# Presentation: 811953

## Neuropathology ofParkinson’s Disease Dementia 

**James B. Leverenz, MD**
**Associate Professor****Neurology and Psychiatry and Behavioral Sciences****University of Washington School of Medicine **
**UW Alzheimer’s Disease Research Center**
**VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Clinical Centers**

## Overview—Neuropathology of PDD

** ****Dementia in elderly PD patients is primarily due to**** Lewy body pathology, and not just coexistent AD **
**Review of AD pathology**
**Review of PD pathology**
**Neuropathologic changes in PDD**
** ****PDD is associated with severe deficits in the cholinergic system**
**Biochemical and neuroimaging data**
**Neuropsychologic data**

## Abbreviations and Terminology  

**PD – Parkinson’s Disease without  dementia**
**PDD – Parkinson’s Disease with dementia**
**AD – Alzheimer’s Disease**
**LBP – Lewy Body Pathology**
**“****classic” Lewy body inclusions**
**alpha-synuclein immuno-positive inclusions and neurites**
**CERAD – Consortium to Establish a Registry for Alzheimer’s Disease**

## Alzheimer’s Disease—Pathology

**plaques and tangles**

**Alzheimer’s Disease****—****Pathology**

**Silver stain:**
**neuritic plaques**

**Neurofibrillary**
**tangles**

## Pathological Criteria for AD

**Staging of AD pathologic change**
**Neuritic plaques (CERAD, absent to frequent)**
**Neurofibrillary tangles (Braak staging, I - VI)**
**For pathological diagnosis of AD****†**
**Integrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementia**
**High - CERAD frequent/Braak V or VI**
**Intermediate - CERAD moderate/Braak III or IV**
**Low - CERAD sparse/Braak I or II**

**† *****Neurobiol Aging*****. 1997;18(4 suppl):S1-2. **

## AD Pathologic Change in Non-Demented Elderly

**Knopman et al (*****JNEN***** 2003)****†**
**39 longitudinally followed non-demented cases**
**Mean age 85 years (74 - 95)**
**AD pathologic change**
**38 Braak stage I or greater, 4 Braak stage IV or V**
**37 with sparse or absent neuritic plaques, ****~50% with moderate to frequent diffuse plaques**
***“******...cut off points ...Braak stage ≥ IV ...neuritic plaques ≥ moderate...”***

**† ****Knopman et al. *****J Neurol Pathol Exp Neurol*****. 2003;62:1087-1095.**

## AD Pathologic Change in the Elderly

**Knopman et al. *****J Neuropathol Exp Neurol*****. 2003;62:1087-1095.**

**Diffuse plaques**
**Cored plaques**
**Neuritic plaques**

**Braak and Braak stage**

**CERAD plaque ratings**

**0 - I**

**II**

**III**

**IV - V**

**None**

**Sparse**

**Moderate**

**Frequent**

**Number of subjects**

**Number of subjects**

**0**

**2**

**6**

**8**

**10**

**12**

**4**

**14**

**0**

**5**

**15**

**20**

**10**

**25**

## Neuropathology of Parkinson’s Disease

**Substantia nigra pathology**

**Lewy body inclusions**

**Neuronal loss**

## Improved Detection of Lewy Body Pathology

**Alpha-synuclein mutations in familial PD **
**Alpha-synuclein immunoreactivity in ****all Lewy bodies**
**Classic brainstem Lewy bodies**
**Cortical Lewy bodies**
**Lewy neurites**

## Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex

**Alpha-Synuclein Pathology in the ****Substantia Nigra and Neocortex**

**Substantia nigra   **

## Braak Staging of Lewy Bodies

**Braak H, et al. *****J Neurology*****. 2002;249(suppl 3):1432-1459.**

**Braak Staging of Lewy Bodies**

## What Is the Neuropathologic Basis of Dementia in Parkinson’s Disease?

## Neuropathology of PDDAD Pathologic Change

**	****“...****contrary to published reports, most patients with parkinsonism who exhibit dementia do not have concomitant Alzheimer’s disease...Some pathogenetic mechanism must be sought to account for this increasingly common cause of cognitive decline in the sufferers of Parkinson’s disease.”**
**—****Ball M. *****Can J Neuro Sci*****. 1984;11(1 suppl):180-184.**

## Neuropathology of PDDCortical LB Pathology Correlates With Dementia

**Neuropathology of PDD****Cortical LB Pathology Correlates With Dementia**

| Author, yr | Population | Primary correlate of dementia  |
| --- | --- | --- |
| Kosaka, 1998 | 11 PDD | Cortical LBs |
| Mattila, 1998 | 44 PDD | Cortical LBs |
| Mattila, 2000 | 45 PDD | Frontal cortical LBs |
| Hurtig, 2000 | 22 PDD vs 20 PD only | Cortical LBs |
| Apaydin, 2002  | 13 PDD | Cortical LBs |
| Kovari, 2003 | 22 PDD | LBs in entorhinal cortex andBrodmann 24  |
| Braak, 2005 | 88 PD  | Cortical LBs |

- 1-15\
- DV

**Notes:**
Key point:

## Neuropathology of PDDAD Pathologic Change

**Case selection**
**Treatment-responsive PD **_**precedes**_** dementia**
**Neuropathology**
**Alpha-synuclein immunohistochemistry**
**Up-to-date criteria for AD diagnosis**
**Braak IV to VI and CERAD plaque ****stage B or C**

## Neuropathology of PDDAD Pathologic Change

**Apaydin et al (*****Arch Neurol*****, 2002)**
**Clinical**
**13 PDD cases (mean age 78.1yr, ****range 64 - 89)**
**Pathology**
**12 with diffuse or transitional Lewy body pathology**
**1 case with intermediate likelihood of AD (Braak stage IV, CERAD plaque stage B)**
**1 case with PSP (no LBP)**

**Apaydin H, et al. *****Arch Neurol*****. 2002;59:102-112.**

## Neuropathology of PDDAD Pathologic Change

**Braak et al (*****Neurology*****, 2005)**
**88 clinical PD cases with autopsy confirmation of LBP ****(mean age 75.9 yr; range 60 - 89)**
**79 with mild to severe cognitive impairment**
**MMSE score correlated with stage of LBP (using Braak’s staging of LBP)**
**Only 2 cases fulfilled criteria for AD pathologically (VI C and IV B)**

**Braak H, et al. *****Neurology*****. 2005;64:1404-1410.**

## PDD - AD Pathologic Change

**Aarsland et al (*****Ann Neurol*****, 2005)**
**Community-based sample of PD (N = 245)**
**Longitudinal follow-up with cognitive evaluation**
**22 autopsied cases (18 demented)**
**All with limbic or neocortical stage LBP**
**Correlation of LB score to last MMSE**
**AD pathology limited (all Braak stage IV or less)**
**No correlation of AD pathology and last MMSE**

**Aarsland D, et al. *****Ann Neurol*****. 2005;58:773-776.**

## Summary—Neuropathology of PDDAD Pathologic Change 

**Total of 110 cases with PDD studied**
**DSM III or III-R criteria for dementia diagnosis**
**Age in late 70s at death**
**Neocortical LB pathology correlates ****with dementia**
**Only 7(6%) cases fulfilled pathologic criteria****for AD**

**Aarsland D, et al. *****Ann Neurol*****. 2005;58:773-776.**
**Apaydin H, et al. *****Arch Neurol*****. 2002;59:102-112.**
**Braak H, et al. *****Neurology*****. 2005;64:1404-1410.**

## Conclusion—Neuropathology of PDDAD Pathologic Change

**Clinical diagnosis highly predictive of Lewy body pathology**
**Significant AD pathology is relatively rare in clinically diagnosed PDD cases**
_**Dementia in elderly PD patients is **_
_**primarily due to Lewy body pathology **_
_**and not just coexistent AD**_

## Is the Cholinergic System Dysfunctional in Parkinson’s Disease with Dementia?

## Neurochemistry of PDD and AD Cholinergic System

**Cholinergic basal forebrain**
**Neuronal loss and Lewy body pathology in PD and PDD**
**Neuronal loss and neurofibrillary tangles in AD**
**Pedunculopontine (PPT) nucleus**
**Neuronal loss and Lewy body pathology in PD and PDD**
**Neuronal loss and neurofibrillary tangles in AD**

**Jellinger K. *****J Neurol Neurosurg Psychiatry*****. 1988;51:540-543.**

## Two Distinct Disorders With aCommon Cholinergic Deficit

**Two Distinct Disorders With a****Common Cholinergic Deficit**

## Neurochemistry of PDD and AD Cholinergic System

| Author | Technique | Disease subgroups |  |  |
| --- | --- | --- | --- | --- |
|  |  | AD | PD | PDD |
| Perry, 1985 | Neurochem (ChAT) |  |  |  |
| Ruberg, 1986 | Neurochem (AChE) | N/A | / | /† |
| Tiraboschi, 2000 | Neurochem (ChAT) |  | N/A |  |
| Mattila, 2001 | Neurochem (ChAT) | N/A | ‡ | ‡ |
| Bohnen, 2003 | PET (AChE activity) |  |  |  |

**† ****AChE total/AChE 10S form.**
**‡ ****Included PD/PDD together.**

**Neurochemistry of PDD and AD**** ****Cholinergic System**

## Percentage Reductions of Cerebral Acetylcholinesterase Activity inPD, PDD, and AD 

**Alzheimer disease**
**PD without dementia**
**Parkinsonian dementia**

**Mean cortex**

**Amygdala**

**Hippocampus**

**Inferior temporal**

**Superior temporal**

**Parietal**

**Frontal**

**Region of the brain, %**

**Percentage reductions of cerebral acetylcholinesterase (AChE) activity in the various patient groups compared with healthy control subjects.**
**Bohnen NI, et al. *****Arch Neurol.***** 2003;60:1745-1748.**

**0**

**–****5**

**–****10**

**–****15**

**–****20**

**–****25**

**–****30**

**% reduction in AChE activity**

## Correlation Coefficients Between Individual Cognitive Tests and Cortical AChE Activities in the Combined PDD and PD Groups

| Cognitive test | Correlation coefficient(significance) |
| --- | --- |
| California Verbal Learning Test-STM | Rs = 0.13 ns |
| California Verbal Learning Test-LTM | Rs = 0.20 ns |
| Judgment of Line Orientation Test | Rs = 0.43  (p < 0.05) |
| Stroop Color Word Test | Rs = 0.46  (p < 0.05) |
| Trail Making Test B-A | Rs = 0.44  (p < 0.05) |
| WAIS-III Digit Span | Rs = 0.57  (p < 0.005) |

**Bohnen NI, et al. *****J Neurol.***** 2006;253:242-247.**

## Neurochemistry of PDD and AD Cholinergic System

**Cholinergic nuclei are pathologically involved in PDD**
**Reduced cortical cholinergic activity is more severe in PDD than in mild AD****‡**
**Cholinergic dysfunction in PDD is associated with decreased performance on tests of attentional and executive functioning****§**

**† ****Mattila, et al. *****Acta Neuropathol.***** 2001;32:397-402.****‡ Bohnen, et al. *****Arch Neurol.***** 2003;60:1745-1748.****§ Bohnen NI, et al. *****J Neurol.***** 2006;253:242-247.**

## Conclusion

**Clinical PDD is highly predictive of specific neuropathologic and neurochemical characteristics**
**Neuropathology **
**Lewy body pathology**
**Limited AD pathologic change**
**Biochemistry**
**Profound loss of cholinergic function**
**Cholinergic deficit associated with impairments in attentional and executive functions**