Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study

Abstract

ObjectiveThe pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype.MethodsFrom a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA‐binding protein (TDP‐43) inclusions, we selected those with PNLD and analyzed their clinicopathological features.ResultsEleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP‐43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneiderʼs staging or Nishihiraʼs typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP‐43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP‐43 aggregates from the cerebral cortex to the substantia nigra.InterpretationThe PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP‐43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302–312

Role of the nigrosome 1 absence as a biomarker in amyotrophic lateral sclerosis

“…Thus, in postmortem studies, the SNpc becomes involved in about 20-30% of patients [2,4,33], a similar proportion to the nigrosome 1 loss found in our study. Different neuropathological patterns of involvement of the SNpc can be distinguished among ALS cases.…”

“…In this study, we show for the first time that nigrosome 1 is absent, on at least one side of the SNpc, in 30% of ALS patients with different phenotypes, compared to about 95% of PD patients and 10% of healthy controls [ 22 ]. Interestingly, the neuropathologic involvement of the SNpc has been found in a similar percentage of patients in postmortem studies [ 2 , 4 , 33 ].…”

“…On the one hand, the SNpc involvement is a feature of a subset of cALS patients being in an advanced neuropathological stage (2–4) [ 2 , 4 ]. On the other hand, the SNpc involvement is a hallmark of ALS with pallidonigroluysian degeneration [ 2 , 4 , 33 ]. Similarly, different clinical patterns of patients combining motor neuron disease and parkinsonism have been described (e.g.…”

“…Thus, the absence of nigrosome 1 in ALS patients could be a marker of the cerebral neuropathological expansion of the disease to the second neuropathological stage, as proposed by Brettschneider et al [ 2 ]. In this respect, the lack of association between the nigrosome absence and disability or disease duration is not surprising, since the neuropathological extension in ALS is not related with none of these variables [ 2 , 3 , 33 ].…”

Estudos genéticos e funcionais sobre os genes VAPB e VRK1 em duas famílias portadoras de Esclerose Lateral Amiotrófica

“…Tratam-se, portanto de fenótipos associados à degeneração nos gânglios da base. Nesses casos, extremamente raros e que podem vir ou não acompanhados de ELA, os indivíduos têm sido classificados dentro de outro espectro fenotípico, que também inclui as Paralisias Supranucleares Progressivas (Uchino et al, 2018;Ito et al, 2020).…”