Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor

Abstract

Based on accumulating post-mortem evidence of abnormalities in Purkinje cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P=0.01), 465.9 versus 592.5 µm (branch length, P=0.01), 22.5 versus 29.0 (maximum branch order, P=0.001), and 165.3 versus 311.7 (number of terminations, P=0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians=0.82 versus 1.02 µm(-1), P=0.03). Our demonstration of regressive changes in Purkinje cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje cell biology in this disease, which affects multiple neuronal cellular compartments including their axon, cell body, dendrites and spines.

Memory Similarities Between Essential Tremor and Parkinson’s Disease: A Final Common Pathway?

“…Cerebellar degenerative changes (e.g., Purkinje cell loss, axonal swelling, and reduced dendritic complexity) are thought to contribute to motor manifestations of ET, but an emerging line of evidence implicates a role of this pathology in the development of cognitive deficits, such that selective impairments may depend upon the particular corticocerebellar circuits affected by the disorder (Louis et al, 2014; Middleton & Strick, 2000; Troster et al, 2002). As documented in histological studies in primates, a two-stage system links the cerebellum with cortical regions involved in cognitive functioning.…”

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

“…These changes span across all Purkinje cell compartments (Figs. 1, 2, 3, 4, and 5), including (1) the dendritic compartment, where there is an increase in number of Purkinje cell dendritic swellings, a pruning of the dendritic arbor, and a reduction in spine density [5,6]; (2) the cell body, where aside from reductions in Purkinje cell linear density in some studies, with an increase in the number of empty baskets (i.e., basket cell axonal processes without an accompanying Purkinje cell), there is an increase in the number of heterotopic Purkinje cell soma [7][8][9]; and (3) the axonal compartment, where a broad range of changes in axonal morphology have been observed, including an increase in the number of thickened axonal profiles, torpedoes, arciform axons, axonal recurrent collaterals, axonal branching, and terminal axonal sprouting with increase in the Purkinje cell infraganglionic plexus [8]. Additional changes, possibly the result of secondary remodeling, have also been observed in neighboring neuronal populations.…”

Neuropathology of Essential Tremor

“…Whereas limited previous clinic pathological studies of ET patients have been elusive, more recent controlled postmortem studies demonstrated a considerable number of structural changes in the ET cerebellum, involving Purkinje cell and neighboring neuronal populations [9,10,12,13]. Purkinje cell loss has been documented in some, although not all studies [8,10,[14][15][16][17].…”

“…Purkinje cell loss has been documented in some, although not all studies [8,10,[14][15][16][17]. Hence, there are conflicting data resulting in considerable controversy over the issue of Purkinje cell loss and related changes of cerebellar structures as well as abnormal climbing fiber-Purkinje cell connections, loss of dendritic spines and the occurrrence of Purkinje cell axonal swellings ("torpedoes") in ET, whereas no changes in parallel counts and density were seen in ET [9,11,13,[17][18][19][20]. Three recent clinicopathological studies of ET patients reported deviating results concerning cerebellar pathology.…”