian family with frontotemporal dementia-motor neuron disease was shown to have the cytochrome lysine 63 deubiquitinase (CYLD) gene mutation as the cause (60); 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 three 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 (91). A rare mutation in the cytoplasmic dynein 1 heavy chain gene has been associated with ALS-FTD (147) 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 (198). 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 (41). Studies suggest that 30% of patients with ALS-FTD have genetic pathogenic mutations or variants (193).
Machine learning studies suggest polygenic risk 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 (182). The genetics of ALS-FTD show significant overlap (06; 187).
A cryptic exon is a piece of DNA, usually found in introns, that is expressed in mature mRNA during splicing, and it occurs when the factors that suppress these sequences are absent or when mutations affect the splicing sites. Such cryptic exons can disrupt gene expression, cause short or nonfunctional proteins, and trigger a nonsense-sequence-mediated decay of mRNA (202). With the loss of TDP-43, misspliced transcripts are formed of cryptic exons that generate de novo proteins. These intronic sequences or cryptic exons give rise to new proteins, which can be identified in the CSF of patients with ALS-FTD. Cryptic exons are translated and contribute to the mechanism of disease pathogenesis. Cryptic exons in pluripotential stem cells were found in CSF from patients with ALS-FTD. Cryptic exons lead to new proteins with cryptic peptide sequences that interact with other proteins, resulting in loss of function and contributing to disease--a downstream mechanism of TDP-43 dysfunction in ALS-FTD. Eighteen de novo proteins have been detected in the CSF of patients with ALS-FTD (202). In ALS-FTD, there is de-repression and inclusion of cryptic exons, which gives rise to loss of function of critical proteins, which are key players in pathogenesis like stathmin-2 (STMN2), a protein found in neurons that regulates microtubule dynamics, and proteins that modify disease progression like UNC13A, a gene that encodes a protein critical for neurotransmitter release at synapses (145). These aberrant splicing events promote novel therapeutic targets that influence gene expression and suggest biomarkers unique to specific brain areas (145).
In one study, a single-nuclei RNA sequencing dataset from the frontal and occipital lobes of C9orf72 patients with ALS-FTD was examined for cryptic exons. Transcripts containing cryptic exons in the gene STMN2 were identified in the Kalirin gene (KALRN), a protein that has a role in synaptic plasticity, the formation of dendritic arbors and spines (174). These cryptic exons were identified with the highest frequency in excitatory neurons; the neurons having the highest proportion of cryptic exons being von Economo neurons, which are thought to be vulnerable to TDP-43 pathology (85). These findings illustrate heterogeneous and biochemical abnormalities associated with transcriptomic alterations in TDP-43 pathology in ALS-FTD. Concentrating on STMN2 function offers a novel therapeutic approach to ALS-FTD.
A pathway has been identified in the pathogenesis of neurodegenerative diseases known as the stimulator of interferon genes (STING). STING is a series of chemical reactions important in immune cells. Postmortem cortical and spinal motor neurons from patients with familial or sporadic amyotrophic lateral sclerosis, particularly in layer 5 of cortical motor neurons, and in human-induced pluripotent cells, show that the STING pathway is activated in neurons. The stimulated interferon gene pathway is triggered by the cytosolic build-up of TDP-43 aggregates and nuclear envelope rupture. This path is switched on by vulnerable motor neurons and contributes to neuroinflammation and neurodegeneration. The STING pathway offers an alternative therapeutic approach in ALS-FTD (140).
Neurophysiology. Physiological mechanisms operate in the pathophysiology of ALS-FTD. Studies of C9orf72 repeat expansion mutations in ALS-FTD indicate hyperexcitability, both an 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 (176). Transcranial magnetic stimulation is the best technique to explore cortical hyperexcitability in ALS-FTD (76; 215).
Mechanisms of neurophysiological impairments in the cortex and lower motor neurons in C9orf72RE ALS
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 the frontal and temporal cortex is more extensive than the usual depletion of Betz cells observed in amyotrophic lateral sclerosis without dementia (100; 69; 139; 178). 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 (103). Familial cases also show ubiquitin-positive inclusions in the temporal and frontal lobes (155; 113).
Affected areas show dropout of interneurons that immunolabel with calbindin D-28k but not those that label with parvalbumin (70); 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 the cortex may reflect damage to neuronal dendritic processes (178). Furthermore, cortical lesions are more prominent at the crests of gyri than in sulci (111). 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 (229).
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 (158), 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 (79). 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 (136).
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 (111).
Degeneration of the substantia nigra is common in frontal lobe dementia cases and may be a marker for dementing cases of amyotrophic lateral sclerosis (100; 87; 139). The nucleus basalis of Meynert, locus ceruleus, and dorsal raphe appear unaffected (100; 139). 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 (87). Cholinergic activity, especially in the nucleus basalis, has been normal in several studies (100; 87).
MR spectroscopy has shown a reduction of the N-acetylaspartate and creatine ratio in the 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 (219).
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 (63; 230). 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 (223).
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 (168; 170).
Studies have focused on the potential role of astrocyte abnormalities that contribute to neuroinflammation, protein aggregation, atrophy, and degeneration in ALS-FTD. Astrocyte pathology is seen in animal and cellular models, paints a picture of molecular dysfunction in glial cells as important in the pathophysiology of ALS-FTD, and raises the question of treatments directed towards astrocytic function and dysfunction (231).
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Hypothetical stage-dependent involvement of astrocytes in the pathogenesis of ALS/FTD
(1) Under physiological conditions, astrocytes engage in homeostatic signaling with neurons (thick green arrow) and other glial cell types to maintain the optimal milieu within the CNS. (2) The expression of ALS/FTD-mutant prot...
Inflammasomes are intracellular macromolecular complexes that are sensors for the innate immune system and develop in response to cellular stress, activating inflammatory pathways. Inflammasomes form an acute response to infection and other processes, giving rise to tissue damage by a pore-forming caspase 1-mediated activation of gasdermin D that leads to a form of programmed cell death known as pyroptosis. Protein aggregates form neurodegenerative processes, activate inflammasomes, and amplify the neuropathology with cellular death and disease progression. In the CNS, the inflammasomes are mostly found in the microglia and nonmyeloid cells, but more work is required to establish exactly what role inflammasomes have in neurodegeneration, including misfolded protein aggregation, suggesting an alternative immune-mediated therapeutic pathway (210).
Autophagy is considered one of the major mechanisms of neuropathological reactions in C9orf72 ALS-FTD, with toxic gain-of-function driven by expanded-repeat RNA and dipeptide proteins, which impairs the autophagy-lysosome system, resulting in less mobile enlarged lysosomes, reduced autophagic flux, and increased TDP-43 mislocalization, leading to neurodegeneration. The gene mutations of ALS-FTD impair the autophagy-lysosome system in neurons (24). Autophagy is important, but it may not be adequate to cause disease, and upstream events that disturb the endolysosomal system might drive disease (227).
It has been emphasised that the common genes associated with ALS-FTD, including C9orf72, FUS, TARDBP, CHMP2B, FUS, and CHCHD10, are presynaptic in location, raising the likelihood that their altered regulation gives rise to synaptic dysfunction such that these disorders may be considered synaptopathies and that presynaptic mechanisms are important in ALS-FTD (48). The physiological impairment of synaptic function may be the earliest embodiment of neurologic disease in ALS-FTD; that synapse dysfunction is the fundamental lesson of ALS-FTD and the basis for the early excitatory hypothesis. That is, mutations causing ALS-FTD lead to a synaptopathy with presynaptic dysfunction. At the presynapse, synaptic vesicle recruitment, fusion, and recycling necessary for neurotransmitter release are impaired, pointing to synaptic dysfunction and synaptopathy as a fundamental mechanism in early ALS-FTD. These effects result in misregulation of presynaptic vesicle pools, impaired exo- and endocytosis, and disruption of the endolysosomal systems.
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Major known genes causative for ALS and FTD associated with synaptic dysfunction
(From: Clayton EL, Huggon L, Cousin MA, Mizielinska S. Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis. Brain 2024;147[7]:2289-307. Creative Commons Attribution 4.0 Internation...
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Molecular mechanisms underlying presynaptic dysfunction in ALS and FTD pathogenesis
(From: Clayton EL, Huggon L, Cousin MA, Mizielinska S. Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis. Brain 2024;147[7]:2289-307. Creative Commons Attribution 4.0 Internation...
Studies have implicated astrocytes, oligodendrocytes, microglial cells, and peripheral immune cells in loss and gain of function in C9orf72 ALS-FTD, with TDP-43 aggregates leading to toxicity of glial cells. The emerging role of glial cells points to possible therapeutic options and promotes their role in disease progression and prognosis (55).
Isolation of endothelial cells from postmortem human cortex with intranuclear indexing of transcriptomes and epitopes revealed a group of endothelial cells in FTD-ALS that show TDP-43 disruption, indicating that TDP-43 in endothelial cells may result in blood-brain barrier dysfunction not only in an ALS-FTD but other neurodegenerative disorders, with reduced nuclear beta-catenin and beta-catenin downstream genes with elevated TNF/NF-κB markers correlating with the loss of nuclear TDP-43, and increase in cytosomal TDP-43 with deplete RNA-binding proteins, suggesting that disruption in the blood-brain barrier contributes to the neuropathology, not only ALS-FTD but other neurodegenerative process (164).
Neurologic reactions that decrease translation cause the formation of cytoplasmic RNA/protein deposits known as stress granules. Proteins identified in these stress granules, as well as their formation and disruption, are involved in neurodegenerative processes. It is uncertain whether the stress granules are harmful or protective. Experimental studies using alphavirus protein nsP3 that binds to the central stress granule nuclear protein G3BP reduced stress granule formation without disrupting protein translational inhibitory pathways that trigger stress granule formation. In experimental models, reducing stress granule formation does not affect lifespan, whereas reducing stress granule formation in ALS-FTD models promoted the disease phenotype. Stress granules might, in fact, promote neurodegenerative disorders (86).
Single-cell dissection of human motor and prefrontal cortices in ALS-FTD generated a single-cell molecular atlas, which showed that vulnerable populations exist in cortical layers and that amyotrophic lateral sclerosis and frontotemporal dementia motor and spindle cells have similar molecular characteristics, and that neuronal loss in layers relates more to transcriptional activity than morphology and provides insight into cellular mechanisms (181).
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 (09). 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 (102). 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 are also considered one of the important mechanisms in frontotemporal dementia and 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 (124). The 4C2G expansion found in C9orf72 mutations gives rise to dipeptide repeat polypeptides (DPRs), which are neurotoxic. The dipeptide repeat polypeptides interfere with the 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 (88). 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 neuron 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 (175). Inflammation is thought to be 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 (132). 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 (74). Protein synthesis modulation is a possible therapeutic intervention in ALS-FTD; therapies that restore protein imbalance, but do not affect the 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) (44).
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 | |
|
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 | |
|
19. Stathmin 2 – TDP | |
|
20. Liquid-liquid phase separation | |
MicroRNAs (miRNAs) are single-stranded noncoding RNAs less than 22 nucleotides in length. They recognize sequences in the three 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 signatures in behavioral variant frontotemporal dementia is found in blood serum and CSF, including miR-233-3P, miR-22-3P, miR-15A-5P, and miR124. These micro-MRI are thought to be 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 (141).
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 (206).
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 (173).
Phenols such as flavanone and non-flavanone molecules have been successfully used in experimental models of ALS-FTD and might be a future therapy (161). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are important in ALS-FTD; hnRNPs are a 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 (18).
TDP43 is a member of this hnRNP family and is mislocated into the cytoplasm and has an effect on the 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 pathways; and TDP is implicated in acute and chronic inflammatory processes (18; 37). Amyotrophic lateral sclerosis patients have increased intrathecal T cell activation (194).
Mislocalization of FUS and TDP-43 into the cytoplasm are prominent pathophysiological mechanism, and a rapid in vitro test to quantify mislocalization has been developed (166). 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 (209).
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 inhibiting folding catalyzed by PPIA (17). The TDP-43 “knock in” mouse shows parvalbumin interneuron loss and impaired neurogenesis, which might be relevant to the pathophysiology of ALS-FTD (131). 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 (81).
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 (122). TDP-43 oligomers and their interactions may be important in ALS-FTD (151). Measurement of serum protein levels suggests impaired calcium and immune dysregulation in frontotemporal dementia-amyotrophic lateral sclerosis (112).
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 (160).
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 (73). Pathogenic Huntington repeat expansions have been identified in frontotemporal dementia and amyotrophic lateral sclerosis; their significance is unclear, but they might reflect spontaneous mutations (58). Studies of the UNC13A polymorphism suggest vesicle maturation during exocytosis, and neurotransmitter release might be affected in ALS-FTD (222). 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 (176).
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 (27).
It is now regarded that the TDP-43 proteinopathies are amyotrophic lateral sclerosis, frontotemporal dementia, ALS plus FTD, and late-onset TDP-43 encephalopathy. In ALS-FTD, there is gain of toxicity and loss of the normal function of TDP-43, with TDP-43 aggregates acting as self-templating seeds and propagating pathology via a prion mechanism (201).
It has been found that TDP-43 influences the splicing of many genes, including its own gene TARDBP. It is recognized that TDP-43 influences the splicing of a number of genes, including UNC13A, a TDP-43 target gene. Interestingly, single-nucleotide polymorphs (SNPs) in UNC13A are the most common risk factors for ALS-FTD. TDP-43 has been found to decrease the cryptic exon inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon causes an increased RNA level of UNC13A, retaining the cryptic exon. TDP-43 self-regulates by alternative splicing, and this is influenced by aging linked to DNA methylation, suggesting that this aging mechanism brings about sporadic ALS-FTD by affecting autoregulation and UNC13A. TDP-43 levels are influenced by alternative splicing of TARDBP mRNA (123). Demethylation reduces alternative splicing and increases TARDBP mRNA levels; with aging, this TARDBP is demethylated and associated with early-onset amyotrophic lateral sclerosis (123). Thus, TDP43 autoregulates itself. It has been revealed that shortened TAR DNA binding proteins 43 (sTDP-43) isoforms are generated by this autoregulation. sTDP-43 levels are regulated through nonsense-mediated decay and proteasomal and autophagic degradation mechanisms, which lead to toxicity by a dominant negative effect on TDP-43 splicing. These mechanisms show that sTDP-43 accumulation and toxicity influence disease (207).
It should be noted that TDP-43 is a multidomain protein involved in regulating DNA metabolism, with aggregates depositing in neurodegenerative diseases. TDP-43 can undergo liquid-liquid phase separation in vitro and is a component of biological condensates. All atom and coarse-grained molecular dynamics simulations have revealed a network of interdomain interactions implicated in TDP-43 phase separation. All simulations reveal transient interdomain interactions involving flexible linkers, RNA-recognition motif domains, and a charged segment of a disordered C-terminal domain. CG simulations influence interdomain interactions, which affect the conformation of TDP-43 in the dilute and condensed phases. Transient interdomain contacts are electrostatic in nature and highlight the heterogeneous interactions of TDP-43 that might present as a possible future therapeutic implication (150).
The complex network of interactions involved in the formation of TDP‐43 condensates
(From: Mohanty P, Rizuan A, Kim YC, et al. A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior. Protein Sci 2024;33[2]:e4891. Creative Commons...
TDP-43 nuclear RNA-processing function destabilizes the transcriptome by multiple mechanisms: disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid-liquid phase and aggregation, traps TDP-43 in the cytoplasm and disrupts a number of mechanisms, including the trafficking of RNA granules, local translation within axons, and mitochondrial function. This suggests that therapeutic attempts to increase the clearance of TDP-43 aggregates and address other causes of TDP-43 disruption (eg, stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and reversal of aberrant splicing events) are promising therapeutic approaches (96).
RNA methylation at adenosine N6 (m6A) is probably one of the most common RNA modifications, influencing RNA stability, transport, and translation. RNA destabilization is evident in amyotrophic lateral sclerosis with increased TDP43. TDP43 recognizes m6A RNA, and that RNA methylation is critical for TDP binding and autoregulation. Extensive RNA hypomethylation in ALS spinal cord equals methylated TDP43 substrates. m6A seems to be important for TDP43 binding and function, and several factors have been identified that interact with m6A that increase or decrease TDP43-mediated toxicity using single-cell CRISPR-Cas9 experiments. The most promising factor is YTHDF2 (YTH Domain Family member – a protein that reads N6–methyladenosine [m6A] marks on RNA and is an important regulator of RNA metabolism), which accumulates in ALS spinal cords, and its knockdown prolonged the survival of human motor neurons in ALS mutated cells; this offers a novel future therapeutic approach (144).
It has been shown that plasma extracellular vesicles contain tau and TDP-43, which can be measured; such an assay might be a useful diagnostic biomarker, as full-length 3R and 4R tau can be calculated, which may be useful in the diagnosis of FTD-ALS spectrum disorders (45).
The protein 14.3.3 is ubiquitously expressed in the cytoplasm and regulates the cell cycle, signal transduction, metabolism, and apoptosis through phosphorylation. 14.3.3 is an important protein that, in the CSF, aids in the diagnosis of prion diseases. This protein is abundant in the brain and involved in brain development and other functions. It has been shown that 14.3.3 binds to TDP-43. Increased neuronal 14.3.3 encourages TDP-43 pathology. TDP binds to 14.3.3 and causes cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43-enhancing pathology. This raises an important therapeutic principle that reduction of TDP-43 using a gene approach to 14.3.3 might be a means of treating patients with ALS-FTD, and this concept has been supported by experiments using gene therapy vectors (114).
TAR DNA-binding protein-43 is found within ribonucleoprotein granules and is tethered to lysosomes by the protein Annexin A11. The Annexin A11 protein forms aggregates in ALS with pathogenic variants of its own gene, ANXA11. It is found that A11 aggregates colocalize with TDP-43 in patients with FTD/TDP type C. ALS-FTD type C has TDP inclusions in the language areas of the brain (ie, the semantic variant of primary progressive aphasia), namely, in the anterior temporal lobes. Annexin A11 inclusions have also been demonstrated in sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. Co-aggregation of Annexin A11 and TDP-43 aggregates in ALS with the pathogenic ANXA11 variants has been recorded. Abundant Annexin A11 inclusions have also been found in a pathological variant of a rare type of progressive supranuclear palsy with prominent striatal vacuolisation due to a novel ANXA11 mutation. It is highlighted that Annexin A11 forms abundant deposits in sporadic and genetic forms of TDP-43 proteinopathies and that, by itself, Annexin A11 aggregates may cause neurodegeneration (192).
It has been shown with cryo-electron microscopy that Annexin A11 co-assembles with TDP-43 to form heteromeric amyloid filaments. Immunohistochemistry has disclosed the co-localization of ANXA11 and TDP-43, redefining the classification of FTD/TDP type C. The concept of amyloid assembly as a fundamental mechanism of neurodegenerative disorders raises the possibility that multiple proteins may co-aggregate, forming heteromeric amyloid filaments (14).
The study of TDP-43 raises options for therapeutic intervention by activating protein clearance from the cytoplasm, restoring nuclear function, and reinstating its other functions in RNA metabolism, DNA repair, mitochondrial disorder, oxidative stress, apoptosis, axonal transport, and reducing phase separation (245).
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 is important physiologically and pathologically. Liquid-liquid phase separation of important proteins 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 (65).
Molecular insights into ALS-FTD using cryo-electron microscopy. Cryo-electron microscopy uses a transmission electron microscope with biological samples suspended in ethane to prevent crystal formation, which preserves the structure of biomolecules. After examination with transmission electron microscopy, computer software generates images to construct molecular models. Cryo-electron microscopy has provided insights into heterogeneous nuclear riboproteins (hnRNP), which represent a large group of RNA-binding proteins that control RNA synthesis, like TDP-43, FUS, and others. These hnRNPs assemble into active amyloids that bind to DNA and RNA; this amyloid process causes disease (75).
Electromicroscopic studies of TDP-43 aggregates, taken from the frontal motor cortices of two patients who died from ALS-FTLD, revealed an identical amyloid-like filament structure comprising a single protofilament in both patients. The TDP-43 molecule adopts a double-spiral-shaped fold, without beta-sheet stacking. Cryo-microscopy has shown that TDP-43 aggregates from individuals with ALS form pathogenic amyloid-like filaments (13).
Cryo-electron microscopy has shown that poly-PR and poly-GR dipeptide proteins with more than 20 repeats block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Cryo-electron microscopy has shown how these dipeptide repeats block the ribosome tunnel, inhibit translation, and contribute to disease pathogenesis of C9orf72 ALS-FTD (135).
Other cryo-electron microscopic studies have shown that TDP-43 fibrils are polymorphic and adopt three amyloid structures. The structures differ in the number and orientation of these protofilaments but share an amyloid motif (205).
Studies of patients with FTLD-TDP type C(ie, semantic dementia) revealed that a second protein, Annexin A11 (ANXA11), co-assembles with TDP-43 to form heteromeric amyloid filaments; immunocytochemical studies on the brain confirmed the co-localization of ANXA11 and TDP-43, which has redefined the pathological foundation of FTLD-TDP type C and makes this protein interaction a likely fundamental process in ALS-FTD. This exciting finding, indicating that more than one protein may aggregate to form amyloidogenic proteins and cause neurodegenerative disorders, needs to be searched for in other neurodegenerative conditions (14).
It has also been revealed that TDP-43 forms distinct amyloid fibrils in FTLD-TDP type A (ie, behavioral variant frontotemporal dementia and progressive nonfluent aphasia with TDP43 intraneural inclusions and short dystrophic neurites) with a new fold that resembles a chevron badge and is distinct from the double-spiral-shaped fold of ALS and Type B FTLD-TDP (diffuse inclusions). These observations establish that TDP-43 forms amyloidogenic proteins by self-assembly and with other proteins, like Annexin A11, to form heteromeric amyloid filaments that misfold, aggregate, and propagate into toxic amyloid fibrils that disturb cellular function, activate inflammation, and cause oxidative stress and neuronal death. These discoveries expand our understanding of the TDP-43 proteinopathies (12).
Cryo-electron structures of TDP-43 amyloid filaments from individuals with Type A and Type B FTLD-TDP + ALS
(From: Arseni D, Chen R, Murzin AG, et al. TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 2023;620[7975]:898-903. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommo...
Intrinsically disordered regions, including prion-like domains and RG/RGG-rich areas, form ribonucleic protein granules and stress granules through liquid-liquid phase separation and progress to pathological assemblies like hydrogels, inclusions, and amyloid fibrils. These mechanisms are mediated by RNA/DNA and ATP. Similar mechanisms apply to normally folded proteins and mutations. These mechanisms in physiological circumstances are important in transcription, splicing, microRNA formation, RNA stability and transport, and DNA repair (213).
Interplay of IDR-rich proteins and mutants of folded proteins in LLPS and amyloid fibrillation, which is universally mediated by ATP and nucleic acids
(From: Song J. Molecular mechanisms of phase separation and amyloidosis of ALS/FTD-linked FUS and TDP-43. Aging Dis 2024;15[5]:2084-112. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/li...
Epidemiology
Estimates of the prevalence of dementia in amyotrophic lateral sclerosis range from 15% to 40% (133; 190), with a wider range of estimates, from 10% to 75%, for cognitive or behavioral impairments not meeting criteria for the diagnosis of dementia (184; 71). Historical estimates placed the frequency of dementia at 1% to 2% in sporadic amyotrophic lateral sclerosis (152; 177) and higher (15%) for familial amyotrophic lateral sclerosis (103).
Investigators are still debating whether dementia associated with amyotrophic lateral sclerosis is the equivalent of the motor neuron disease variant of frontotemporal dementia (156; 157). However, there is emerging evidence for the overlap of these two entities (31) based on the convergence of clinical, neuropathological, and genetic evidence suggesting a continuum model of the diseases (79). Most investigators agree that the order of appearance (neurologic changes before cognitive impairment or vice versa) does not preclude classification of the dementia associated with amyotrophic lateral sclerosis as a frontotemporal dementia syndrome.
Prevention
Until the pathogenesis and pathophysiology of these disorders are fully ascertained, there can be no definitive comments about prevention.
Once the molecular mechanisms have been elucidated, it may be possible to use technologies such as CRISPR and preimplantation genetic diagnoses to eradicate amyotrophic lateral sclerosis-frontotemporal dementia and other neurodegenerative conditions (238).
Now that many of the genetic and molecular mechanisms are understood, prevention of ALS-FTD is possible, especially in the situation where genetic mutations are recognized, but more difficult in the more common sporadic cases of frontotemporal dementia-amyotrophic lateral sclerosis (29). Investigations with induced pluripotent stem cells derived motor neurons carrying the hexanucleotide repeat mutation induced by CRISPR show correction of the amyotrophic lateral sclerosis phenotype, suggesting a possible role of gene editing in prevention ALS-FTD (01).
Differential diagnosis
The differential diagnosis may include a dementia specifically resulting from neuropathological changes associated with amyotrophic lateral sclerosis or the co-occurrence of amyotrophic lateral sclerosis and another dementing illness. It may be difficult to distinguish the etiology of the dementia until one can make a pathologic diagnosis from brain biopsy or autopsy. Postmortem studies on patients with dementia associated with amyotrophic lateral sclerosis commonly reveal concomitant frontotemporal lobar degeneration, and less commonly Alzheimer disease, Creutzfeldt-Jakob disease, or Pick disease. Dementia has been reported rarely in spinal muscular atrophy (67).
Similar clinical dementia syndromes can be found with non-amyotrophic lateral sclerosis motor neuron disorders. Motor neuron involvement has been recognized in postencephalitic states and in forms of Creutzfeldt-Jakob disease. An association of these symptoms with pantothenate kinase-associated neurodegeneration has also been recognized (33; 172).
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. Consensus recommendations (217) 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 deemed not yet suitable for clinical use as predictive tools (217). Structural neuroimaging studies on patients with amyotrophic lateral sclerosis reveal frontotemporal atrophy in patients with and without dementia (110; 118; 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 four 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 (16).
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 (225; 23). 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; 224). 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 two illnesses (92).
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 (238).
Management
Several drugs have been approved by the FDA for the treatment of amyotrophic lateral sclerosis, including riluzole, a glutamate antagonist, and edaravone, an antioxidant. Tofersen, an anti-sense oligonucleotide, received approval by the FDA in 2023 for patients with SOD1 mutations only; SOD1 mutations do not cause ALS-FTD (148). 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 (221; 10). Open-label trials of the NMDA-receptor antagonist memantine have demonstrated variable results in treating the behavioral symptoms of frontotemporal dementia (34; 59). Randomized, controlled clinical trials have failed to demonstrate a benefit of memantine in frontotemporal dementia (234; 35). 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 (237).
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 (117). The cholinesterase inhibitor donepezil increased frontal behaviors in a small group of patients (146), whereas rivastigmine showed some benefit (153). However, larger, more rigorous studies are required to investigate the role of neurotransmitter modulation in frontotemporal dementia (104). 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 (125). Medications targeting proteostasis might be useful in ALS-FTD, and one example is trehalose, which has been shown to inhibit protein misfolding (66). Monoaminergic dysfunction might suggest treatment possibilities for frontotemporal dementia-amyotrophic lateral sclerosis, but not kynurenine genetic pathways (108).
Experimental neurotherapeutics. Intronic G4C2 repeat expansions cause bidirectional transcription of sense and antisense repeat RNA sequences, leading to dipeptide proteins. Toxicity is identified in both sense and antisense RNA and dipeptide repeats. CRISPR-Cas13 targeting reduces C9orf72 repeats in HEK cells. C9orf72 patient-obtained pluri-potential stem cells showed that CRISPR-CasRx reduces sense and antisense RNA and dipeptide repeats, reducing glutamate toxicity. Adenovirus vectors of CRISPR-CasRx in a mouse model affected sense and antisense transcription. Using CRISPR-Cas13 technology reduced overexpressed C9orf72 sense and antisense repeat transcripts and dipeptide repeat polypeptides in experimental cells. Patient-derived pre-potential stem cells also reduced exogenous sense and antisense using CRISPR-CasRx approaches, protecting against glutamate-induced excitotoxicity. Adenovirus delivery of CRISPR-CasRx C9orf72 mouse models reduced both sense and antisense repeat-containing transcripts, indicating the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS-FTD (115).
Animal models of C9orf72 repeat expansions leading to ALS-FTD revealed that polyunsaturated fatty acids are protective in this disease. Overexpression of fatty acid desaturated molecules suppressed stressor-induced neuronal death in pluripotent stem cells derived from patients with TDP-43 ALS-FTD. Treatments that increase neuronal polyunsaturated fatty acids might help in ALS-FTD (84).
Outcomes
There have been a bewildering number of developments in the understanding of ALS-FTD from new genes, single-cell techniques, cryptic exons, cryo-electron microscopy, cell biology, pharmacology, molecular biology, methylation, biophysics of liquid phase separation, the importance of amyloid filament formation, and endosome-phagosome interactions. These activities have increased our understanding of ALS-FTD, but much more work is required before a new treatment becomes available. These insights have relevance to other neurodegenerative disorders.
Media
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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 FANZAN
Dr. Panegyres, Director of Neurodegenerative Disorders Research Pty Ltd, has no relevant financial relationships to disclose.
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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
- Tiffany W Chow MD
- Peter Hedera MD PhD
- 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-10
-
- Motor neuron disease: G12.2
- Dementia in other specified diseases classified elsewhere: F02.8
- Unspecified dementia: F03
- OMIM
-
- Amyotrophic lateral sclerosis 1: #105400
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