Cardiovascular variability in Parkinson's disease and extrapyramidal motor slowing.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. INTERPRETATION: 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.

Joint symbolic dynamics as a model-free approach to study interdependence in cardio-respiratory time series.

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.

The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70-90 years.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Frontotemporal dementia and dementia with Lewy bodies in a case-control study of Alzheimer's disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Variable phenotype of Alzheimer's disease with spastic paraparesis.

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.

Contributions of age and alcohol consumption to cerebellar integrity, gait and cognition in non-demented very old individuals.

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.

Cognitive, extrapyramidal, and magnetic resonance imaging predictors of functional impairment in nondemented older community dwellers: the Sydney Older Person Study.

OBJECTIVES: To identify the clinical correlates of functional incapacity in the community living "old-old." DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: One hundred six nondemented people aged 80 to 94. MEASUREMENTS: Participants were medically and cognitively assessed, underwent magnetic resonance imaging scanning (MRI), and were interviewed regarding their functional status: activities of daily living (ADLs), instrumental ADLs (IADLs), and the complex IADL functions of reading, hobbies, and socializing. RESULTS: Dependency in IADLs, but not ADLs, was present. After controlling for age, sex, and education, extrapyramidal (EP) signs were significantly associated with two of the three IADLs, with EP signs comprising a composite score of 10 EP signs (e.g., resting tremor) and a 5-meter timed walk. Cognitive test performance on a range of tests was also associated with functional status. A hierarchical model confirmed the association between the EP signs and cognitive test performance and functional scores, but no "pattern" of cognitive association emerged. Hippocampal volume was associated with socializing. CONCLUSION: This study has shown that many nondemented very old people living in the community are losing capacity to perform IADL functions and that areas of incapacity are associated with the presence of EP signs and impaired cognition. These results highlight the need for health workers to include an assessment of EP and cognitive status in their evaluation of older persons living in the community, even in the context of a lack of dementia diagnosis. Furthermore, it signifies the need to directly evaluate IADL function to identify need for intervention and support if required. This group of old-old individuals may now be considered the "survivors" of their cohort, and early detection of the difficulties they are experiencing will enable clinicians to respond appropriately, thus providing them a higher quality of life for their years to come.

Comparing white matter lesions on T2 and FLAIR MRI in the Sydney Older Persons Study.

There is suggestion that magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) sequence may be more accurate than T2 images in detecting white matter lesions (WML) in older people. Comparative ratings of these two image sequences have not been directly investigated in very old individuals to date. We compared the ratings of periventricular and deep WML on these two sequences in a sample of 111 community dwellers (mean age 85.5 years) using semiquantitative methods. Periventricular WML were as commonly detected on T2 as on FLAIR but were more severely rated on the latter sequence. No such bias was observed for the deep WML. With one exception, correlations between the two sets of measures were significant at the P < 0.001 level (range: 0.34-0.75). Intrarater reliability coefficients were moderate to excellent for most ratings. These results suggest that ratings performed on T2-weighted images to detect WML in very old individuals are very comparable with those performed on FLAIR images although FLAIR may allow a finer grading of periventricular lesions. Absence of FLAIR does not preclude the identification of WML in this population. These findings have clinical and epidemiological relevance where the acquisition of supplementary MRI data may not always be possible.

A model of executive functions in very old community dwellers: evidence from The Sydney Older Persons Study.

Executive functions (EF) are generally described as showing greater sensitivity to ageing compared to other cognitive domains. Numerous pitfalls exist in the measurement of EF due to loose definitions and lack of agreement on these concepts and uncertainty about the constructs being measured. To this date, the validity of EF constructs has not been examined in the old-old population. Performance of 122 randomly selected community dwellers aged between 81 and 97 years on nine EF tasks (seven of which commonly used in clinical practice) was examined. Factor analytic procedures using structural equation modelling (SEM) failed to satisfactorily explain the data according to four a priori models, the first two models reflecting two major constructs commonly found in current models of EF ("set" and "switch"), the last two reflecting task requirements. The best measure for each task was extracted using statistically driven analyses and further SEM revealed an orthogonal two-factor model which provided a good fit of the data, explaining between 8% and 25% of the total variance. This model can be interpreted in terms of reactive and spontaneous flexibility as proposed by Eslinger and Grattan (1993), with the first factor reflecting internally driven strategies and the second environment dependent strategies. Furthermore, these findings also suggest that: (a) unique tasks of EF may not be applicable to all age groups due to individual experience and changes in strategies; and (b) current clinical instruments may be inadequate to measure very specific aspects of the complex construct of EF.

Laboratory results in the elderly: the Sydney Older Persons Study.

BACKGROUND: The use of laboratory intervals based on younger and healthier populations is of questionable validity in older populations. The aim of this study was to examine haematological and biochemical profiles in a sample of community-dwelling older people and to study the impact of age, disease, disability and medications. METHODS: Basic haematological and biochemical values were obtained for 338 survivors of a random sample of community-living people aged 75 years or over at time of recruitment. These values were compared to the laboratory reference intervals and the effects of age, disease, medication and disability examined. RESULTS: The distribution of the 35 parameters measured differed from those described by the laboratory reference intervals in all but four of the variables. The values showed few significant age associations but did show associations with disease, disability and drug use. CONCLUSIONS: Abnormalities identified in haematological and biochemical testing are not due to age but to age-related illnesses. This is contrary to previous studies reporting a change in haematological and biochemical parameters purely on the basis of age. In the presence of abnormalities, identification and clarification of disease states should be made.

Vascular risk factors, cognition and dementia incidence over 6 years in the Sydney Older Persons Study.

The specific contributions of factors associated with an increased risk of stroke to cognitive decline and vascular dementia in elderly people remain somewhat unclear. We investigated the prevalence of vascular risk factors (RFs) and their role on the incidence of dementia, cognitive decline and death over a 6-year period in a sample of 377 non-demented community dwellers aged 75 years and over at the time of study entry. Presence and history of vascular RFs and cognitive decline over 6 years were ascertained using direct interviews, medical and cognitive examinations. Hypertension and history of heart disease were very common affecting about 50% of the participants. At 6 years, 114 (30%) participants had died, and 63 (16.7%) met diagnostic criteria for dementia. Hypertension was significantly associated with a greater cognitive decline but not with dementia. Smoking and stroke diagnosis showed a significant positive association with death. Reported hypercholesterolaemia was found to be associated with a protective effect for the development of dementia, for cognitive decline and for death over the 6-year period. All other associations were non-significant. Figures of dementia incidence are similar to previous studies in contrast to the lack of anticipated effects of the vascular RFs. The results indicate that in very old participants, the impact of vascular RFs changes with time and may no longer contribute to the development of dementia and cognitive decline.

Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions.

Several pedigrees have recently been reported in which dominantly inherited familial Alzheimer's disease is associated in some family members with spastic paraparesis and non-neuritic 'cotton wool' plaques. Here we report clinical, genetic and neuropathological findings in two further large pedigrees in which this combination of phenotypes is associated with a deletion of exon 9 of the presenilin-1 (PS-1) gene caused by mutations at the splice acceptor site. In both pedigrees, individuals with paraparesis at presentation had a later than average age at onset of symptoms. In addition, one subject with paraparesis had a much less prominent dementia syndrome than his dementia-affected siblings. As PS-1 mutations are almost always associated with a particularly aggressive form of presenile dementia, these findings suggest the existence of a protective or delaying factor in individuals with spastic paraparesis.

Are MRI white matter lesions clinically significant in the 'old-old'? Evidence from the Sydney Older Persons Study.

BACKGROUND: The number of individuals aged over 80 years is the fastest increasing group in developed countries. White matter lesions (WML) observed on magnetic resonance imaging (MRI) have uncertain clinical significance, particularly in the old. OBJECTIVES: To determine the prevalence of periventricular and deep WML in survivors of an original cohort of randomly selected elderly community dwellers, and to examine their associations with clinical markers of vascular and extrapyramidal disorders of ageing, as well as quantitative cognitive measures. METHODS: Brain MRI, lifestyle interview, cognitive testing and medical examination were administered to 122 participants from the Sydney Older Persons Study 6-year review (mean age: 85.5 years). Apolipoprotein E (ApoE) genotype was also established. Presence and severity of periventricular and deep WML were ascertained using semi-quantitative rating methods and their relations to the cognitive and clinical variables investigated. RESULTS: Periventricular WML were present in all participants in similar severity for all three regions sampled. In contrast, a gradient of severity was observed for the deep WML: most severe in the parietal region, followed by the frontal and occipital regions, and least severe in the temporal region. Associations with gender or with the ApoE epsilon4 allele were non-significant. WML were inconsistently associated with age and cognitive functioning or with the clinical markers of dementia. No frontal specificity emerged. Examination of individual lesion types did not change the general pattern of associations. Supporting evidence for a threshold effect was observed on some measures. CONCLUSIONS: WML are extremely common in elderly, non-demented individuals. Unlike in younger individuals, MRI abnormalities may not be evidence of a current pathological process and their importance may change with advancing age.

Subcortical vascular disease and functional decline: a 6-year predictor study.

OBJECTIVES: To identify predictors of activity of daily living (ADL) and instrumental activity of daily living (IADL) decline in a population with subcortical vascular dementia (SVD) and to evaluate potential mechanism of decline. DESIGN: Longitudinal. SETTING: Hospital-based. PARTICIPANTS: Computed tomographic (CT) scanning identified 77 participants as having subcortical infarction. MEASUREMENTS: Participants were neurologically, neuropsychologically, behaviorally, and functionally assessed four times over 5.82 years. Baseline data were grouped into four modules: basic demographic and risk factor, CT scan, neurological and other clinical, and neuropsychological and behavioral. Multivariate analysis determined predictors of decline in ADLs and IADLs. RESULTS: Predictors of ADL decline were age, alcohol consumption, coordination, snout reflex, and performance on a neuropsychological test (Block Design). Predictors of IADL decline were predominantly cognitive and included the presence of paratonia and performance on the two neuropsychological tests (attention and memory tasks). CONCLUSION: These findings suggest that cognitive impairments are most likely to have an effect on IADL function, because the skills involved are complex and involve integrative activity, whereas physical and cognitive impairments combined are likely to compromise ADL function, given the more basic and physical nature of the functions involved. These findings indicate that in people with SVD, both ADL and IADL status should be monitored, because, for many, decline in function over time is likely, and thus the provision of appropriate support required.

Normal aging and executive functions in "old-old" community dwellers: poor performance is not an inevitable outcome.

BACKGROUND: Studies on normal aging and cognitive functioning commonly describe early and more pronounced age-related changes in executive functions (EFs) compared to other cognitive abilities. Two of the three most common neurodegenerative disorders associated with aging (vascular dementia [VaD] and extrapyramidal [EP]-related dementia) show executive dysfunctions in their clinical presentation; and these cognitive deficits are not uncommon in the third one: Alzheimer's disease (AD). METHODS: Nine EF tests (yielding 12 measures) were administered to 123 randomly selected community dwellers, aged 81 years and over, with the view to determine the effect of age on performance. Markers of AD, VaD, and EP-related dementia, as well as sociodemographic and psychological variables, were selected and their contribution to EF performance was investigated. RESULTS: Multiple linear regression analyses revealed the greatest contribution to EF scores from the markers of AD and estimated IQ but not from the markers of VaD and EP-related dementia or from age. CONCLUSIONS: These findings suggest that chronological age acts as a proxy variable mediating the impact of other factors such as subclinical signs of neurodegenerative disorders and that it has little independent contribution to make. They also indicate the importance of cognitive abilities supported by posterior cortical circuits in EF problem resolution. This study demonstrates that cognitive decline is not an ineluctable process that is associated with "normal" aging but rather represents, in many cases, a byproduct of neurodegenerative disorders, albeit themselves highly age-related.