Dementia in Parkinson's Disease Correlates with α-Synuclein Pathology but Not with Cortical Astrogliosis

Abstract

Dementia is a common feature in Parkinson's disease (PD) and is considered to be the result of limbic and cortical Lewy bodies and/or Alzheimer changes. Astrogliosis may also affect the development of dementia, since it correlates well with declining cognition in Alzheimer patients. Thus, we determined whether cortical astrogliosis occurs in PD, whether it is related to dementia, and whether this is reflected by the presence of glial fibrillary acidic protein (GFAP) and vimentin in cerebrospinal fluid (CSF). We have examined these proteins by immunohistochemistry in the frontal cortex and by Western blot in CSF of cases with PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and nondemented controls. We were neither able to detect an increase in cortical astrogliosis in PD, PDD, or DLB nor could we observe a correlation between the extent of astrogliosis and the degree of dementia. The levels of GFAP and vimentin in CSF did not correlate to the extent of astrogliosis or dementia. We did confirm the previously identified positive correlation between the presence of cortical Lewy bodies and dementia in PD. In conclusion, we have shown that cortical astrogliosis is not associated with the cognitive decline in Lewy body-related dementia.

Figure 1

GFAP immunoreactivity in the human frontal cortex. (a–h) examples of GFAP immunoreactivity in grey (a–d) and white matter (e–h) of a 77-year-old female control (C) donor (NBB 2001-104; a, e), a 77-year-old male Parkinson's disease (PD) patient (NBB 2005-069; b, f), a 71-year-old male Parkinson's disease with dementia (PDD) patient (NBB 2004-045; c, g), and 76-year-old female dementia with Lewy bodies (DLB) patient (2001-025; d, h). (i-j) Boxplot of the quantification of GFAP staining in grey (i) and white matter (j) of 8 C, 6 PD, 11 PDD, and 9 DLB cases. (k) correlation of GFAP expression in the grey matter with age of the 34 donors. GM: grey matter; WM: white matter; inserts show higher magnification images of the same patients. Scale bars represent 50 μm for the lower magnification and 20 μm for the higher magnification images.

Figure 2

Vimentin immunoreactivity in the human frontal cortex. (a–h) examples of vimentin immunoreactivity in grey (a–d) and white matter (e–h) of a 71-year-old male control (C) donor (NBB 2002-087; a, e), a 86-year-old male Parkinson's disease (PD) patient (NBB 2001-122; b, f), a 75-year-old female Parkinson's disease with dementia (PDD) patient (NBB 2003-059; c, g), and 72-year-old male dementia with Lewy bodies (DLB) patient (2002-017; d, h). (i-j) Boxplot of the quantification of vimentin staining in grey (i) and white matter (j) of 8 C, 6 PD, 11 PDD, and 9 DLB cases. Outliers are shown as dots. (k) correlation of vimentin expression in the grey matter with age of the 34 donors. GM: grey matter; WM: white matter; inserts show higher magnification images of the same patients. Scale bars represent 50 μm for the lower magnification and 20 μm for the higher magnification images.

Figure 3

Astrocytic protein levels in ventricular cerebrospinal fluid (CSF). (a) example of a Western blot for GFAP (top row) and vimentin (bottom row) on CSF of different donors (from left to right: NBB 2006-030, 2007-007, 2007-008, 2007-019, 2005-017, 2005-050, 2005-055, 2005-069, and 2005-077). (b) correlation of the GFAP and vimentin protein levels (in arbitrary units) in CSF of 36 donors. (c) Boxplot of GFAP protein levels in CSF of 8 control (c), 8 Parkinson's disease (PD), 11 PD with dementia (PDD), and 9 dementia with Lewy bodies (DLB) cases. (d) Boxplot of vimentin protein levels in CSF of 8 C, 8 PD, 11 PDD, and 9 DLB cases.

Figure 4

α-synuclein pathology in the human frontal cortex. (a–c) Lewy bodies (arrows) and Lewy neurites (arrowheads) in the grey matter of a Parkinson's disease (PD; NBB 1999-038), Parkinson's disease with dementia (PDD; NBB 2004-045), and dementia with Lewy bodies (DLB; NBB 1997-092) case. (d) a Lewy body (arrow) in the white matter (WM) of the frontal cortex of case NBB 2004-045. (e) Boxplot of the quantification of Lewy body number in the frontal cortex of 8 control, 6 PD, 11 PDD, and 9 DLB cases. (f) Lewy body numbers per ApoE genotype. Scale bars represent 100 μm.