In a longitudinal cohort study of 824 older Catholic clergy members (mean age at baseline 75.4, SD 6.9 years) without clinical evidence of AD or PD at baseline, Wilson et al. found that 114 persons (13.8 percent) developed AD over the course of an average of 4.6 years of follow-up. The global UPDRS score increased in 79 percent of the participants, mainly due to worsening gait/posture and rigidity, and the relationship of progression to AD disease risk was examined in a proportional hazards model. Compared with the 21 percent of subjects without progression, the risk of developing AD more than doubled in the subgroup with the least progression (P = .08), more than tripled in the moderate progression subgroup (P = .02), and shot up by more than eightfold in the subgroup with the most rapid progression (P < .001). Rate of change on the global UPDR measure, was inversely correlated with rate of change on a global measure of cognitive function using 19 cognitive tests (r = 0.64).

The data strongly suggest that progression of parkinsonian signs in old age is associated with...  Read more

In a longitudinal cohort study of 824 older Catholic clergy members (mean age at baseline 75.4, SD 6.9 years) without clinical evidence of AD or PD at baseline, Wilson et al. found that 114 persons (13.8 percent) developed AD over the course of an average of 4.6 years of follow-up. The global UPDRS score increased in 79 percent of the participants, mainly due to worsening gait/posture and rigidity, and the relationship of progression to AD disease risk was examined in a proportional hazards model. Compared with the 21 percent of subjects without progression, the risk of developing AD more than doubled in the subgroup with the least progression (P = .08), more than tripled in the moderate progression subgroup (P = .02), and shot up by more than eightfold in the subgroup with the most rapid progression (P < .001). Rate of change on the global UPDR measure, was inversely correlated with rate of change on a global measure of cognitive function using 19 cognitive tests (r = 0.64).

The data strongly suggest that progression of parkinsonian signs in old age is associated with decline in cognitive function and the development of AD. Gait disorders and rigidity may be seen in subjects with subcortical lacunes and (pre)frontal white matter lesions (3-5), and periventricular cerebral white matter lesions have also been shown to predict rate of cognitive decline (6). The reasons for the predominant signs of progression of both parkinsonian-like signs and cognitive decline seen in this cohort are unclear, since the authors did not perform CCT or MRI studies to exclude or to measure such subcortical and prefrontal lesions that may also be associated with AD or with atypical parkinsonian syndromes.

However, even without further discussion of this open question, their data on the correlation between progression of extrapyramidal signs and the development of AD largely parallel our personal experience with a cohort of 200 autopsy-proven PD patients from a specialized Austrian brain bank (90 males, 104 females, mean age at onset of 68.6, SD 9.5 years, and an average disease duration of 8.4, SD 9.65 years) (2). Retrospective assessment of major initial clinical symptoms (tremor, akinesia, rigidity), moderate/severe dementia (MMSE < 20), and duration of illness were correlated with associated AD pathology using CERAD, Braak, and NIA-Reagan institute criteria. While gender had no influence on the clinical motor symptoms and outcome, tremor-dominant-type PD had a significantly better outcome than akinetic-rigid forms (p = .022), even after adjusting for age at onset and associated AD pathology. Patients with late onset showed significantly shorter duration of illness, irrespective of dementia. Moderate to severe dementia, reported in 33 percent of the sample, was significantly correlated with neuritic AD pathology (all three postmortem criteria) that showed significantly negative correlation with survival (p < 0.001).

Comparison of 32 patients (12 males, 20 females) with old-age onset of PD (mean age 82.4, SD 3.2 years) with 94 patients with middle-age onset (44-66, mean age 61.8, SD 9.8 years) showed that the duration of old-age-onset PD, ranging from 1-10 (mean 4.3, SD 2.2) years, was significantly shorter than that of middle-age onset (2-38, mean 10.5, SD 9.3) years (unpubl. data). This difference was similar to that found in the whole sample between patients with coexistent severe neuritic AD pathology (CERAD B or C, Braak stages 4.5-5) showing a mean survival of 4.46 (SD 3.55) years compared to 10.1 (SD 9.3) years in the patients without dementia and/or severe AD. Severe dementia (MMSE < 15) was significantly more frequent in PD patients with old-age onset than in those with onset under 66 years of age (72.0 vs. 11.7 percent; p < 0.001).

Most of the demented old-age-onset PD patients showed coexistent high-grade AD pathology (Braak stages 4-5, mean 4.7), and AD pathology was almost as severe (Braak stages 3-5, mean 4.5) in demented middle-age-onset patients. The finding that old age at onset is associated with more rapid disease process and increased incidence of dementia due to coexistent autopsy-proven AD pathology in this cohort is in keeping with the findings by Wilson et al. that progression of parkinsonian-like signs in old age is associated with decline in cognitive function and the development of AD. The strong association of dementia with frequently underlying AD pathology in both PD and non-PD patients may not only be a marker of an ongoing pathologic process inducing both dementia and parkinsonian-like signs that may reduce survival. It may also emphasize the importance of therapeutic approaches targeting progression of both dementia and parkinsonism—in particular, gait disorders and rigidity—in older persons, in order to improve their quality of life and life expectancy. However, as stated above, one should try to elucidate the causes of gait/posture disorders without classical PD signs and symptoms using CCT and MRI in order to exclude other treatable conditions, even in old-age subjects.

References:
1. Wilson RS, Schneider JA, Bienias JL, Evans DA, Bennett DA. Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003 Apr;60:539-44. Abstract

2. Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm 2002;109;329-39. Abstract

3. Baloh RW, Vinters HV. White matter lesions and disequilibrium in older people. Arch Neurol 1995; 52:975-81. Abstract

4. Van Zagten M, Lodder J, Kessels F. Gait disorder and parkinsonian signs in patietns with stroke realted to small deep infarcts and white matter lesions. Mov Disord 1998;13:89-95. Abstract

5. O'Keeffe ST, Kazeem H, Philpott RM, Playfer JR, Gosney M, Lye M. Gait disturbance in Alzheimer's disease: a clinical study. Age Ageing. 1996 Jul;25(4):313-6. Abstract

6. De Groot JC, De Leeuw FE, Oudkerk M, Van Gijn J, Hofman A, Jolles J, Breteler MM. Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol. 2002 Sep;52(3):335-41. Abstract

View all comments by Kurt A. Jellinger

The Wilson et al. paper is relevant to the findings in our paper. While the authors do not establish the extent of co-morbid tau and α-synuclein in their patient cohort, it is likely that this is occurring, and it emphasizes once again the clinical relevance of the in-vitro data we report on cross-fibrillization of these two amyloidogenic proteins. We speculate about the basis for this, but obviously there is more to learn about mechanisms underlying this in human patients.

View all comments by Virginia Lee
View all comments by John Trojanowski

This paper demonstrates a much higher incidence of dementia in PD patients than previously reported. This might reflect the disease mechanisms we investigate in our current paper, Giasson et al., 2003. The percentage of patients with Parkinson’s disease who will also develop dementia is unknown. While there are reports of the prevalence of dementia among PD patients, none of the longitudinal studies conducted have included a representative PD patient sample. Longitudinal studies can give us an estimate of the proportion of patients with PD who will eventually develop dementia.

This prospective study followed 224 diagnosed PD patients drawn from among 220,000 residents of western Norway, who were free of dementia at baseline. Patients received two clinical examinations by a neurologist at study onset. Patients and their caregivers were interviewed to establish a history of their disease. Collected data included demographics, drug therapy information, history of hallucinations while on anti-PD drugs, motor...  Read more

This paper demonstrates a much higher incidence of dementia in PD patients than previously reported. This might reflect the disease mechanisms we investigate in our current paper, Giasson et al., 2003. The percentage of patients with Parkinson’s disease who will also develop dementia is unknown. While there are reports of the prevalence of dementia among PD patients, none of the longitudinal studies conducted have included a representative PD patient sample. Longitudinal studies can give us an estimate of the proportion of patients with PD who will eventually develop dementia.

This prospective study followed 224 diagnosed PD patients drawn from among 220,000 residents of western Norway, who were free of dementia at baseline. Patients received two clinical examinations by a neurologist at study onset. Patients and their caregivers were interviewed to establish a history of their disease. Collected data included demographics, drug therapy information, history of hallucinations while on anti-PD drugs, motor symptoms information, laboratory tests. DSM-III-R criteria, plus three rating scales for cognitive impairment served to diagnose dementia. During follow-up examinations four and eight years later, two physicians evaluated study participants for dementia using cognitive screening, neuropsychological testing, and a clinical interview.

The control group consisted of 3,295 residents of Odense, Denmark, who were aged 65 to 84 and did not have PD. For this group, a diagnosis of dementia was made and follow-up evaluations were conducted two and five years after the baseline evaluation.

In the PD group, 139 participants were evaluated at the four-year follow up, and 87 at eight years. At baseline, 26 percent (51 cases) of the PD study subject group were diagnosed with dementia; 43 additional cases were diagnosed four years later, and 28 new cases were identified at the eight-year point, totaling 122 cases of dementia among the PD group. This means a prevalence for dementia among PD patients of 78.2 percent (95 percent CI, 71.1-84.0 percent) at the eight-year follow-up, whereas the five-year prevalence in the control group was 18.5 percent. Logistic regression analysis identified hallucinations prior to baseline examination and mixed tremor/akinetic PD as significant predictors of dementia. The extended periods of time between evaluations lead to loss of subjects at each follow-up point, suggesting that dementia rates among PD patients may be even higher than recorded here, the authors note. This potential consequence of Parkinson’s should be addressed. See also Wilson et al., 2003.

View all comments by Virginia Lee
View all comments by John Trojanowski