Pathologic correlates of dementia in individuals with Lewy body disease

Abstract

Cognitive impairment and dementia are more common in patients with Parkinson disease (PD) than age-matched controls and appear to become more frequent as PD progresses. However, estimates of dementia in patients with PD have varied widely, likely due in part to differences in case definition, case ascertainment and methodology. First, we review investigations of usual pathologic correlates of dementia in patients with brainstem (b) Lewy Body Disease (LBD) and report our findings from the initial 266 brain autopsies from a population-based study of brain aging and incident dementia. Our results showed that 2.6% of subjects were diagnosed with PD during life but that 20% had bLBD at autopsy. Seventy percent of individuals with bLBD had high level of one or more cerebral pathologic changes significantly associated with dementia: Alzheimer's disease (AD), cerebral (c) LBD or microvascular brain injury (microVBI); these were commonly co-morbid. Next we consider proposed contributors to cognitive impairment and dementia in the approximately 30% of patients with only bLBD, including regionally selective dendritic degeneration of neostriatal medium spiny neurons. Diseases contributing to cognitive impairment and dementia in patients with bLBD are heterogeneous, providing diagnostic challenges as well as multiple opportunities for successful intervention in patients with PD.

Figure 1

Photomicrograph of Lewy body (×600) from the locus ceruleus stained with hematoxylin and eosin.

Figure 2

Pie chart demonstrating frequencies of disease among the initial 266 ACT participants who donated their brains for research. Approximately 3% of the ACT autopsy sample was diagnosed with Parkinson disease (PD) during life (purple). The remaining members that were not diagnosed with PD (no PD) were roughly divided into equal thirds: no dementia/high Cognitive Abilities Screening Instrument (CASI) score (blue), no dementia/low CASI score (red) and dementia (green).

Figure 3

Scatter plot (mean ± SD) with each point representing the number of primary dendrites for a medium spiny neuron (MSN) in the neostriatum rostral to the anterior commissure (Pre‐Com), at the level of the anterior commissure (Com), and caudal to the anterior commissure (Post‐Com). Samples for rapid Golgi staining (44) were obtained from patients diagnosed with Parkinson disease (PD) (n = 8) without dementia during life and who at autopsy showed brainstem Lewy body disease (LBD) that included the substantia nigra but who had none/low levels of pathologic change from Alzheimer's disease (AD) or vascular brain injury (VBI). Control samples were obtained from individuals (n = 5) who died without neurologic disease and who had no LBD and none/low levels of AD or VBI by neuropathologic examination; data did not differ among regions and so were combined. There was a progressive decrease in the number of MSN primary dendrites from normal in the most rostral region to significantly reduced in the caudal region. Nonparametric analysis of variance had P < 0.0001 for all four groups. Corrected multiple paired comparisons had P < 0.01 for Pre‐Com vs. Post‐Com in PD, and P < 0.001 for Post‐Com in PD vs. Control.

Figure 4

Scatter plot (mean ± SD) with each point representing the number of primary dendrites for a medium spiny neuron (MSNs) in the neostriatum rostral to the anterior commissure. Samples for rapid Golgi staining (44) were obtained from: (i) patients diagnosed with Parkinson disease (PD) without dementia during life and who at autopsy showed brainstem Lewy body disease (bLBD) that included the substantia nigra (n = 8); (ii) patients diagnosed with dementia with Lewy bodies (DLB) or PD with dementia (PD‐D) during life and who at autopsy showed cerebral and bLBD (n = 8); and (iii) individuals who died without neurologic disease and who did not have any LBD (n = 5). None of these cases showed high level of pathologic changes from Alzheimer's disease or vascular brain injury. There was a significant decrease in the number of anterior MSN primary dendrites from normal in those patients with PD‐D or DLB, but not those with PD. Nonparametric analysis of variance had P < 0.001 for all four groups. Corrected multiple paired comparisons had P < 0. 01 for PD vs. PD‐D/DLB or P < 0.001 for PD‐D/DLB vs. Control.