# Presentation: 806132

## Summary of Neuropathological and Clinical Features of PDD

**Clive Ballard, MD**
**Professor of Age Related Diseases****Institute of Psychiatry****King’s College London**

## Overview

**PDD is a distinct dementia syndrome**
**PDD can be diagnosed unambiguously in routine clinical practice**
**PDD is a rational target for treatment**

## Genetic Associations of PDD in Familial PD—Kurz et al, 2006†

| 
Study by | Clinical information |  | Neuropathology |  |
| --- | --- | --- | --- | --- |
|  | N  | Families | Lewy bodies | Genetic findings |
| Golbe et al, 1990, 1996;
Duda et al, 2002 | 60 | 1 | SN + NC | A53T SNCA mutation |
| Waters and Miller, 1994; Muenter et al, 1998;Farrer et al, 1999;Singleton et al, 2003 | 22 | 1 | SN + NC | PARK4. SNCA gene triplication. |
| Spira et al, 2001 | 5 | 1 | SN + NC | A53T SNCA mutation |
| Ohtake et al, 2004 | 1 | 1 | Autopsy not performed | V70M beta synuclein mutation |
| Krüger et al, 1998, 2001 | 5 | 1 | Autopsy not performed | A30P SNCA mutation |
| Zarranz et al, 2004 | 5 | 1 |  SN + NC | E46K SNCA mutation  |

**Genetic Associations of PDD in Familial PD—Kurz et al, 2006****†**

**SN = Sub-stantia nigra; NC = Neocortex.  **
**† ****Kurz et al. *****Dementia and Geriatr Cog Disorders. *****In press.**

## Relationship Between Pathology and Duration of PD Before Dementia

|  | Plaques (CERAD)n (%) | Braak stagen (%) | Meet diagnosticcriteria for ADn (%) |
| --- | --- | --- | --- |
| DLB (n = 29)†§ | Frequent  19 (66) |   5/6  3 (10) | 9 (31) |
| PD for 1 - 9.5 yrbefore dementia(n = 14)†‡ | Frequent     2 (14)
 |   5/6  2 (14)
 | 2 (7)
 |
| PD for > 9.5 yrbefore dementia(n = 14)†‡ | Frequent     3 (21)
 | 5/6  0 (0)
 |  |

**† ****Aarsland D, et al. *****Ann Neurol. *****2005:58;773-776.**
**‡ ****Perry R, et al. *****Neurol. *****2006. In press.**
**§ Ballard C, et al. *****Am J Psychiat. *****2004:161;843-849.**

## PDD Predicts a Characteristic Neuropathologic and Clinical Profile

**Lewy body pathology (LBP) is the predominant substrate of cognitive decline in PDD**
**Overlapping AD plaque pathology is not the main correlate of dementia in PDD patients **
**93% to 94% of patients with PDD lack sufficient pathologic changes to meet diagnostic criteria ****for AD**
**Dementia in PDD has a characteristic profile of neuropsychiatric, cognitive, neurologic, and autonomic features**

## Attention and Fluctuating Attention in PDD and AD

**Ballard C, et al. *****Neurology*****. 2002; 59:1714-1720. **

***p < *****0.0001***** ***** **

***p < *****0.0001***** ***** **

## Clinical Symptoms of PDD vs AD

|  | PDD(N = 34) | AD(N = 92) |
| --- | --- | --- |
| Major depression |   28% |   8% |
| Fluctuation |   82% |   4% |
| Falls |   71% | 21% |
| Visual hallucinations |   74% | 16% |
| Parkinsonism | 100% |   7% |

**Ballard C, et al. *****Am J Psych. *****1999;156:1039-1045.**
**Ballard C, et al. *****J Clin Psych.***** 2001;2001:46-49.**

## Autonomic Function (Parasympathetic) in AD and PDD

|  | Median(IQR) |  |  |
| --- | --- | --- | --- |
| Diagnosis | Control(N = 42) | AD (N = 39) | PDD(N = 40)  |
| Median of mean change in heart rate during deep breathing | 7.4(5.3-9.7) | 7.5(3.3-9.2) | 3.3(2.3 - 5.8) |
| Median Valsalva Ratio | 1.33(1.20-1.62) | 1.34(1.19-1.56) | 1.14(1.06 - 1.22) |
| Median heart rate response to standing | 1.14(1.09-1.19) | 1.10(1.03-1.23) | 1.04(1.01 - 1.11) |

**Autonomic Function (Parasympathetic) in AD and PDD**

**PDD vs. AD: p-value <0.05 for all comparisons. ****PDD vs. Controls: p-value <0.001 for all comparisons. **
**Kenny RA, et al. *****Dementia with Lewy Bodies and Parkinson’s Disease ******Dementia. 2006.***** Taylor & Francis Pub.**

## PDD Can be Diagnosed Simply and Unambiguously in Routine Clinical Practice  

**Diagnosis of PDD is straightforward in routine clinical practice using 3 simple principles**
**Established diagnosis of Parkinson’s disease**
**Developing dementia at least 1 to 2 yrs after onset of PD**
**Exclusion of other causes of dementia, ****eg, VaD, MSA, PSP**

## Severe Neuroleptic Sensitivity Reactions in PDD and AD

**Severe neuroleptic sensitivity reactions (NSR), characterized by severe parkinsonism, autonomic instability, increased confusion, rhabdomyolysis, and often death**
**Severe NSR occurs in**
**> 30% of DLB****†‡§**** and PDD****†**
**0% of AD****†‡§**

**† ****Aarsland D, et al. *****J Clin Psych.***** 2005;66:633-637.**
**‡ ****McKeith I, et al. *****BMJ. *****1992;305:673-678.**
**§ Ballard C, et al. *****Lancet. *****1998;351:1032-1033.**

## Cholinergic Deficits in PDD

**There is established cholinergic deficit in PDD**
**The cholinergic deficits are associated with many of the key neuropsychiatric symptoms and cognitive deficits**

| 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.**

## Conclusions

**Lewy body-related alpha-synucleinopathy is the pathology predominantly associated with cognitive impairment in PDD**
**PDD can most effectively be diagnosed using simple clinical criteria based on the presence of PD and the time course of development of dementia**
**The shared cholinergic deficit in PDD and AD presents a common treatment target**