[show abstract][hide abstract] ABSTRACT: Heart rate and respiration display fluctuations that are interlinked by central regulatory mechanisms of the autonomic nervous system (ANS). Joint assessment of respiratory time series along with heart rate variability (HRV) may therefore provide information on ANS dysfunction. The aim of this study was to investigate cardio-respiratory interaction in patients with Parkinson's disease (PD), a neurodegenerative disorder that is associated with progressive ANS dysfunction. Short-term ECG and respiration were recorded in 25 PD patients and 28 healthy controls during rest. To assess ANS dysfunction we analyzed joint symbolic dynamics of heart rate and respiration, cardio-respiratory synchrograms along with heart rate variability. Neither HRV nor cardio-respiratory synchrograms were significantly altered in PD patients. Symbolic analysis, however, identified a significant reduction in cardio-respiratory interactions in PD patients compared to healthy controls (16 ± 3.6 % vs. 20 ± 6.1 %; p= 0.02). In conclusion, joint symbolic analysis of cardio-respiratory dynamics provides a powerful tool to detect early signs of autonomic nervous system dysfunction in Parkinson's disease patients at an early stage of the disease.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:3680-3.
[show abstract][hide abstract] ABSTRACT: Parkinson's disease (PD) is a degenerative neurological condition, associated with cardiovascular dysfunction. Many studies have utilised heart rate variability (HRV) to assess the autonomic nervous system in PD, but blood pressure variability (BPV) has received less attention. The purpose of the present study was to compare HRV and BPV between participants with established PD, extrapyramidal motor slowing (EPMS) (not reaching clinical criteria for PD), older healthy controls (OHC), and young healthy controls (YHC), in order to ascertain whether either of these measures can be used as an early marker of non-motor symptoms in PD.
HRV was assessed at rest and during 2 min of slow deep breathing in 97 participants, divided into four groups: YHC (20-30 years; n = 19); OHC (67-83 years; n = 28); EPMS (59-91 years; n = 25) and PD (61-84 years; n = 25).
Spectral analysis of blood pressure was performed on stable non-invasive recordings of blood pressure obtained in 76 of the participants. Low frequency (LF) and high frequency (HF) components, and the LF/HF ratio, were measured. Significant differences were only seen between the YHC and the three older groups. For HRV this was seen at rest and during 2 min of slow deep breathing, whereas for BPV this was only seen during 2 min of slow deep breathing.
These data indicate that there are only age-related changes in HRV and BPV, and that neither technique is sensitive enough to provide an index of pre-clinical PD.
Clinical Autonomic Research 04/2012; 22(4):191-6. · 1.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Sydney Memory and Ageing Study (Sydney MAS) was initiated in 2005 to examine the clinical characteristics and prevalence of mild cognitive impairment (MCI) and related syndromes, and to determine the rate of change in cognitive function over time.
Non-demented community-dwelling individuals (N = 1037) aged 70-90 were recruited from two areas of Sydney, following a random approach to 8914 individuals on the electoral roll. They underwent detailed neuropsychiatric and medical assessments and donated a blood sample for clinical chemistry, proteomics and genomics. A knowledgeable informant was also interviewed. Structural MRI scans were performed on 554 individuals, and subgroups participated in studies of falls and balance, metabolic and inflammatory markers, functional MRI and prospective memory. The cohort is to be followed up with brief telephone reviews annually, and detailed assessments biannually.
This is a generally well-functioning cohort mostly living in private homes and rating their health as being better than average, although vascular risk factors are common. Most (95.5%) participants or their informants identified a cognitive difficulty, and 43.5% had impairment on at least one neuropsychological test. MCI criteria were met by 34.8%; with 19.3% qualifying for amnestic MCI, whereas 15.5% had non-amnestic MCI; 1.6% had impairment on neuropsychological test performance but no subjective complaints; and 5.8% could not be classified. The rate of MCI was 30.9% in the youngest (70-75) and 39.1% in the oldest (85-90) age bands. Rates of depression and anxiety were 7.1% and 6.9% respectively.
Cognitive complaints are common in the elderly, and nearly one in three meet criteria for MCI. Longitudinal follow-up of this cohort will delineate the progression of complaints and objective cognitive impairment, and the determinants of such change.
International Psychogeriatrics 12/2010; 22(8):1248-64. · 2.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is been said that ‘traditional legal theory either presumes that judges have no operative emotions about litigants and issues before them, or mandates that any such emotions be actively suppressed, reflecting an untested, commonsense wisdom that emotion distorts the legal reasoning demanded by the judicial role’. In contrast to this presumption however, recent neuroscience research has demonstrated that emotion is likely to play a key facilitative role in legal decision-making via participation of the ventromedial cortex; in particular, areas of law where personal, social, and moral circumstances are considered, areas that include criminal law and sentencing. The leading High Court decision reflecting upon deliberation and reasoning in sentencing is Markarian v The Queen. This paper will evaluate the decision-making processes proposed by the judges in that decision, and potential alternative approaches, in the light of what is possible neurobiologically.
Australian Journal of Forensic Sciences 03/2010; 42(1):11-18. · 0.53 Impact Factor
[show abstract][hide abstract] ABSTRACT: The clinical presentations in dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) overlap considerably with that of Alzheimer's disease (AD) despite different pathological processes. Autopsy studies have also shown that multiple brain pathology occurs frequently, even in cases with a single clinical diagnosis. We aimed to determine the frequency of clinical diagnosis of FTD and DLB and the underlying pathology in a well-characterized cohort of patients with a clinical diagnosis of probable or possible AD.
We conducted a retrospective analysis of 170 AD patients (probable AD = 83; possible AD = 87) originally enrolled in a case-control study, 27 with postmortem examination, to establish the number of cases meeting probable diagnosis for FTD and DLB, using a checklist of features compiled from their consensus criteria.
23/83 probable AD cases and 32/87 possible AD cases met probable criteria for another dementia, more commonly DLB than FTD. AD pathology was present in 8/15 probable AD and 8/12 possible AD cases coming to autopsy. DLB pathology was seen in four cases and FTD pathology in eight cases. In the AD cases reaching clinical diagnosis for a second dementia syndrome and coming to autopsy, a minority showed non-AD pathology only.
Presence of core clinical features of non-AD dementia syndromes is common in AD. Concordance between clinical and pathological diagnoses of dementia remains variable. We propose that repeat clinical examinations and structural neuroimaging will improve diagnostic accuracy. In addition, clinical diagnostic criteria for the main dementia syndromes require refinement.
International Psychogeriatrics 07/2009; 21(4):688-95. · 2.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objectives: To examine the determinants of service use in a community dwelling sample aged 75 or over.Methods: Subjects (n = 537) were interviewed about use of community and medical services and the provision of unpaid support from their social network. Measures of disease and disability, detailed network support data and factors that may either enable or predispose subjects to service use were obtained and their prediction of service use examined.Results: Unpaid support and community service use were predicted predominantly by disability, with disease providing little additional prediction. Medical service use was predicted by both disease and disability. With disease and disability controlled for, other variables did not significantly predict medical service use or unpaid support; but did predict small additional variation in some community service use.Conclusions: Disability and disease are the major determinants of service use with other factors contributing to the use of some community services.
[show abstract][hide abstract] ABSTRACT: Objectives: To assess difficulty of access to both private and public transport experienced by older people living in the community in Sydney, to identify demographic and disability-related risk factors for poor access to transport, and to gauge the extent to which transport needs were met by assistance from relatives and friends.Method: An interview survey of a random sample of 620 people aged 75 years and older living in the community was conducted in the inner western suburbs of Sydney between August 1991 and September 1993. Questions covered demographic background, self-perceived disability, difficulty of access to transport, and assistance given by relatives and friends.Results: Slightly over half of the respondents said that access to private transport was difficult or impossible for them; one-third said that using public transport was difficult; 29% had difficulty with both forms of transport; yet only a quarter received help from relatives or friends. Fifteen per cent of all respondents were transport deprived in that they found access to both forms of transport difficult but did not receive any assistance. In general, the severely disabled were not significantly at risk of transport deprivation.Conclusions: There was a sizeable group of older people living in the community for whom access to transport posed considerable difficulties and who received no transport assistance from relatives or friends. Further research is needed on the impact of transport deprivation and the extent to which this is ameliorated by formal services.
[show abstract][hide abstract] ABSTRACT: Objectives: To assess satisfaction with medical and allied health services among community-living aged persons and to determine whether satisfaction had changed over a three-year period.Method: An interview survey of a random sample of 320 people aged 75 years and older was conducted in the inner western suburbs of Sydney between August 1991 and September 1993 and repeated between August 1994 and October 1996 with 227 surviving members of the cohort. Questions covered the use of, and satisfaction with, medical and allied health services during the preceding 12 months.Results: The proportion Very satisfied’ with general practitioner (GP) surgery attendances and house calls over the two surveys ranged between 88% and 100%. The proportion ‘;very satisfied’ with specialist medical services ranged between 87% and 91%. The proportion ‘;very satisfied’ with allied health services ranged from 69% for optometry in 1992 to 93% for audiometry in 1995. There was no significant change over time.Conclusions: These older people displayed high levels of satisfaction with allied health services and very high levels of satisfaction with medical services.
[show abstract][hide abstract] ABSTRACT: Objective: To examine the association between alcohol consumption and incident functional disability in community-living older people after adjustment for other risk factors.Method: Randomly sampled community-living people aged 75 years and older from the inner western suburbs of Sydney underwent a clinical interview and medical examination by a physician experienced in geriatric medicine. This was repeated three years later. The examination included an assessment of functional disability and chronic systemic and neurodegenerative illnesses and impairments. Self-reported alcohol consumption was recorded. The relationship between alcohol consumption and incident disability was examined by logistic regression analysis.Results: Cross-sectional analysis at the first wave showed that those who did not drink were more likely to be disabled than drinkers (39.3% and 30.4% respectively, p = 0.032). Although 11.3% were drinking at hazardous or harmful levels there was no concurrent association between disability and hazardous/harmful drinking. Incident disability between waves did not differ between non-drinkers at the first wave and those who drank at non-hazardous/harmful levels (35.3% and 29.3% disabled respectively, p=0.306). However 80% of those who drank at hazardous/harmful levels experienced incident disability as compared with 32.5% among non-drinkers and non-hazardous/harmful drinkers combined (p<0.001). Logistic regression showed that, among the risk factors examined, hazardous/harmful consumption had by far the strongest effect with an adjusted odds ratio of 12.9 (95% CI 3.1–53.9).Conclusion: Alcohol consumption at defined hazardous/harmful levels is a major independent risk factor for incident functional disability in older people.
[show abstract][hide abstract] ABSTRACT: Objectives: To examine the inter-relationships between formal and informal unpaid services in an elderly population.Methods: 537 community-dwelling elderly (75 or older) were interviewed about use of community and medical services and the provision of unpaid support. Disease and disability were assessed by medical practitioners. The relationship between service use and unpaid support among persons with the same disease/disability profile was examined.Results: Unpaid network support for instrumental activities of daily living (IADL) needs was utilised when community services were not. Unpaid ADL and IADL network support is used in conjunction with medical services. Higher socioeconomic status, female gender and having fewer coresidents predicted higher use of community services. Males spent more days in hospital.Conclusions: Community IADL services and unpaid IADL network support work in a compensatory fashion. In contrast, higher users of medical services were greater users of unpaid network support.
[show abstract][hide abstract] ABSTRACT: This paper reviews the Sydney Older Persons Study, a longitudinal study following an initial cohort of 630 subjects aged 75 and over, community living in the inner west region of Sydney, carried out over seven years in four waves from 1991. We discuss the epidemiology of neurodegenerative disorders (NDDs) in relation to: each other, systemic disorders, death, lifestyle, risk factors and their impact on quality of life, service use and carers.
[show abstract][hide abstract] ABSTRACT: Objectives: Disability is an important predictor of health and community service utilisation. Understanding its pathogenesis has implications for planning of future health services. The aim of our study was to examine the contribution of systemic, psychiatric and neurodegenerative diseases to disability in an “old-old” population.Methods: 647 men and women over the age of 75 participated in the Sydney Older Person's Study. Disability in activities of daily living (ADL), instrumental activities of daily living (IADL) and mobility was assessed using self report, informant and clinician assessments. Diagnoses of systemic, psychiatric, neurodegenerative diseases were made by clinicians. Individual disease contribution to disability was assessed using multiple regression analysis. Contribution to disability by the groups of systemic, neurodegenerative and psychiatric diagnoses was assessed, using hierarchical regression. Results: Neurodegenerative diseases were the major contributors to ADL impairment. Systemic and psychiatric diseases played a role in IADL and mobility impairment, as did the neurodegenerative diseases. Of the neurodegenerative diseases, dementia/cognitive impairment and Parkinsonism/gait slowing particularly contributed to disability. Self-report under-identified the role of the neurodegenerative diseases in disability. It also introduced a gender effect, that the clinical measures did not share to the same extent.Conclusions: Neurodegenerative diseases are important contributors to disability and assessments and diagnosis of neurodegenerative diseases should be included in disability assessments. Self report under-identifies the importance of these conditions.
[show abstract][hide abstract] ABSTRACT: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD).
A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA.
Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling.
Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.
Annals of Neurology 11/2008; 64(4):446-54. · 11.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.
Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.
APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.
These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.
Journal of Neuroinflammation 09/2008; 5:36. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
Journal of Neurochemistry 03/2008; 104(3):573-83. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transcranial sonography reveals an increase in echogenicity in the substantia nigra of patients with idiopathic Parkinson's disease. Marked hyperechogenicity has also been described in 9% of the healthy population and is associated with subtle clinical or functional neuroimaging findings suggestive of changes in nigrostriatal function. It has therefore been hypothesised that a hyperechogenic substantia nigra represents an early stage of nigral degeneration or a predisposition for Parkinson's disease. In the present study, we correlated sonographic findings with motor and cognitive deficits in a group of healthy, very elderly subjects. Marked and moderately increased substantia nigra echogenicity was present in 25% and 21% of our healthy, very elderly subjects, respectively, and correlated strongly with the presence of extrapyramidal symptoms in the absence of cognitive deficits. The high incidence of substantia nigra hyperechogenicity measured in our very elderly subjects compared with previous TCS studies suggests that the prevalence of this feature increases with age and is consistent with the higher prevalence of Parkinson's disease in advanced age, as well as the increased frequency of extrapyramidal symptoms. Our results indicate that this simple technique can be used to identify and quantify brain changes associated with subtle motor dysfunction in the very elderly.
[show abstract][hide abstract] ABSTRACT: Gait disturbance and cognitive changes are common with ageing. The cerebellum contributes to motor coordination and participates in various aspects of cognition. However, no research has investigated the possible cerebellar contribution to gait and cognition in non-demented very old individuals. The current study aimed to determine the associations between indices of cerebellar size (vermal area and total volume) and measures of motor and cognitive integrity, as well as the role of variables known to impact on cerebellar size (alcohol consumption and chronological age) in a sample of 111 community dwellers (mean age: 85 years; range: 81-97 years). A marginally significant association was present between age and total vermal area. Significant correlations between current daily alcohol intake and some vermal areas were observed. These associations were more pronounced in men, particularly after controlling for cerebrum size. Multiple linear regression models revealed limited unique contributions of cerebellar predictors to neurological and cognitive measures. In summary, the results indicate that the cerebellum may be susceptible to alcohol-related shrinkage in non-demented very old individuals, more so in men, even at low dose. It also appears that the observed changes in cerebellum size in this population contribute little to neurological and cognitive changes.
European Archives of Psychiatry and Clinical Neuroscience 01/2007; 256(8):504-11. · 3.20 Impact Factor