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Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia

From the Departments of Neurology (E.E.B., A.M.S., B.N.D., P.S., P.A.L.) and Anatomic Pathology (J.E.P.), Mayo Clinic, Rochester, MN.

Address correspondence and reprint requests to Dr Benarroch, Mayo Clinic, Department of Neurology, 811 Guggenheim Bldg., 200 First Street SW, Rochester, MN 55905 benarroch.eduardo{at}mayo.edu

Background: Experimental studies indicate that dopaminergic neurons in the ventral periaqueductal gray matter (PAG) are involved in maintenance of wakefulness. Excessive daytime sleepiness (EDS) is a common manifestation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) but involvement of these neurons has not yet been explored.

Methods: We sought to determine whether there is loss of dopaminergic neurons in the ventral PAG in MSA and DLB. We studied the midbrain obtained at autopsy from 12 patients (9 male, 3 female, age 61 ± 3) with neuropathologically confirmed MSA, 12 patients (11 male, 1 female, age 79 ± 4) with diagnosis of DLB and limbic or neocortical Lewy body disease, and 12 controls (7 male, 5 female, ages 67 ± 4). Fifty-micron sections were immunostained for tyrosine hydroxylase (TH) or -synuclein and costained with thionin. Cell counts were performed every 400 µm throughout the ventral PAG using stereologic techniques.

Results: Compared to the total estimated cell numbers in controls (21,488 ± 8,324 cells), there was marked loss of TH neurons in the ventral PAG in both MSA (11,727 ± 5,984; p < 0.01) and DLB (5,163 ± 1,926; p < 0.001) cases. Cell loss was more marked in DLB than in MSA. There were characteristic -synuclein inclusions in the ventral PAG in both MSA and DLB.

Conclusions: There is loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons in both multiple system atrophy and dementia with Lewy bodies, which may contribute to excessive daytime sleepiness in these conditions.

Abbreviations: AD = Alzheimer disease; B&B = Braak and Braak; CERAD = Consortium to Establish a Registry for Alzheimer's Disease; CPAP = continuous positive airway pressure; DLB = dementia with Lewy bodies; ECG = electrocardiogram; EDS = excessive daytime sleepiness; EOG = electrooculography; ESS = Epworth Sleepiness Scale; GCI = glial cytoplasmic inclusion; LBD = Lewy body disease; MSA = multiple system atrophy; MSA-P = MSA with predominant parkinsonism; MSA-C = MSA with predominant cerebellar involvement; OSA = obstructive sleep apnea; PAG = periaqueductal gray matter; PSG = polysomnogram; RBD = REM sleep behavior disorder; TH = tyrosine hydroxylase.

Supplemental data at www.neurology.org

This study was supported by NIH grant NS32352-P2 and Mayo Funds.

Disclosure: Author disclosures are provided at the end of the article.

Received January 16, 2009. Accepted in final form April 2, 2009.