New neuropathological findings in Unverricht-Lundborg disease: neuronal intranuclear and cytoplasmic inclusions.

Unverricht-Lundborg disease (EPM1A), also known as Baltic myoclonus, is the most common form of progressive myoclonic epilepsy. It is inherited as an autosomal recessive trait, due to mutations in the Cystatin-B gene promoter region. Although there is much work on rodent models of this disease, there is very little published neuropathology in patients with EPM1A. Here, we present the neuropathology of a patient with genetically confirmed EPM1A, who died at the age of 76. There was atrophy and gliosis affecting predominantly the cerebellum, frontotemporal cortex, hippocampus and thalamus. We have identified neuronal cytoplasmic inclusions containing the lysosomal proteins, Cathepsin-B and CD68. These inclusions also showed immunopositivity to both TDP-43 and FUS, in some cases associated with an absence of normal neuronal nuclear TDP-43 staining. There were also occasional ubiquitinylated neuronal intranuclear inclusions, some of which were FUS immunopositive. This finding is consistent with neurodegeneration in EPM1A as at least a partial consequence of lysosomal damage to neurons, which have reduced Cystatin-B-related neuroprotection. It also reveals a genetically defined neurodegenerative disease with both FUS and TDP-43 related pathology.

Pathophysiology of dementias and implications for therapy.

Dementia is characterized clinically by progressive cognitive decline, often with impairment of memory. The pathology of dementias is either focal as with infarcts in Vascular Dementia or diffuse as typified by Alzheimer's disease. In many cases of Alzheimer's disease there is a mixture of focal infarcts and diffuse changes. Diffuse pathology in dementias comprises mainly intracellular and extracellular protein deposits. Intracellular inclusions are of tau protein (Alzheimer's disease; and some frontotemporal dementias), alpha-synuclein (Dementia with Lewy bodies) and huntingtin (Huntington's disease). Soluble and insoluble peptides also accumulate in the extracellular spaces of brain parenchyma in dementias with diffuse pathology, mainly amyloid-beta (Abeta) in parenchymal plaques and in artery walls as cerebral amyloid angiopathy (Alzheimer's disease and Dementia with Lewy bodies). Insoluble prion protein (PrP) is deposited in brain parenchyma in Creutzfeldt-Jakob disease and other insoluble amyloid peptides accumulate in brain and vessel walls infamilial dementias. The pattern of extracellular deposits in brain and artery walls suggests that there is a failure of elimination of peptides, such as Abeta along perivascular interstitial fluid drainage pathways ("lymphatics") from the aged brain and in Alzheimer's disease. Such failure may be due to reduced pulsations as arteries stiffen with age and cerebrovascular disease. Immunization against Abeta removes insoluble deposits of Abeta from brain parenchyma and may allow improved clearance of soluble Abeta. Reducing cerebrovascular disease and facilitating elimination of Abeta along perivascular drainage routes may offer long-term preventative measuresfor both Vascular Dementia and for Alzheimer's disease.