Papers by Roger Clarnette
Journal of Aging Research, 2015
The Risk Instrument for Screening in the Community (RISC) is a short, global risk assessment to i... more The Risk Instrument for Screening in the Community (RISC) is a short, global risk assessment to identify community-dwelling older adults' one-year risk of institutionalisation, hospitalisation, and death. We investigated the contribution that the three components of the RISC (concern, its severity, and the ability of the caregiver network to manage concern) make to the accuracy of the instrument, across its three domains (mental state, activities of daily living (ADL), and medical state), by comparing their accuracy to other assessment instruments in the prospective Community Assessment of Risk and Treatment Strategies study. RISC scores were available for 782 patients. Across all three domains each subtest more accurately predicted institutionalisation compared to hospitalisation or death. The caregiver network's ability to manage ADL more accurately predicted institutionalisation (AUC 0.68) compared to hospitalisation (AUC 0.57, P = 0.01) or death (AUC 0.59, P = 0.046), comparing favourably with the Barthel Index (AUC 0.67). The severity of ADL (AUC 0.63), medical state (AUC 0.62), Clinical Frailty Scale (AUC 0.67), and Charlson Comorbidity Index (AUC 0.66) scores had similar accuracy in predicting mortality. Risk of hospitalisation was difficult to predict. Thus, each component, and particularly the caregiver network, had reasonable accuracy in predicting institutionalisation. No subtest or assessment instrument accurately predicted risk of hospitalisation.
Background and purpose: In Alzheimer disease (AD), elevated brain iron concentrations in gray mat... more Background and purpose: In Alzheimer disease (AD), elevated brain iron concentrations in gray matter suggest a disruption in iron homeostasis, while demyelination processes in white matter increase the water content. Our aim was to assess whether the transverse proton relaxation rate, or R2, an MR imaging parameter affected by changes in brain iron concentration and water content, was different in
Maturitas, Jan 20, 2015
Few case-finding instruments are available to community healthcare professionals. This review aim... more Few case-finding instruments are available to community healthcare professionals. This review aims to identify short, valid instruments that detect older community-dwellers risk of four adverse outcomes: hospitalisation, functional-decline, institutionalisation and death. Data sources included PubMed and the Cochrane library. Data on outcome measures, patient and instrument characteristics, and trial quality (using the Quality In Prognosis Studies [QUIPS] tool), were double-extracted for derivation-validation studies in community-dwelling older adults (>50 years). Forty-six publications, representing 23 unique instruments, were included. Only five were externally validated. Mean patient age range was 64.2-84.6 years. Most instruments n=18, (78%) were derived in North America from secondary analysis of survey data. The majority n=12, (52%), measured more than one outcome with hospitalisation and the Probability of Repeated Admission score the most studied outcome and instrument re...
Journal of Alzheimer's disease : JAD, 2005
Neurodegeneration is associated with increased frequency of neurological soft signs (NSS). We des... more Neurodegeneration is associated with increased frequency of neurological soft signs (NSS). We designed the present study to investigate the association between NSS and subjective memory complaints, cognitive function and apolipoprotein E genotype in a community-dwelling sample of volunteers participating in an ongoing longitudinal program investigating predictors of cognitive decline. NSS were found to be associated with apolipoprotein E (APOE) epsilon4 genotype (p = 0.015), age (p = 0.012) and poor cognitive performance, as assessed by the Mini Mental State Examination (p = 0.053). There was no significant difference between subjects with and without memory complaints in relation to the frequency of NSS (p = 0.130). The association with age and the APOE epsilon4 genotype suggests that the systematic investigation of NSS may contribute to identify subjects at risk of clinically significant cognitive decline in later life.
Eleven early-onset dementia families, all with affected individuals who have either presented cli... more Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.
Journal of Alzheimer's disease : JAD, 2008
Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated w... more Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated with increased risk of cognitive decline and developing dementia. Compared to controls, men with Alzheimer's disease (AD) have been shown to have lower serum testosterone levels and higher serum luteinizing hormone (LH) levels. As serum free testosterone concentration is negatively correlated with LH in older men, the independent contributions of these hormones to the pathogenesis of AD warrants further clarification. To explore this notion, we measured plasma amyloid-beta (Abeta), serum testosterone, serum LH and other biochemical parameters in 40 cognitively normal elderly men. Multiple linear regression analysis revealed that serum LH concentration is the only parameter that significantly correlates with plasma Abeta levels in these men (r=0.5, p=0.041). These results suggest that increased serum LH concentration, rather than lower serum free testosterone, is associated with the ac...
Neuroscience Letters, 1998
We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene.... more We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.
Neuroscience Letters, 1997
We measured the concentration of apolipoprotein E (apoE) in plasma from 184 non-fasted subjects i... more We measured the concentration of apolipoprotein E (apoE) in plasma from 184 non-fasted subjects in order to determine whether important variations might exist linking plasma apoE levels to clinical phenotypes among early and late onset sporadic Alzheimer's disease (AD) and Down's syndrome (DS). A significant increase in the level of plasma apoE was observed in non-fasted late-onset AD patients (with a mean level of 3.26 +/- 0.08 microgram apoE/mg total protein for n = 84 patients) when compared with the plasma apoE levels of control individuals (mean of 2.32 +/- 0.10 microgram apoE/mg total protein, n = 51 patients; P < 0.001). A similar increase was found for non-fasted early-onset AD patients (mean of 3.69 +/- 0.17 microgram apoE/mg total protein, n = 20) when compared with the plasma apoE levels of control individuals (P < 0.001). Plasma apoE levels for DS patients did not differ significantly from those of controls (P > 0.05). The association of elevated plasma apoE levels in AD may be relevant to clarifying the mechanism(s) whereby apoE isoforms specify differential risk for development of AD.
NeuroReport, 1995
We studied the apoE genotypes of 279 Australians in order to determine what relationships might e... more We studied the apoE genotypes of 279 Australians in order to determine what relationships might exist in this group between apoE genotype and dementia associated with either early- or late-onset sporadic Alzheimer's disease (AD) or with Down's syndrome (DS). ApoE epsilon 4 allele frequency was increased in Australians with either early-onset sporadic AD (p < 0.002) or late-onset sporadic AD (p < 0.0001) and apoE epsilon 2 allele frequency was decreased in the late-onset sporadic AD group (p < 0.01). The apoE genotype distribution among patients with DS was not different from that of the control group. One individual with DS and an apoE epsilon 4/epsilon 4 genotype developed dementia at the earliest age of dementing DS patients, consistent with a role for apoE epsilon 4 in determining age of onset of dementia in AD and DS. Another DS patient with an apoE epsilon 2/epsilon 3 genotype developed dementia within an age range similar to that of four demented DS patients with an apoE epsilon 3/epsilon 3 genotype, an observation which would appear inconsistent with the proposed protective effect of apoE epsilon 2 to delay onset of dementia in DS. These results extend the evidence that the apoE genotype, particularly apoE epsilon 4, modulates dementia in early- and late-onset sporadic AD and DS. The protective role of apoE epsilon 2 in DS, however, may vary among different populations or ethnic groups.
Neuropsychologia, 2006
The aim of this study was to examine inspection time (IT) performance in older adults with mild c... more The aim of this study was to examine inspection time (IT) performance in older adults with mild cognitive impairment (MCI), who are at higher risk of developing further cognitive decline or dementia. IT is described as an index of speed of informational intake. IT correlates with measures of fluid intelligence and is possibly a marker for the integrity of the cholinergic system of the brain. IT may therefore be useful in aiding the diagnosis of early-stage progressive cognitive impairment. The current study compares IT in 28 people with MCI to 28 age, gender and education-matched controls. The computer-based, visual IT task required participants to discriminate between two visual stimuli that were presented for brief periods. Participants' IT performance was compared to their performance on cognitive and memory tasks. Group comparison showed that participants with MCI performed significantly worse on IT than controls and was not affected by years of education. In combination with other clinical, neuropsychological and biological tests, IT may be a useful assessment tool for improving the identification of older adults at risk for clinically relevant cognitive decline.
Neurobiology of Aging, 2004
(1.06-1.77) for those subjects in possession of the variant coding for valine at this locus. Conc... more (1.06-1.77) for those subjects in possession of the variant coding for valine at this locus. Conclusions: The non-synonymous M129V polymorphism in the prion protein gene is associated with sporadic Alzheimer's disease in the relatively genetically homogeneous Northern Ireland population.
Neurobiology of Aging, 2002
Presenilin-1 mutations account for nearly 50% of all early-onset familial cases of Alzheimer's di... more Presenilin-1 mutations account for nearly 50% of all early-onset familial cases of Alzheimer's disease. Most of these mutations are completely penetrant, although the recently described Glu318Gly substitution seems to have only partial penetrance. These findings suggest that the Glu318Gly mutation may work as a genetic risk factor for Alzheimer's disease. We designed the present study to investigate the frequency of this mutation among non-demented volunteers with subjective memory impairment (n ϭ 58) and controls (n ϭ 66). Four (6.8%) subjects with complaints of memory problems, but no controls, carried this mutation. The presence of the Glu318Gly mutation was associated with significantly lower cognitive performance when compared to controls (P ϭ 0.011). However, there was no significant association between the presence of the mutation and the cognitive performance of individuals within the memory complainers group. Follow-up studies should clarify whether the Glu318Gly mutation increases the risk of cognitive decline in later life.
Molecular Psychiatry, 2002
Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of earlyonset... more Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of earlyonset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-⑀4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P Ͻ 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.
Molecular Psychiatry, 2002
The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of cer... more The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the ⑀4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, −491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, −491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the ⑀4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the −491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P Ͻ 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the ⑀4 allele of apolipoprotein E and the −491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.
The Journal of Clinical Psychiatry, 2003
Objective: Patients (30-50%) with non-psychotic major depression will not respond despite an adeq... more Objective: Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication. Method: Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3 mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of 610 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire. Results: Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR = 3.33, p = .011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS 6 10) compared to 24% of the placebo augmentation group (CMH(1) = 6.48, p = .011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone. Conclusion: Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
The Journal of Clinical Endocrinology & Metabolism, 2006
Context: Reduced testosterone levels have been implicated as a potential causative factor in cogn... more Context: Reduced testosterone levels have been implicated as a potential causative factor in cognitive decline with older age. Men who possess the apolipoprotein E (APOE) ⑀4 allele have an increased risk of developing Alzheimer's disease; however, no studies have examined whether the influence of testosterone on cognition in healthy older men may be modulated by this genetic predisposition.
International Journal of Geriatric Psychiatry, 2005
To evaluate the efficacy and safety of low-dose risperidone in treating psychosis of Alzheimer&am... more To evaluate the efficacy and safety of low-dose risperidone in treating psychosis of Alzheimer's disease (AD) and mixed dementia (MD) in a subset of nursing-home residents who had dementia and aggression and who were participating in a randomized placebo-controlled trial of risperidone for aggression. This post-hoc analysis included only patients diagnosed with AD or MD with psychosis, defined by a score of >or= 2 on any item of the Behavioral Pathology of Alzheimer's Disease (BEHAVE-AD) psychosis subscale at both screening and baseline. Co-primary efficacy endpoints were changes in scores on BEHAVE-AD psychosis subscale and Clinical Global Impression of Change (CGI-C). Overall, 93 patients (46 risperidone and 47 placebo) fulfilled the psychosis of AD criteria. Mean change at endpoint in BEHAVE-AD psychosis subscale with risperidone was superior to placebo (-5.2 vs -3.3; p = 0.039). Distribution of CGI-C at endpoint also favoured risperidone (p < 0.001). The superior improvement with risperidone compared with placebo occurred as early as the first two weeks and persisted to the end of the treatment period. At endpoint, 59% of risperidone-treated patients were responders (i.e. were 'very much' or 'much' improved) compared with 26% of patients receiving placebo. The mean risperidone dose was 1.03 +/- 0.61 mg/day. Twelve weeks of treatment were completed by 37 patients treated with risperidone (80%) and 35 with placebo (74%). A total of 46 (98%) placebo- and 44 (96%) risperidone-treated patients experienced at least one adverse event, with only somnolence occurring more frequently in the risperidone group. Risperidone effectively reduces psychosis and improves global functioning in elderly patients with moderate-to-severe psychosis of AD and MD.
International Journal of Geriatric Psychiatry, 2001
Data from 157 individuals with serious mental illness and comorbid diabetes enrolled in an ongoin... more Data from 157 individuals with serious mental illness and comorbid diabetes enrolled in an ongoing treatment study were used to examine clinical correlates of diabetes control. Factors assessed included depressive symptoms (Montgomery-Åsberg Depression Rating Scale), global psychopathology severity (Brief Psychiatric Rating Scale), and glycosylated hemoglobin (HbA1c), a biomarker of diabetes control. Seventy-seven participants had depression, 40 had schizophrenia, and 40 had bipolar disorder. Most were moderately to severely depressed with poor diabetes control. No correlation between diagnosis and diabetes control was found after adjustment for gender, race, health literacy, diabetes duration, and diabetes knowledge. Greater depression severity and longer diabetes duration were related to poorer diabetes control. Lower severity of global psychopathology was related to poorer diabetes control, perhaps because of overall low levels of psychosis and mania. People with serious mental illness and diabetes face multiple challenges, which, along with severe depression, may impede diabetes self-management.
Diabetologia, 2008
Aims/hypothesis Diabetes is associated with an increased risk of dementia but the reasons for thi... more Aims/hypothesis Diabetes is associated with an increased risk of dementia but the reasons for this association are unclear because there are many potential mechanisms. We explored the relative contribution of diabetes-related variables as predictors of dementia in older individuals with diabetes. Methods Survivors, aged ≥70 or more, were recruited from an existing observational cohort study 7.6±1.0 years after baseline, when they underwent a comprehensive assessment of diabetes, complications and cardiovascular risk factors. Dementia, probable Alzheimer's disease and cognitive impairment without dementia were diagnosed clinically. Logistic regression modelling determined independent predictors of cognitive diagnoses. Results Of 302 participants, aged 75.7±4.6 years, 28 (9.3%) had dementia (16 with probable Alzheimer's disease) and 60 (19.9%) had cognitive impairment without dementia. The major independent longitudinal predictors of dementia were older age (per decade; odds ratio 4.0, 95% CI 1.59-10.10), diabetes duration (for each 5 years; odds ratio 1.69, 95% CI 1.24-2.32), peripheral arterial disease (odds ratio 5.35, 95% CI 2.08-13.72) and exercise (which was protective; odds ratio 0.26, 95% CI 0.09-0.73). For Alzheimer's disease, diabetes duration was an independent predictor in addition to age and diastolic blood pressure. The results of the cross-sectional analyses were similar with respect to diabetes duration and peripheral arterial disease. Conclusions/interpretation Peripheral arterial disease is a strong independent risk factor for dementia in diabetes. After adjustment for a wide range of potential risk factors, diabetes duration remains independently associated with dementia and probable Alzheimer's disease, indicating that factors not measured in this study may be important in the pathogenesis of dementia in diabetes.
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Papers by Roger Clarnette