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Later-Developing Dementia and Loss of the Levodopa Response

Hulya Apaydin, MD; J. Eric Ahlskog, PhD, MD; Joseph E. Parisi, MD; Bradley F. Boeve, MD; Dennis W. Dickson, MD

Arch Neurol. 2002;59:102-112.

Objective  To investigate the neuropathologic substrate for dementia occurring late in Parkinson disease (PD).

Design  We identified 13 patients with a clinical diagnosis of PD who experienced dementia at least 4 years after parkinsonism onset (mean, 10.5 years) and subsequently underwent postmortem examination. Despite levodopa therapy, 9 patients later became severely impaired and nonambulatory, requiring total or near-total care; this included 4 patients treated with 1200 mg/d or more of levodopa (with carbidopa), which was consistent with loss of the levodopa response. These 13 patients were compared with 9 patients clinically diagnosed as having PD, but without dementia, who had undergone autopsies.

Results  Twelve of 13 PD patients with dementia had findings of diffuse or transitional Lewy body disease as the primary pathologic substrate for dementia; 1 had progressive supranuclear palsy. This pathology also apparently accounted for the levodopa refractory state. Among the 12 PD patients with dementia, mean and median Lewy body counts were increased nearly 10-fold in neocortex and limbic areas compared with PD patients without dementia (P.002). Alzheimer pathology was modest. Only one patient met the criteria defined by the National Institute on Aging and the Reagan Institute Working Group on the Diagnostic Criteria for the Neuropathologic Assessment of Alzheimer's Disease for "intermediate probability of Alzheimer's disease." There were, however, significant correlations between neocortical Lewy body counts and senile plaques as well as neurofibrillary tangles. Senile plaque counts did not significantly correlate with tangle counts in any of the analyzed nuclei. Arteriolar disease may have contributed to the clinical picture in 2 patients.

Conclusions  Diffuse or transitional Lewy body disease is the primary pathologic substrate for dementia developing later in PD. This same pathologic substrate seemed to account for end-stage, levodopa refractory parkinsonism. The occurrence of Alzheimer pathology was modest, but was highly correlated with Lewy body pathology, suggesting common origins or one triggering the other.

From the Department of Neurology, Istanbul University, Cerrahpaa Medical School, Istanbul, Turkey (Dr Apaydin); Departments of Neurology (Drs Ahlskog and Boeve) and Pathology (Dr Parisi), Mayo Clinic, Rochester, Minn; and Department of Pathology, Mayo Clinic, Jacksonville, Fla (Dr Dickson).

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