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March 2003

Time to Focus on the Locus

Arch Neurol. 2003;60(3):320. doi:10.1001/archneur.60.3.320

CLINICOPATHOLOGIC EXAMINATION of human brains is the traditional starting point for our understanding of disease pathophysiology, disease treatment, and the functional-anatomical organization of the brain. In this issue of the ARCHIVES, Zarow et al1 report major cell loss in the brainstem, noradrenergic locus coeruleus (LC), in brains from patients with Alzheimer disease (AD) and Parkinson disease (PD) compared with healthy controls. The findings are, per se, not surprising as LC pathology has been previously documented in experimental and idiopathic parkinsonism.2 What is remarkable is the observation that LC neuron loss is uniformly severe across PD cases and roughly 75% of AD cases. Moreover, the degree of LC loss appears more extensive than that in 2 brain regions to which the main clinical features of AD and PD are commonly ascribed: cholinergic neurons of the nucleus basalis (AD) and dopaminergic neurons in the substantia nigra (PD). While the analysis by Zarow et al1 has several methodologic shortcomings, it is the largest single series of quantitated autopsy material from PD, AD, and control cases to be presented to date. It reemphasizes that involvement of neurochemically heterogeneous pathways by neurodegenerative diseases is likely to be the rule rather than the exception. Increasingly, the cellular pathology that is shared at a systems level, as evidenced here, is also realized at the subcellular level. Many neurodegenerative diseases ultimately derive from shared disturbances in biochemical cascades of intracellular protein trafficking.3 How these facts account for the apparent vulnerability of the LC and other neurochemically defined brain regions (eg, serotonergic dorsal raphe and cholinergic pedunculopontine nucleus, among others) in a host of neurodegenerative diseases remains unclear.

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