Prevalence and patterns of cognitive impairment in sporadic ALS

Ringholz, George; Appel, Stanley H.; Bradshaw, Major; Cooke, Norma; Mosnik, Diane; Schulz, Paul E.

doi:10.1212/01.wnl.0000172911.39167.b6

Cited by 747 publications

(503 citation statements)

References 42 publications

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“…FTLD and ALS belong to a clinicopathological spectrum of overlapping central nervous system (CNS) disorders and might also have common genetic etiologies. Clinically, both phenotypes may occur in the same patient (FTLD-ALS) [Lomen-Hoerth et al, 2003;Ringholz et al, 2005] or in the same family [Hosler et al, 2000;Vance et al, 2006;Morita et al, 2006;Valdmanis et al, 2007]. Pathologically, the TAR DNA binding protein 43 (TDP-43) was found as a major constituent of polyubiquitinated neuronal inclusions [Neumann et al, 2006] in both FTLDU and ALS patients [Neumann et al, 2006;Arai et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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Section: Introductionmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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“…Inhibitory activity can also explain neuromuscular and neurological disease predisposition in the elderly, as the sensitivity to GABA inhibitory activity is known to increase with age 51 . Finally, GABAergic activity has been implicated in cognitive dysfunction 52– 54 , which is a hallmark feature of neurological diseases and is often observed in late-stage neuromuscular disease 2– 7 . Taken together, these findings support the notion that the clinical features associated with neuromuscular and neurological diseases can be induced by activating the inhibitory system.…”

Section: The Clinical Features Of Neuromuscular and Neurological Disementioning

confidence: 99%

“…Thus, if RI overstimulation precedes SI involvement, the patient can present with an initial diagnosis of ALS and can progress to ALS-FTD, a common manifestation of cognitive dysfunction observed in 20–50% of patients with late-state ALS patients 2– 7 . Alternatively, if SI overstimulation precedes RI involvement, FTD is the initial diagnosis, and the disease can progress to FTD-ALS when the RI pathway becomes involved.…”

Section: The Si and Ri Pathways Can Explain Both The Progression Of Amentioning

confidence: 99%

“…With respect to Alzheimer’s disease and Parkinson’s disease, dysphagia and respiratory depression–related aspiration pneumonia are the most common causes of death 16, 17 . Neuromuscular diseases also present with the severe and potential fatal clinical manifestations listed in Table 1; 1– 7, 9– 11, 13, 15, 17– 21 thus, the ability to prevent these symptoms could significantly prolong the life expectancy of these patients. From a treatment perspective, it is interesting to note that the selective GABA antagonist SGS-742 has been shown to be both clinically feasible and safe 52 .…”

Section: Therapeutic Potential For Targeting Inhibitory Activitymentioning

confidence: 99%

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Inhibitory system overstimulation plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis

Tuk

2016

F1000Res

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Based upon a thorough review of published clinical observations regarding the inhibitory system, I hypothesize that this system may play a key role in the pathogenesis of a variety of neuromuscular and neurological diseases. Specifically, excitatory overstimulation, which is commonly reported in neuromuscular and neurological diseases, may be a homeostatic response to inhibitory overstimulation. Involvement of the inhibitory system in disease pathogenesis is highly relevant, given that most approaches currently being developed for treating neuromuscular and neurological diseases focus on reducing excitatory activity rather than reducing inhibitory activity.

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“…While traditionally considered a purely motor disease, neuronal abnormalities in the prefrontal and temporal cortex may also lead to frontal executive dysfunction, with about 15 % of patients manifesting frontotemporal dementia [2]. The worldwide incidence of ALS is 2-4 cases per 100,000 persons, although there is some ethnic variation [3].…”

Section: Introductionmentioning

confidence: 99%

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

2015

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Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor neurons without a known cure. Based on the possibility of cellular neuroprotection and early preclinical results, stem cells have gained widespread enthusiasm as a potential treatment strategy. Preclinical models demonstrate a protective role of engrafted stem cells and provided the basis for human trials carried out using various types of stem cells, as well as a range of cell delivery methods. To date, no trial has demonstrated a clear therapeutic benefit; however, results remain encouraging and are the basis for ongoing studies. In addition, stem cell technology continues to improve, and induced pluripotent stem cells may offer additional therapeutic options in the future. Improved disease models and clinical trials will be essential in order to validate stem cells as a beneficial therapy.

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Prevalence and patterns of cognitive impairment in sporadic ALS

Abstract: 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.

Cited by 747 publications

References 42 publications

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Inhibitory system overstimulation plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

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