The Neuropathology of Neurodegeneration with Brain Iron Accumulation

Abstract

Neuropathology plays a key role in characterizing the pathogenesis of neurodegenerative diseases including forms of neurodegeneration with brain iron accumulation (NBIA). Despite important differences, several genetically diverse forms of NBIA nevertheless share common features in addition to iron deposition, such as the presence of neuroaxonal spheroids. Multiple forms of NBIA also demonstrate tau or synuclein pathology, suggesting parallels with both Alzheimer and Parkinson diseases. This chapter summarizes what has been learned from the study of human patient tissues. Gross and microscopic findings are delineated, and similarities and differences between forms of NBIA are presented. Neuropathologic findings often help characterize fundamental features of disease and provide a springboard for more focused hypothesis-driven studies. Lessons learned from neuropathology thus contribute much to the characterization of the molecular mechanisms of disease.

Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study

“…This would be consistent with genetic diseases causing brain iron elevation, such as neurodegeneration with brain iron accumulation, not usually being complicated by Aβ pathology 17. However, elevated brain iron levels in AD might facilitate further deposition of Aβ once Aβ pathology takes hold.…”

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

“…The most common of the NBIA is panthothenate-associated neurodegeneration (PKAN) that is characterized by progressive dystonia and parkinsonism associated with intellectual decline [47]. Perl’s staining of PKAN tissue shows a widespread perivascular deposition of iron largely confined to the globus pallidus.…”

Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus

“…Histologically, all NBIA disorders feature iron accumulation in the basal ganglia with neuroaxonal spheroids (Kruer, 2013). Additional neuropathologic features may be specific to NBIA subtypes and include Lewy bodies and neurofibrillary tangles (Kruer, 2013).…”