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Biomedical subjects

D J Burn

Publications and source records attributed to D J Burn.

At least 19 recordsLinked to original sources
PubMed2006

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Disease Susceptibility↗
PubMed2006

The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia. AIM: To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP. METHODS: The muscarinic M2 (presynaptic) and M4 (postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease (AD; n = 39) and controls (n = 50). RESULTS: In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls. CONCLUSIONS: The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.

Aged↗
PubMed2006

A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

Aged↗
PubMed2006

Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies.

BACKGROUND: Levodopa (L-dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L-dopa use in patients with parkinsonism and dementia. Therefore, the effect of L-dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear. AIM: To ascertain the acute and long-term effects of L-dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease. METHOD: Baseline cognitive and motor function was assessed off L-dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard "bedside" measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L-dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L-dopa to assess the prolonged effect. RESULTS: Acute L-dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L-dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L-dopa treatment. CONCLUSION: The use of L-dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.

Aged↗
PubMed2006

POLG1 in idiopathic Parkinson disease.

We studied POLG1 in 140 UK patients with idiopathic Parkinson disease (PD) and 279 Italian patients with PD and compared them to a UK control group (n = 207) and an Italian control group (n = 285). Our observations do not support a role for common POLG1 genetic variants in PD and indicate that dominant POLG1 mutations are a rare cause of parkinsonism in the general population.

Aged↗
PubMed2006

Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies.

BACKGROUND: A previous cross sectional study found over-representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD). AIMS: (1) To examine rates of cognitive and motor decline over two years in PD (n=40), PDD (n=42) and DLB (n=41) subjects, compared with age matched controls (n=41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype. RESULTS: Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non-demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE -4.5 and -3.9, respectively), compared with PD (-0.2) and controls (-0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (chi2=6.7, Fisher's exact test p<0.05). CONCLUSION: A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.

Aged↗
PubMed2006

Parkinson's disease dementia: what's in a Lewy body?

This brief review deals with pathological aspects of dementia associated with Parkinson's disease (PDD). PDD has been variably linked with cortical Lewy body topography and density. alpha-Synuclein and Alzheimer-type pathology frequently co-exist, suggesting that a combination of pathology related to protein dysmetabolism, possibly with synergistic protein-protein interaction, underpins the cognitive impairment in PDD. Dementia may therefore ensue when a "toxic threshold" is reached, irrespective of the combination of pathologies involved in reaching that threshold. The nature of this putative protein-protein interaction needs to be further elucidated, and also whether there are specific clinical correlates of the pathological substrate. Serum and cerebrospinal fluid proteins or imaging techniques may be useful in future as biomarkers to identify the relative contribution of Lewy-related and Alzheimer-type pathology in a given case of PDD and to inform the rational use of drugs that can reduce alpha-synuclein aggregation and beta-amyloid production.

Cerebral Cortex↗
PubMed2005

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Age of Onset↗
PubMed2005

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Brain↗
PubMed2005

Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies.

OBJECTIVE: To investigate the extent of medial temporal lobe atrophy (MTA) on MRI in Parkinson disease (PD) with and without dementia compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB) and to determine whether MTA correlates with cognitive impairment in PD and PD dementia (PDD). METHODS: Coronal T1-weighted MRI scans were acquired from control subjects (n = 39) and patients with PD (n = 33), PDD (n = 31), DLB (n = 25), and AD (n = 31), diagnosed according to standardized clinical diagnostic criteria. Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized (Scheltens) scale. RESULTS: More severe MTA was seen in PDD (p = 0.007), DLB (p < 0.001), and AD (p < 0.001) vs control subjects. PD subjects had greater hippocampal atrophy than control subjects (p = 0.015) but less than subjects with DLB and AD, though not with PDD. MTA correlated with CAMCOG score and memory scores in the DLB group and with age in control, PDD, and AD groups. There were no correlations between MTA and cognitive impairment in PD, PDD, and AD. PDD and DLB had a similar profile of cognitive impairment and MTA. CONCLUSIONS: Medial temporal lobe atrophy (MTA) was seen in cognitively intact older subjects with Parkinson disease (PD) and was not more pronounced in Parkinson disease dementia (PDD). Alzheimer disease (AD) and, to a lesser extent, dementia with Lewy bodies (DLB) showed more pronounced MTA. Results suggest early hippocampal involvement in PD and that when dementia develops in PD, anatomic structures apart from the hippocampus are predominantly implicated. Greater hippocampal involvement in AD vs PDD and DLB is consistent with clinical, cognitive, and pathologic differences between the disorders.

Age Factors↗
PubMed2005

Cholinergic systems in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Basal Ganglia↗
PubMed2005

The role of levodopa in the management of dementia with Lewy bodies.

BACKGROUND: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms. AIM: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD). METHOD: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa. RESULTS: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p < 0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion. CONCLUSION: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.

Administration, Oral↗
PubMed2005

Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year.

BACKGROUND: Brain perfusion deficits have been reported previously in subjects with Parkinson's disease in comparison with healthy controls. OBJECTIVE: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year. METHODS: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum. RESULTS: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year. CONCLUSIONS: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.

Aged↗
PubMed2004

Visual perception in Parkinson disease dementia and dementia with Lewy bodies.

OBJECTIVE: To quantify visual discrimination, space-motion, and object-form perception in patients with Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD). METHODS: The authors used a cross-sectional study to compare three demented groups matched for overall dementia severity (PDD: n = 24; DLB: n = 20; AD: n = 23) and two age-, sex-, and education-matched control groups (PD: n = 24, normal controls [NC]: n = 25). RESULTS: Visual perception was globally more impaired in PDD than in nondemented controls (NC, PD), but was not different from DLB. Compared to AD, PDD patients tended to perform worse in all perceptual scores. Visual perception of patients with PDD/DLB and visual hallucinations was significantly worse than in patients without hallucinations. CONCLUSIONS: Parkinson disease dementia (PDD) is associated with profound visuoperceptual impairments similar to dementia with Lewy bodies (DLB) but different from Alzheimer disease. These findings are consistent with previous neuroimaging studies reporting hypoactivity in cortical areas involved in visual processing in PDD and DLB.

Activities of Daily Living↗
PubMed2004

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease.

BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.

Adult↗
PubMed2004

SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies.

The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

Adult↗