M. A. Hely

The Sydney multicenter study of Parkinson's disease: The inevitability of dementia at 20 years

After 20 years follow‐up of newly diagnosed patients with Parkinsons disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non‐levodopa responsive features of the disease. Dementia is present in 83% of 20‐year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.

Sydney multicenter study of Parkinson's disease: Non‐L‐dopa–responsive problems dominate at 15 years

One‐third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinsons disease have survived. The original study compared low‐dose levodopa with low‐dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L‐dopa–induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end‐of‐dose failure appeared at a similar time once L‐dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long‐term problems of Parkinsons disease relate to the emergence of symptoms that are not improved by L‐dopa. Neuroprotective interventions in Parkinsons disease should be judged by their ability to improve non‐L‐dopa–responsive aspects of the disease, rather than just by their capacity to delay the introduction of L‐dopa or reduce its associated side effects.

The Sydney multicentre study of Parkinson’s disease: progression and mortality at 10 years

OBJECTIVES To report on a 10 year follow up of patients with idiopathic Parkinson’s disease, particularly with respect to mortality and the effect of early treatment with bromocriptine. METHODS The patients are from the 149 new patients recruited for a double blind, randomised study of low dose levodopa-carbidopa versus low dose bromocriptine. Patients were examined neurologically at least yearly. Neuropsychological examinations were performed at 0, 3, 5, and 10 years. Mortality and cause of death in these patients were compared with the Australian population using standardised mortality ratios (SMRs). Mortality and disease progression were compared by sex and treatment group. Predictors of death within 10 years, nursing home admission, and progression in Columbia score of ⩾20 points were examined by logistic regression analysis. RESULTS Thirteen patients were excluded as having atypical Parkinsonism and six were lost to follow up. All available patients have been followed up for 10 years. Fifty patients (38%) were dead by 10 years and 63 by the last follow up. The SMR was 1.58 for all patients (p<0.001). There was no significant difference in SMRs between the sexes. The mean duration of disease until death was 9.1 years. Parkinson’s disease was thought to have contributed substantially to the death of 30 patients. The most common cause of death was pneumonia. Women progressed at a similar rate to men until 8 years, when the severity of their disease as measured by Hoehn and Yahr stage became greater (p<0.05). Older age of onset correlated with increased risk of death but the SMR was increased even in those aged <70 years (SMR 1.80, p=0.03). Early use of bromocriptine did not reduce mortality or slow progression of disease. One quarter of all patients had been admitted to nursing homes by 10 years. Only four patients were still employed. CONCLUSIONS Mortality in Parkinson’s disease remains increased despite low dose levodopa-carbidopa therapy and no additional benefit was gained from early use of bromocriptine. Duration of disease was similar to that in the era before levodopa.

The Sydney Multicentre Study of Parkinson's disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa.

149 previously untreated patients with Parkinsons disease were recruited over a three year period and randomly allocated to either low dose levodopa-carbidopa (< or = 600/150 mg/day) or low dose bromocriptine (< or = 30 mg/day). A five year follow up is reported on the 126 patients who completed the dose titration and who have not developed features of atypical Parkinsonism. Levodopa-carbidopa in low dosage adequately controlled symptoms in most patients and delayed the appearance of dyskinesia and end of dose failure for about two years longer than conventional doses. Only a few patients could be managed for more than one year on low dose bromocriptine alone; these patients had mild disease and asymmetric signs. Patients randomised to bromocriptine did not develop dyskinesia or troublesome end of dose failure until levodopa-carbidopa was added. The prevalence of dyskinesia in this group was lower than in patients given levodopa-carbidopa alone. The prevalence of end of dose failure was similar in the two randomisation groups once levodopa was introduced.

Dementia in Parkinson's disease: a 20-year neuropsychological study (Sydney Multicentre Study)

Objective To determine whether neuropsychological measures differ between patients with idiopathic Parkinsons disease (PD) who acquire dementia within 10 years of disease onset versus those who acquire dementia later in the disease course, using data from the longitudinal Sydney Multicentre Study of PD. Methods The Sydney Multicentre Study of PD is a cohort of 149 community-living de novo patients with idiopathic PD studied over a 20-year period. Detailed clinical and neuropsychological tests were administered at baseline and at 3, 5, 10, 15 and 20 years, and the dementia status was assessed at each time point. For the present study, the pattern of longitudinal neuropsychological measures was compared between PD patients with the onset of dementia in the middle (5–10 years, mid-stage PD dementia, N=20) or late (>10 years, late-stage PD dementia, N=10) disease stages using analysis of variance and multiple linear regression modelling, and the relationship between age and dementia onset assessed using survival statistics. Results Mid-stage PD dementia patients were differentiated from late-stage PD dementia patients by having greater deficits in vocabulary skills prior to and at dementia onset. The pattern of cognitive deficits following dementia onset are similar, and there is no difference in the age of dementia onset between the different PD groups. Conclusions These data suggest that the evolution of dementia within PD occurs at around 70 years of age, regardless of the time of PD onset, and affects cognitive domains in a similar way, although patients with earlier-onset PD have a preserved linguistic ability prior to dementia onset.

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease

There have been no previous three‐dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinsons disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimers disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinsons disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease. Ann Neurol 2000;47:718–728

Midbrain neuropathology in idiopathic Parkinson's disease and diffuse Lewy body disease

We have quantified midbrain cell loss in idiopathic Parkinsons disease (PD) compared with controls; six patients had PD with onset before 70 years, five patients had late onset PD (>70 years) and nine patients had diffuse Lewy body disease. The pattern of cell loss in these last two groups has not been previously described. No age associated neuronal loss was seen in controls. There was cell loss and reduced area of the pars compacta in all cases but no difference in the pattern of cell loss, which was predominantly ventral. The amount of cell loss in the dorsolateral cluster correlated with the duration of Parkinsonian symptoms, while greater cell loss in the dorsomedial cluster correlated with the presence of tremor and the absence of early dementia. These results suggest that the topography of midbrain pathology does not assist in differentiating these overlapping syndromes.

Randomized trial of tolcapone versus pergolide as add‐on to levodopa therapy in Parkinson's disease patients with motor fluctuations

In this 12‐week, randomized, open‐label, blinded‐rater, parallel‐group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included “off” time (reduced by 2–3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinsons disease questionnaire (PDQ)‐39 scores, and Unified Parkinsons Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ‐39 score at week 12 were −8.7 and −14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigators global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone‐treated patients and in 78% of pergolide‐treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3‐month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse‐event profile than pergolide.

Age at onset: the major determinant of outcome in Parkinson's disease.

Factors at presentation which influenced the course of the disease and response to treatment were assessed in 125 de novo patients with Parkinsons disease. Ninety‐eight patients were available for re‐assessment at 5 years. Older patients presented earlier after the onset of symptoms, deteriorated more rapidly, and were significantly more likely to develop dementia and impairment of balance. Increasing age and symmetrical disease predicted the new appearance of imbalance. Age of onset did not predict dyskinesia or end of dose failure. A low tremor score at baseline and female gender were predictive of the early appearance of dyskinesia. Patients who experienced end of dose failure were taking a significantly higher dose of levodopa. Once dose and duration of treatment were corrected for, no baseline features were predictive of end of dose failure. The dose of levodopa at 5 years was positively correlated to baseline disease severity as measured by the Columbia score. We conclude that the age of onset of symptoms of Parkinsons disease is a major determinant of the course of the disease and response to treatment.

A longitudinal of Parkinson's disease: clinical and neuropsychological correlates of dementia

Neuropsychological assessments were performed in ninety-one de novo patients participating in the Sydney Multicentre Study of Parkinsons disease. Assessments were made at baseline and after 3 and 5 years. Performance at baseline and after 5 years was compared with controls. At baseline 37% of patients whose symptoms of Parkinsons disease had begun after the age of 70 years were demented. This compared with a prevalence of dementia of 8.8% in patients whose symptoms had begun before the age of 70 years. By 5 years the prevalence of dementia in the two groups had risen to 62.3% and 17.3% respectively. The death rate was higher over the 5 year period in the demented patients. Demented patients had more symmetrical signs, higher disability and bradykinesia scores and more impairment of gait and balance at baseline than non-demented patients. The presence of dementia at baseline predicted a poor response to treatment. The dementia at baseline had features of a subcortical dementia. Subsequently, aphasia, apraxia and agnosia emerged, making the dementia indistinguishable from that of Alzheimers disease. Patients with well preserved cognitive function at baseline had a good response to levodopa and were more likely to develop levodopa induced dyskinesia. These results show that the clinical features of Parkinsons disease and response to treatment are influenced by the age of onset of symptoms and by the presence of dementia.