To examine the effects of age at onset on neuropsychological functioning in a group of patients w... more To examine the effects of age at onset on neuropsychological functioning in a group of patients with probable Alzheimer disease (AD) and, within this group, to scrutinize further those patients with mild early-onset disease as it was hypothesized that within this group specific patterns of cognitive impairment could be identified that correlated with neuropathological staging of the disease. Each patient underwent an extensive neuropsychological test battery to examine a wide range of cognitive processes to provide information to identify subtypes of dementia. The Memory Clinic in the Department of Geriatric Medicine, Concord Hospital, Concord, New South Wales, Australia. One hundred forty-five community-residing case patients with probable AD were studied; within this group, 51 case patients with mild AD and a Mini-Mental State Examination score greater than 19 were further examined; 36 similarly aged control patients who were part of a larger case-control study of AD in an urban population were also examined. A diagnosis of probable and possible AD was made if the case patient had evidence of memory impairment and met criteria according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. Individual neuropsychological test scores were compared. The tests were then grouped into 7 cognitive domains. Patterns of early cognitive impairment were derived from these comparisons. With an earlier age at onset, significantly more impairment on tests of digit span and praxis was seen, while the duration of disease had no independent effect once the age at onset was fixed. Patients with mild early-onset dementia and a Mini-Mental State Examination score greater than 19 showed significant impairment in tests of attention, memory, frontal/executive functions, visuospatial ability, praxis, and visual agnosia compared with that shown by control patients. In this group, further analyses revealed that impairment in memory and frontal/ executive functions were the earliest signs of cognitive impairment. These data showed that when the duration of disease was adjusted for, case patients with an earlier age at onset of AD demonstrated significantly more impairment on tests of attention span and working memory (digit span), graphomotor function (copy loops), and apraxia than those with an older age at onset. Our findings support the view that the hippocampus and its connections are affected in the early stages of AD. The deficits in the frontal/executive functions also suggest that a disruption of cortical pathways to the frontal lobes and the pathological changes in this region occur early in the disease.
Background: There has been no analysis of brain tissue from longitudinally observed, cognitively ... more Background: There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. Objective: To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. Design and Main Outcome Measures: A 5-year postmortem tissue collection was performed after a casecontrol study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables.
One hundred and seven newly diagnosed, untreated patients with Parkinson's disease (PD) were ... more One hundred and seven newly diagnosed, untreated patients with Parkinson's disease (PD) were divided into two groups according to their age at reported onset of symptoms. Of these, 79 patients were under age 70 (early-onset) and 28 patients were age 70 and over (late-onset). The group of 50 control subjects comprised spouses, friends of the PD patients, and community volunteers. The patients were participants in a multicenter drug study of Parkinson's disease. Each had received a detailed neurological and neuropsychological assessment in the baseline placebo phases of the study. Thirty-4 patients with early-onset and 12 patients with late-onset were reassessed 3 years after treatment with low-dose levodopa, with bromocriptine, or with a combination of the two drugs. The results of the baseline phase of the study revealed that 8% of the early-onset group and 32% of the late-onset group were classified as demented. The 3-year follow-up revealed that the prevalence of dementia ...
Dementia with cortical Lewy bodies (LBD) was first described by Okazaki et al in 1961 and is now ... more Dementia with cortical Lewy bodies (LBD) was first described by Okazaki et al in 1961 and is now recognised as a relatively common cause of the dementia syndrome. The true prevalence of LBD is unknown. In post-mortem studies of patients diagnosed as having dementia in life, the mean frequency of Lewy body dementia is 12.5% (Byrne, 1997). Clinically diagnosed LBD (using operational clinical criteria) is found in 10–23% of patients presenting to, or in the care of, psychogeriatric services (Collerton et al, 1996). What is not yet certain is its nosological status; opinion is divided between regarding it as a variety of Alzheimer's disease (the Lewy body variant), a distinct disease (senile dementia of the Lewy body type) or a spectrum disorder related to both Parkinson's disease and to Alzheimer's disease (Byrne, 1992).
To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This pat... more To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This patient presented with a clinical picture of mania which proved difficult to treat until an EEG revealed the presence of photoconvulsive epilepsy. Treatment with haloperidol and lithium was unsuccessful but the addition of carbamazepine produced a dramatic response. Haloperidol was stopped and the patient maintained on lithium and carbamazepine. A successful outcome was achieved with carbamazepine and the patient has remained well on this treatment for 2 years. The authors postulate that there may be an association between photoconvulsive epilepsy and mania, perhaps on a kindling basis. The literature pertaining to the psychiatric aspects of photoconvulsive epilepsy is reviewed.
One hundred de novo patients with Parkinson's disease (PD) were classified into two groups ac... more One hundred de novo patients with Parkinson's disease (PD) were classified into two groups according to age of onset of symptoms. Seventy two patients were under 70 years and 28 were 70 years and over. All patients were given neurological and neuropsychological assessments, and the severity of the signs was rated on a modified Columbia scale. The neuropsychological assessment was also administered to 50 age-and-education-matched controls. The neuropsychological test battery included tests of verbal learning, visual memory, verbal fluency, visuospatial skill, simple and choice reaction time, language and maze learning. The late-onset patients had significant impairment in nonverbal reasoning, auditory verbal learning, visual memory and choice reaction time in contrast to early-onset patients and controls. A relationship was found between bradykinesia and widespread cognitive impairment. Severity of tremor was found to be significantly correlated with impairment in auditory verbal...
One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parki... more One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parkinson's 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 Ldopa-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 Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's 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.
We report a case in which typical clinical features of idiopathic Parkinson&#... more We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause.
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (7... more After 20 years follow-up of newly diagnosed patients with Parkinson's 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.
Journal of Neurology, Neurosurgery & Psychiatry, 2011
To determine whether neuropsychological measures differ between patients with idiopathic Parkinso... more To determine whether neuropsychological measures differ between patients with idiopathic Parkinson's 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. 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. 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. 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.
Journal of Neurology, Neurosurgery & Psychiatry, 1996
To further elucidate the relation between diffuse Lewy body disease and Parkinson&amp... more To further elucidate the relation between diffuse Lewy body disease and Parkinson's disease. The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer's neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson's disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson's disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson's disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson's disease.
Journal of Neurology, Neurosurgery & Psychiatry, 1989
One hundred and twenty nine de novo patients with idiopathic Parkinson's disease are being follow... more One hundred and twenty nine de novo patients with idiopathic Parkinson's disease are being followed over a 5 year period in a double-blind multicentre study comparing low-dose bromocriptine (< 30 mg/day) with low-dose levodopa-carbidopa (< 600/150 mg/day). Sixty six patients have been randomised to bromocriptine and 63 patients to levodopa-carbidopa. Improvement has been greater in the levodopa-carbidopa group than in the bromocriptine group. Involuntary movements have so far only occurred in patients on levodopa-carbidopa, the incidence being much lower than is usually described with conventional doses. Mild, end-of-dose failure has occurred in both treatment groups; however, no patient has developed the "on-off' phenomenon. Low-dose levodopa-carbidopa appears to be a more effective anti-Parkinsonian treatment than lowdose bromocriptine but more prone to cause dyskinesia.
Concensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies hav... more Concensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies have recently been proposed based on retrospective studies (McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 113-1124.) The present study tests these criteria prospectively in three cases which came to autopsy: a 57-year-old female followed for 5 years, an 86-year-old male followed for 3 years and a 66-year-old male followed for 11 years. All were considered to have dementia with Lewy bodies clinically, and at autopsy all had pathologically confirmed Lewy body disease. However, the Lewy bodies found in the 57-year-old were scanty and she also had marked Alzheimer-type pathology, making the contribution of Lewy bodies to the dementia uncertain. The 66-year-old had unusual cortical Lewy body pathology, previously only described in one other case (Masliah E, Galasho D, Wiley CA, Hansen LA. Lobar atrophy with dense-core (brain stem type) Lewy bodies in a patient with dementia. Acta Neuropathol 1990; 80: 453-458.) While this study prospectively validates the current criteria for dementia with Lewy bodies, there was considerable pathological variability in the cases.
Neuropsychological assessments were performed in ninety-one de novo patients participating in the... more Neuropsychological assessments were performed in ninety-one de novo patients participating in the Sydney Multicentre Study of Parkinson's 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 Parkinson's 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 Alzheimer's 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 Parkinson's disease and response to treatment are influenced by the age of onset of symptoms and by the presence of dementia.
... The Role of Cholinergic Deficiency in Neuropsychological Deficits in Idiopathic Parkinson&... more ... The Role of Cholinergic Deficiency in Neuropsychological Deficits in Idiopathic Parkinson&#x27;s Disease WGJ Reid, GA Broe, JGL Morris, MA Hely, NG Moss, SA Genge, DJ O&#x27;Sullivan, PMWilliamson The Sydney Multicentre Study of Parkinson&#x27;s Disease, Department of Geriatric ...
This study measured brain atrophy in patients with idiopathic Parkinson&amp;amp;amp;amp;#39;s... more This study measured brain atrophy in patients with idiopathic Parkinson&amp;amp;amp;amp;#39;s disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimer&amp;amp;amp;amp;#39;s disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimer&amp;amp;amp;amp;#39;s disease and is likely to be the anatomical substrate for the memory deficits found in each of these patients groups. Frontal lobe atrophy was a feature of both late-onset Parkinson&amp;amp;amp;amp;#39;s disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopammergic deafferentation, frontal atrophy and dementia.
Australian and New Zealand Journal of Psychiatry, 1996
To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This pat... more To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This patient presented with a clinical picture of mania which proved difficult to treat until an EEG revealed the presence of photoconvulsive epilepsy. Treatment with haloperidol and lithium was unsuccessful but the addition of carbamazepine produced a dramatic response. Haloperidol was stopped and the patient maintained on lithium and carbamazepine. A successful outcome was achieved with carbamazepine and the patient has remained well on this treatment for 2 years. The authors postulate that there may be an association between photoconvulsive epilepsy and mania, perhaps on a kindling basis. The literature pertaining to the psychiatric aspects of photoconvulsive epilepsy is reviewed.
There has been no analysis of brain tissue from longitudinally observed, cognitively tested patie... more There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. A 5-year postmortem tissue collection was performed after a case-control study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables. The Centre for Education and Research on Ageing and the Prince of Wales Medical Research Institute, Sydney, Australia. Twelve patients with Alzheimer disease (5 taking anti-inflammatory drugs) and 10 nondemented controls (3 taking anti-inflammatory drugs) were selected (50% of available sample). Of the patients with Alzheimer disease, anti-inflammatory drug users performed better on neuropsychological test scores than did nonusers. However, there were no significant differences in the amount of inflammatory glia, plaques, or tangles in either diagnostic group. Long-term anti-inflammatory medications in patients with Alzheimer disease enhanced cognitive performance but did not alleviate the progression of the pathological changes. Arch Neurol. 2000.
To examine the effects of age at onset on neuropsychological functioning in a group of patients w... more To examine the effects of age at onset on neuropsychological functioning in a group of patients with probable Alzheimer disease (AD) and, within this group, to scrutinize further those patients with mild early-onset disease as it was hypothesized that within this group specific patterns of cognitive impairment could be identified that correlated with neuropathological staging of the disease. Each patient underwent an extensive neuropsychological test battery to examine a wide range of cognitive processes to provide information to identify subtypes of dementia. The Memory Clinic in the Department of Geriatric Medicine, Concord Hospital, Concord, New South Wales, Australia. One hundred forty-five community-residing case patients with probable AD were studied; within this group, 51 case patients with mild AD and a Mini-Mental State Examination score greater than 19 were further examined; 36 similarly aged control patients who were part of a larger case-control study of AD in an urban population were also examined. A diagnosis of probable and possible AD was made if the case patient had evidence of memory impairment and met criteria according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer&amp;amp;#39;s Disease and Related Disorders Association. Individual neuropsychological test scores were compared. The tests were then grouped into 7 cognitive domains. Patterns of early cognitive impairment were derived from these comparisons. With an earlier age at onset, significantly more impairment on tests of digit span and praxis was seen, while the duration of disease had no independent effect once the age at onset was fixed. Patients with mild early-onset dementia and a Mini-Mental State Examination score greater than 19 showed significant impairment in tests of attention, memory, frontal/executive functions, visuospatial ability, praxis, and visual agnosia compared with that shown by control patients. In this group, further analyses revealed that impairment in memory and frontal/ executive functions were the earliest signs of cognitive impairment. These data showed that when the duration of disease was adjusted for, case patients with an earlier age at onset of AD demonstrated significantly more impairment on tests of attention span and working memory (digit span), graphomotor function (copy loops), and apraxia than those with an older age at onset. Our findings support the view that the hippocampus and its connections are affected in the early stages of AD. The deficits in the frontal/executive functions also suggest that a disruption of cortical pathways to the frontal lobes and the pathological changes in this region occur early in the disease.
Background: There has been no analysis of brain tissue from longitudinally observed, cognitively ... more Background: There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. Objective: To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. Design and Main Outcome Measures: A 5-year postmortem tissue collection was performed after a casecontrol study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables.
One hundred and seven newly diagnosed, untreated patients with Parkinson's disease (PD) were ... more One hundred and seven newly diagnosed, untreated patients with Parkinson's disease (PD) were divided into two groups according to their age at reported onset of symptoms. Of these, 79 patients were under age 70 (early-onset) and 28 patients were age 70 and over (late-onset). The group of 50 control subjects comprised spouses, friends of the PD patients, and community volunteers. The patients were participants in a multicenter drug study of Parkinson's disease. Each had received a detailed neurological and neuropsychological assessment in the baseline placebo phases of the study. Thirty-4 patients with early-onset and 12 patients with late-onset were reassessed 3 years after treatment with low-dose levodopa, with bromocriptine, or with a combination of the two drugs. The results of the baseline phase of the study revealed that 8% of the early-onset group and 32% of the late-onset group were classified as demented. The 3-year follow-up revealed that the prevalence of dementia ...
Dementia with cortical Lewy bodies (LBD) was first described by Okazaki et al in 1961 and is now ... more Dementia with cortical Lewy bodies (LBD) was first described by Okazaki et al in 1961 and is now recognised as a relatively common cause of the dementia syndrome. The true prevalence of LBD is unknown. In post-mortem studies of patients diagnosed as having dementia in life, the mean frequency of Lewy body dementia is 12.5% (Byrne, 1997). Clinically diagnosed LBD (using operational clinical criteria) is found in 10–23% of patients presenting to, or in the care of, psychogeriatric services (Collerton et al, 1996). What is not yet certain is its nosological status; opinion is divided between regarding it as a variety of Alzheimer's disease (the Lewy body variant), a distinct disease (senile dementia of the Lewy body type) or a spectrum disorder related to both Parkinson's disease and to Alzheimer's disease (Byrne, 1992).
To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This pat... more To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This patient presented with a clinical picture of mania which proved difficult to treat until an EEG revealed the presence of photoconvulsive epilepsy. Treatment with haloperidol and lithium was unsuccessful but the addition of carbamazepine produced a dramatic response. Haloperidol was stopped and the patient maintained on lithium and carbamazepine. A successful outcome was achieved with carbamazepine and the patient has remained well on this treatment for 2 years. The authors postulate that there may be an association between photoconvulsive epilepsy and mania, perhaps on a kindling basis. The literature pertaining to the psychiatric aspects of photoconvulsive epilepsy is reviewed.
One hundred de novo patients with Parkinson's disease (PD) were classified into two groups ac... more One hundred de novo patients with Parkinson's disease (PD) were classified into two groups according to age of onset of symptoms. Seventy two patients were under 70 years and 28 were 70 years and over. All patients were given neurological and neuropsychological assessments, and the severity of the signs was rated on a modified Columbia scale. The neuropsychological assessment was also administered to 50 age-and-education-matched controls. The neuropsychological test battery included tests of verbal learning, visual memory, verbal fluency, visuospatial skill, simple and choice reaction time, language and maze learning. The late-onset patients had significant impairment in nonverbal reasoning, auditory verbal learning, visual memory and choice reaction time in contrast to early-onset patients and controls. A relationship was found between bradykinesia and widespread cognitive impairment. Severity of tremor was found to be significantly correlated with impairment in auditory verbal...
One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parki... more One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parkinson's 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 Ldopa-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 Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's 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.
We report a case in which typical clinical features of idiopathic Parkinson&amp;amp;amp;amp;#... more We report a case in which typical clinical features of idiopathic Parkinson&amp;amp;amp;amp;#39;s disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson&amp;amp;amp;amp;#39;s disease and Pick&amp;amp;amp;amp;#39;s disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson&amp;amp;amp;amp;#39;s disease, our case illustrates that Pick&amp;amp;amp;amp;#39;s disease is one such cause.
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (7... more After 20 years follow-up of newly diagnosed patients with Parkinson's 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.
Journal of Neurology, Neurosurgery & Psychiatry, 2011
To determine whether neuropsychological measures differ between patients with idiopathic Parkinso... more To determine whether neuropsychological measures differ between patients with idiopathic Parkinson&amp;amp;amp;amp;#39;s 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. 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 (&amp;amp;amp;amp;gt;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. 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. 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.
Journal of Neurology, Neurosurgery & Psychiatry, 1996
To further elucidate the relation between diffuse Lewy body disease and Parkinson&amp;amp;amp... more To further elucidate the relation between diffuse Lewy body disease and Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;#39;s neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease.
Journal of Neurology, Neurosurgery & Psychiatry, 1989
One hundred and twenty nine de novo patients with idiopathic Parkinson's disease are being follow... more One hundred and twenty nine de novo patients with idiopathic Parkinson's disease are being followed over a 5 year period in a double-blind multicentre study comparing low-dose bromocriptine (< 30 mg/day) with low-dose levodopa-carbidopa (< 600/150 mg/day). Sixty six patients have been randomised to bromocriptine and 63 patients to levodopa-carbidopa. Improvement has been greater in the levodopa-carbidopa group than in the bromocriptine group. Involuntary movements have so far only occurred in patients on levodopa-carbidopa, the incidence being much lower than is usually described with conventional doses. Mild, end-of-dose failure has occurred in both treatment groups; however, no patient has developed the "on-off' phenomenon. Low-dose levodopa-carbidopa appears to be a more effective anti-Parkinsonian treatment than lowdose bromocriptine but more prone to cause dyskinesia.
Concensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies hav... more Concensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies have recently been proposed based on retrospective studies (McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 113-1124.) The present study tests these criteria prospectively in three cases which came to autopsy: a 57-year-old female followed for 5 years, an 86-year-old male followed for 3 years and a 66-year-old male followed for 11 years. All were considered to have dementia with Lewy bodies clinically, and at autopsy all had pathologically confirmed Lewy body disease. However, the Lewy bodies found in the 57-year-old were scanty and she also had marked Alzheimer-type pathology, making the contribution of Lewy bodies to the dementia uncertain. The 66-year-old had unusual cortical Lewy body pathology, previously only described in one other case (Masliah E, Galasho D, Wiley CA, Hansen LA. Lobar atrophy with dense-core (brain stem type) Lewy bodies in a patient with dementia. Acta Neuropathol 1990; 80: 453-458.) While this study prospectively validates the current criteria for dementia with Lewy bodies, there was considerable pathological variability in the cases.
Neuropsychological assessments were performed in ninety-one de novo patients participating in the... more Neuropsychological assessments were performed in ninety-one de novo patients participating in the Sydney Multicentre Study of Parkinson's 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 Parkinson's 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 Alzheimer's 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 Parkinson's disease and response to treatment are influenced by the age of onset of symptoms and by the presence of dementia.
... The Role of Cholinergic Deficiency in Neuropsychological Deficits in Idiopathic Parkinson&... more ... The Role of Cholinergic Deficiency in Neuropsychological Deficits in Idiopathic Parkinson&#x27;s Disease WGJ Reid, GA Broe, JGL Morris, MA Hely, NG Moss, SA Genge, DJ O&#x27;Sullivan, PMWilliamson The Sydney Multicentre Study of Parkinson&#x27;s Disease, Department of Geriatric ...
This study measured brain atrophy in patients with idiopathic Parkinson&amp;amp;amp;amp;#39;s... more This study measured brain atrophy in patients with idiopathic Parkinson&amp;amp;amp;amp;#39;s disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimer&amp;amp;amp;amp;#39;s disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimer&amp;amp;amp;amp;#39;s disease and is likely to be the anatomical substrate for the memory deficits found in each of these patients groups. Frontal lobe atrophy was a feature of both late-onset Parkinson&amp;amp;amp;amp;#39;s disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopammergic deafferentation, frontal atrophy and dementia.
Australian and New Zealand Journal of Psychiatry, 1996
To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This pat... more To describe a young patient who had a comorbidity of mania and photoconvulsive epilepsy. This patient presented with a clinical picture of mania which proved difficult to treat until an EEG revealed the presence of photoconvulsive epilepsy. Treatment with haloperidol and lithium was unsuccessful but the addition of carbamazepine produced a dramatic response. Haloperidol was stopped and the patient maintained on lithium and carbamazepine. A successful outcome was achieved with carbamazepine and the patient has remained well on this treatment for 2 years. The authors postulate that there may be an association between photoconvulsive epilepsy and mania, perhaps on a kindling basis. The literature pertaining to the psychiatric aspects of photoconvulsive epilepsy is reviewed.
There has been no analysis of brain tissue from longitudinally observed, cognitively tested patie... more There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. A 5-year postmortem tissue collection was performed after a case-control study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables. The Centre for Education and Research on Ageing and the Prince of Wales Medical Research Institute, Sydney, Australia. Twelve patients with Alzheimer disease (5 taking anti-inflammatory drugs) and 10 nondemented controls (3 taking anti-inflammatory drugs) were selected (50% of available sample). Of the patients with Alzheimer disease, anti-inflammatory drug users performed better on neuropsychological test scores than did nonusers. However, there were no significant differences in the amount of inflammatory glia, plaques, or tangles in either diagnostic group. Long-term anti-inflammatory medications in patients with Alzheimer disease enhanced cognitive performance but did not alleviate the progression of the pathological changes. Arch Neurol. 2000.
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