Torpedo Formation and Purkinje Cell Loss: Modeling their Relationship in Cerebellar Disease

Abstract

Background Torpedo formation and Purkinje cell (PC) loss represent standard and inter-related cerebellar responses to injury. Surprisingly, the nature of their relationship has not been carefully characterized across a range of normal and disease states. Are brains with more torpedoes expected to have fewer PCs? We quantified torpedoes and PCs in four groups: essential tremor (ET), spinocerebellar ataxia (SCA), multiple system atrophy-cerebellar (MSA-C), and controls. Methods Brains from 100 individuals (58 ET, 27 controls, 7 SCA, 8 MSA-C) were available at the New York Brain Bank. After complete neuropathological assessment, a standard parasagittal neocerebellar block was harvested, a 7-μm thick section was stained with Luxol Fast Blue/Hematoxylin and Eosin, and torpedoes and PCs were quantified. Results For a given PC count, SCA and MSA-C cases often had higher torpedo counts than ET cases or controls. Furthermore, the relationship between torpedo and PC counts was complex. The correlation between torpedo and PC counts was negative in ET cases (i.e., individuals with more torpedoes had fewer PCs [i.e., more PC loss]) whereas the relationship was positive in MSA-C cases (i.e., individuals with fewer PCs [i.e., more PC loss] had fewer torpedoes). Patients with SCA showed both patterns. When all diagnostic groups were combined, the correlation was best fit by a quadratic (i.e. parabolic) model rather than a simple linear model; this model incorporated data on the negative correlation in ET cases, the mixed results in SCA cases, and the positive correlation in MSA-C cases (r = 0.636). Conclusions The relationship between torpedo and PC counts was complex and heterogeneous across a range of cerebellar disease states, and was best characterized by a quadratic rather than a simple model. With more severe cerebellar disease, torpedoes can be quite numerous, and are likely a common feature of surviving PCs, but eventually, dramatic loss of PC leads to a paradoxical reduction in observable torpedoes.

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

“…Purkinje cell axon torpedoes have been observed in diseased (Louis et al, 2006, 2009, 2014) and aged cerebellum (Baurle and Grusser-Cornehls, 1994), where they have often been associated with Purkinje cell death (Louis et al, 2014). We wondered whether developmental torpedoes might also be related to Purkinje cell death, since developmental apoptosis of Purkinje cells is a normal part of cerebellar development (Light et al, 2002; Jankowski et al, 2009).…”

“…The term “torpedo” was used to identify these focal swellings in 1918 by the Dutch psychiatrist Leendert Bouman (Bouman, 1918), and the term has been used since then to identify swellings or spheroids on Purkinje cell axons. Purkinje cell axonal torpedoes are observed in several diseases, including essential tremor (Louis et al, 2006, 2009, 2014), spinocerebellar ataxias (Sasaki et al, 1998; Yang et al, 2000; Louis et al, 2014), encephalopathy (Yagishita, 1978), and other cerebellar disorders (Hirano et al, 1973; Louis et al, 2014), and are especially prevalent in the cerebellar vermis (Louis et al, 2011). Torpedo-like swellings have also been observed in several spontaneously arising ataxic rodents, for e.g., weaver (Hirano et al, 1973), hyperspiny Purkinje cell (hpc) (Sotelo, 1990), and sticky mice (Sarna and Hawkes, 2011), groggy rats (Takeuchi et al, 1995), and in mouse models of disease such as Autosomal Recessive Ataxia of the Charlevoix-Saguenay Region (ARSACS) (Lariviere et al, 2015).…”

“…Taken together, these observations have led to the belief that Purkinje cell axonal torpedoes are associated with cerebellar damage and degeneration. Indeed, torpedoes can be observed on the axons of surviving cells at the same time as Purkinje cell death is observed (Louis et al, 2014). This suggests that the relationship between cell death and Purkinje cell torpedo accumulation is complex.…”

“…However, in diseases such as multiple system atrophy-cerebellar, torpedoes are more prevalent when Purkinje cell loss is minimal. Multiple system atrophy-cerebellar patients that have greater Purkinje cell loss have fewer torpedoes, possibly because the neurons with torpedoes have died (Louis et al, 2014). It is thus an open question whether torpedoes cause neurodegeneration or are in fact neuroprotective (Babij et al, 2013).…”

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

“…There is already, even at this early stage, some evidence that not all cerebellar diseases (including ET) display the same bland set of changes and that it is the particular combination or constellation of findings that might be useful in terms of distinguishing one disease from another. For example, the number of torpedoes relative to the extent of Purkinje cell loss has been shown to be quite different in ET patients compared to patients with spinocerebellar ataxia and multiple system atrophy [60]. Furthermore, changes in the molecular layer in spinocerebellar ataxia are not apparent in patients with ET [61]; conversely, changes in the region of the Purkinje cell's initial axonal segment are not present in patients with spinocerebellar ataxia but are present in those with ET [11].…”