Characterization of amyotrophic lateral sclerosis and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS) produces progressive weakness, muscular wasting, and spasticity leading to death from respiratory failure at a median of 3 years after onset. ALS and frontotemporal dementia (FTD) overlap in both familial and sporadic cases of ALS. When both occur in families, the affected members may have only ALS, only FTD, or both. This suggests a relationship in the cause of these disorders. We investigated the frequency of ALS in FTD patients and of FTD in ALS patients and found the overlap to be more common than had previously been reported. We report the features of cognitive impairment and pattern of motor involvement in these ALS-FTD patients, and the degree of overlap in both populations.     

The relationship between amyotrophic lateral sclerosis and frontotemporal dementia

Despite the traditional view of amyotrophic lateral sclerosis (ALS) as an isolated motor neuron disorder, recent evidence suggests that ALS is, in fact, a multisystem disorder with a varying presentation and with widespread extramotor neuropathologic involvement. Support for a concept of ALS as a multisystem disorder has some basis in historical clinical reports that have highlighted the existence of a frank dementia in at least a small percentage of ALS patients. More recent evidence of extramotor involvement in ALS, derived from neurocognitive, neuropathologic, genetic, proteomic, and neuroradiologic perspectives, provides further support for these early observations and has drawn considerable attention to a possible association between ALS and frontotemporal dementia (FTD). Literature from these diverse clinical and basic scientific disciplines, when integrated, demonstrates commonalities between ALS and FTD and suggests that these disorders not only affect the same general neuroanatomic substrate, but also may represent two points on the same neuropathologic continuum. This review discusses this putative association between ALS and FTD and provides possible directions for future research in this area.     

The relationship between amyotrophic lateral sclerosis and frontotemporal dementia

Despite the traditional view of amyotrophic lateral sclerosis (ALS) as an isolated motor neuron disorder, recent evidence suggests that ALS is, in fact, a multisystem disorder with a varying presentation and with widespread extramotor neuropathologic involvement. Support for a concept of ALS as a multisystem disorder has some basis in historical clinical reports that have highlighted the existence of a frank dementia in at least a small percentage of ALS patients. More recent evidence of extramotor involvement in ALS, derived from neurocognitive, neuropathologic, genetic, proteomic, and neuroradiologic perspectives, provides further support for these early observations and has drawn considerable attention to a possible association between ALS and frontotemporal dementia (FTD). Literature from these diverse clinical and basic scientific disciplines, when integrated, demonstrates commonalities between ALS and FTD and suggests that these disorders not only affect the same general neuroanatomic substrate, but also may represent two points on the same neuropathologic continuum. This review discusses this putative association between ALS and FTD and provides possible directions for future research in this area.     

The overlap of amyotrophic lateral sclerosis and frontotemporal dementia

Patients with frontotemporal dementia (FTD) with no known diagnosis of ALS or family history of ALS were clinically and electrophysiologically assessed for the presence of ALS. Of 36 patients studied, five met criteria for a definite diagnosis of ALS and two had EMG findings suggestive of denervation in one limb. An additional five patients had prominent fasciculations and six other patients had trouble swallowing but all had normal results on EMG studies. One of the patients with fasciculations and a normal EMG study progressed to definite ALS over the course of 1 year.     

A case of progressive non-fluent aphasia as onset of amyotrophic lateral sclerosis with frontotemporal dementia

The association between Amyotrophic Lateral Sclerosis (ASL) and FrontoTemporal Dementia (FTD) is well known. Most of reports describing ASL-FTD cases show a strong association between ALS and the behavioural form of FTD. Conversely, the association between ALS and pure Semantic Dementia or Progressive Non-Fluent Aphasia (PNFA) is extremely rare, ranging from 1 to 3%. A clinical phenotype characterized by a rapidly progressive aphasic dementia and motoneuron disease (MND) has been described in few case reports; since the updating of PNFA diagnostic criteria in 2011, no clinical report has been related. We want to describe a case of patient presented, at the onset, as PNFA who developed, one year later, ALS with bulbar onset. The patient was screened for the main genes causing or associated with MND and/or dementia but no variants with a pathogenetic effect were observed.     

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.     

UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia

Recent findings highlight a pathologic and functional convergence in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) at the level of protein recycling and disposal. Genes linked to rare cases of familial ALS and ALS-FTD, like UBQLN2, OPTN, SQSTM1/p62, and VCP, may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Interactions between these genes need to be further explored to understand their common molecular pathways. Future efforts should be directed toward generation and characterization of in vivo models to dissect the pathogenic mechanisms of ALS and ALS-FTD and the role of protein degradation pathways, both centrally, at the cell body, and peripherally, at the level of the synapse. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences in ALS and ALS-FTD and, possibly, other neurodegenerative diseases as well.     

Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes

Objective

Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS–FTD.

Methods

The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS–FTD.

Results

Missense changes were identified in an ALS–FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear.

Conclusion

PGRN mutations are not a common cause of ALS phenotypes.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3–5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.¹ Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.² Approximately 5% of ALS patients have FTD (ALS–FTD)³ and approximately half of patients with “classical” ALS have subtle frontal and temporal lobe cognitive impairment.⁴ Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness⁵ and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy.⁶Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD.^7,8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS–FTD for mutations in this gene.     

Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets

Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons. The onset of disease typically occurs in the fifth decade of life and progresses rapidly; death occurs for 75% of patients within 5 years. The only drug that is available to treat ALS is riluzole, which extends survival by just 2-3 months. Thus, new therapeutic directions are being sought to prolong the lifespan of ALS patients. Since the discovery of SOD1 as a genetic determinant of ALS in 1993, SOD1-models of ALS have been extensively employed for the development of ALS therapeutics. Novel genetic targets are now under investigation following the recent discoveries linking TDP-43, FUS/TLS, angiogenin, KIFAP3 and UNC13A to ALS. In this review, we present several of the genetic contributors to both sporadic and familial forms of ALS and discuss their potential as therapeutic targets for this devastating disease.     

Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis

Neurological Sciences - Recently, mutations in TBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the...     

Semantic dementia associated with amyotrophic lateral sclerosis

The association semantic dementia-amyotrophic lateral sclerosis has been rarely reported in the literature. We report a case study of a patient with a severe prosopagnosia in relation with semantic dementia associated, 12 months later, with a motor neuron disease.     

Protein aggregation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.     

Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with adult onset that generally progress rapidly after the onset of symptoms. The 2 conditions are independent, but they also overlap in a significant proportion of families, including 2 families in which the disorders are reported to be linked to chromosome 9p. A locus was established between the markers D9S2154 and D9S1791 by comparing haplotypes between these families. OBJECTIVE: To determine whether additional families have ALS and FTD linked to chromosome 9p. METHODS: Families were identified in Canada and France, and genotyping was performed using sequence tagged site markers around the ALS-FTD candidate interval. RESULTS: Three new families with mapping to the chromosome 9p ALS-FTD locus were identified. Analysis of the largest family shows a peak 2-point logarithm of odds (LOD) score of 2.81 and a multipoint LOD score of 3.01. The particular candidate interval delineated by this family spans 27.1 centimorgans (cM) between markers D9S157 and D9S1805. This reduces the centromeric boundary of the candidate interval compared with previously reported values, shortening the locus to 8.1 cM (8.0 megabase pairs). A maximum multipoint LOD score of 7.22 is obtained when the 3 families are combined. CONCLUSIONS: The identification of new families enables reduction of the ALS-FTD candidate region located on chromosome 9p. The clinical features observed in these families help characterize the profiles of ALS and FTD with linkage to chromosome 9p-linked families.