Prevalence and patterns of cognitive impairment in sporadic ALS
ABSTRACT To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.
Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.
On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.
These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.
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ABSTRACT: The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD–ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.Annals of the New York Academy of Sciences 12/2014; 1338(1). DOI:10.1111/nyas.12638 · 4.31 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, which primarily affects motor neurons leading to progressive paralysis and death within a few years from onset. The pathological hallmark of ALS is the presence of cytoplasmic ubiquitinated protein inclusions in motor neurons and glial cells primarily in the spinal cord. While the vast majority of ALS occurs sporadically (sALS), in ~10% of cases, called familial ALS (fALS), there is clear indication of genetic inheritance. In the last decade, enormous progress was made in unravelling the aetiology of the disease, with the identification of ALS-causing mutations in new genes, as well as key molecular players involved in the origin or progression of ALS. However, much more needs to be done, as the pathogenic mechanisms triggered by a genetic or sporadic event leading to cytotoxicity and neuronal cell death are still poorly understood. The recent discoveries offer new possibilities for devising experimental animal and cellular models, which will hopefully contribute to the development of new techniques for early diagnosis and the identification of therapeutic targets for ALS. Here we review the current understanding of the aetiology, genetics, and pathogenic factors and mechanisms of ALS. We also discuss the challenges in deciphering ALS pathogenesis that result from the high complexity and heterogeneity of the disease.
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ABSTRACT: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.01/2015; 3(1):19. DOI:10.1186/s40478-015-0190-6