Coexisting Lewy body disease and clinical parkinsonism in amyotrophic lateral sclerosis

Abstract

Background Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA‐binding protein (pTDP‐43) inclusions in motor and non‐motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity. Methods All ALS cases held by the New South Wales Brain Bank (n = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined. Results Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities. Conclusion The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.

Parkinson’s disease with a typical clinical course of 17 years overlapped by Creutzfeldt–Jakob disease: an autopsy case report

“…Notably, the coexistence of the deposition of proteins such as amyloid-β, tau, and/or TDP-43 in brains with CJD with LBs has been reported in five out of the seven published autopsy cases (including our patient; Table 1), thus emphasizing the importance of mixed pathologies in clinico-neuropathological studies of CJD as well as in older individuals. Indeed, it has been noted that the comorbidity of neurodegenerative diseases occurs more frequently than would be expected from the epidemiological data for each disease [25][26][27]. Molecular cross-talk among misfolded proteins through cross-seeding might explain the frequent finding of mixed pathologies [28].…”

The etiopathogenetic and pathophysiological spectrum of parkinsonism

“…However, the coexisting Lewy body pathology in ALS may be more frequent than once thought. Yet the concomitant pathology does not seem to influence the clinical phenotype necessarily, and parkinsonism may be clinically evident in only about 50% of cases [59].…”

“…In a limited number of cases of ALS, Lewy bodies, generally associated with PD and Lewy body disease (LBD), have also been documented in ALS cases, although their clinical relevance is unknown [59]. However, the coexisting Lewy body pathology in ALS may be more frequent than once thought.…”

Common Fatal Neurodegenerative Diseases Revisited: Beyond Age, Comorbidities, and Devastating Terminal Neuropathology There Is Hope With Prevention

“…ALS is associated with a spectrum of clinical phenotypes, with cognitive and/or behavioral symptoms and shows progressive degeneration of upper and/or lower motor neurons ( 26 ). Interestingly, PD features have been reported in up to 30% of ALS patients, and Lewy bodies, associated with Lewy body disease (LBD), have been reported in a small number of ALS cases ( 27 ). The overlap of misfolded proteins among patients with AD at autopsy - tau and Aβ, α-synuclein, and TDP-43, along with Braak neurofibrillary tangle stages I to VI-, is not unusual.…”