Authors: Smith, Natalie | Brennan, Laura | Gaunt, Daisy M. | Ben-Shlomo, Yoav | Henderson, Emily
Article Type: Research Article
Abstract: Background: Parkinson’s disease (PD) and frailty are two conditions that are increasingly common with advancing age, yet little is known about their relationship. Objective: The aim of this study was to examine the co-occurrence of frailty in people with PD; to describe the measures used to assess frailty in PD, and assess the prevalence of frailty in subjects with PD. Methods: We conducted a systematic review of Pubmed and Embase in April 2018. Studies that assessed frailty in subjects with PD were included in the review and data was extracted on the prevalence of frailty in subjects with PD. Due …to heterogeneity of studies a meta-analysis was not performed. Results: Eight studies were included in the review, of which 7 were cross-sectional and 1 a prospective cohort study. Mean age of participants with PD in the studies ranged from 66 to 85 years. The majority (6/8) used the 5-item, Fried criteria to measure frailty, with the remainder using index-based measures. 5 studies provided data on the prevalence of frailty in PD, which ranged from 29% to 67%. Conclusions: Few studies have quantified the prevalence of frailty in PD, but those that have suggest a high concurrence of these two conditions. Show more
Keywords: Frailty, Parkinson’s disease, systematic review
DOI: 10.3233/JPD-191604
Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 517-524, 2019
Authors: Kehoe, Patrick Gavin | Davies, Neil Martin | Martin, Richard Michael | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: We investigated whether angiotensin II receptor blockers and angiotensin converting enzyme inhibitors were associated with risk of mortality or inpatient hospitalization for patients with dementia compared to other antihypertensive medications. We extracted a clinical cohort of 6,290 patients with dementia from the United Kingdom General Practice Research Database, prescribed antihypertensive medication at diagnosis of dementia with around 10 years follow-up. Using survival analysis we estimated associations of exposure to antihypertensive medication with subsequent hospitalization and mortality risk, stratified by dementia type (Alzheimer's disease, vascular and other dementias). Angiotensin converting enzyme inhibitors (but not angiotensin II receptor blockers) were associated with …an increased risk of mortality in patients with Alzheimer's disease (adjusted hazard ratio: 1.19; 95% CI 1.07, 1.33, p = 0.002), but no convincing evidence of increased hospitalization. Angiotensin II receptor blockers were inversely associated with hospitalization for any form of dementia, but after adjustment for covariates, these associations became consistent with chance. Further evidence is required to either support or refute the observation that exposure to angiotensin converting enzyme inhibitors in patients with dementia is associated with increased mortality. Show more
Keywords: Alzheimer's disease, amyloid, angiotensin, dementia, hospitalization, mortality, vascular dementia
DOI: 10.3233/JAD-2012-121090
Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 999-1008, 2013
Authors: Morgan, Gemma S. | Gallacher, John | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: Previous studies suggest that physical activity may be protective for dementia and cognitive impairment. We report findings comparing leisure-time and work-related physical activity from the Caerphilly Prospective study (CaPS) with dementia and cognitive impairment not dementia (CIND) after around 16 years of follow-up. We synthesized our results with a meta-analysis specifically testing if length of follow-up was associated with the size of any association. Age-adjusted models found no real association with dementia, and if anything increased risk for CIND (odds ratio (OR) highest versus lowest tertile 2.61, 95% CI 1.58 to 4.31), though this was attenuated after adjustment for other …confounders (OR highest versus lowest tertile 1.38, 95% CI 0.78 to 2.44). There was no evidence that this differed by type (vascular versus non-vascular) of cognitive disease. Meta-analysis of other published effect estimates showed a protective effect of physical activity on cognitive impairment (OR 0.66, 95% CI 0.52 to 0.85) but with significant heterogeneity which was partially explained by length of follow up (p = 0.03). A protective association was also seen for dementia (OR 0.78, 95% CI 0.65, 0.94), which did not appear to be related to follow-up length but there was evidence of small study bias (p = 0.002) suggesting an absence of small null studies. The apparent protective effects of physical activity on cognitive health may partially reflect reverse causation and current estimates may be overly optimistic in terms of cognitive benefits. Show more
Keywords: Cohort studies, dementia, meta-analysis, mild cognitive impairment, motor activity, review
DOI: 10.3233/JAD-2012-112171
Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 569-580, 2012
Authors: Davies, Neil M. | Kehoe, Patrick G | Ben-Shlomo, Yoav | Martin, Richard M.
Article Type: Research Article
Abstract: We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer's disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs. We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti-hypertensive prescribing data. We sampled cases aged ≥60 years and diagnosed between 1997–2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those …prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37–0.58) compared with ACE-Is (odds-ratio; 0.76, 95%CI, 0.69–0.84) (pdifference < 0.001). Associations of ARBs with AD were stronger than for vascular dementia (pdifference = 0.01) and unspecified/other dementia (pdifference = 0.23). There were inverse dose-response relationships between ARBs and ACE-Is with AD (both ptrend < 0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings. Show more
Keywords: All cognitive disorders/dementia, Alzheimer's disease, case control studies, risk factors in epidemiology, vascular dementia
DOI: 10.3233/JAD-2011-110347
Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 699-708, 2011
Authors: Creavin, Samuel T. | Gallacher, John | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: We have examined whether metabolic syndrome is associated with intermediate risk of impaired cognition between people with and without diabetes. Men aged 45 to 59 years were identified from Caerphilly in South Wales, United Kingdom. Participation rate was 89% (41% of the original cohort) and 2,512 men were examined in phase one from July 1979 until September 1983. Follow-up examinations occurred at four intervals until 2004 when 1,225 men participated. Participants were categorized on the basis of their exposure to metabolic syndrome not diabetes (MSND) and diabetes (with or without metabolic syndrome) at each of the first three phases. Neuropsychological …outcomes and clinical diagnosis of cognitive impairment not dementia (CIND) and dementia were assessed at phase five. The prevalence of MSND increased from 1% to 5% and for diabetes from 3% to 9% between phase one and phase three. 15% of participants had CIND and 8% dementia. People with diabetes, but not those with MSND, at phases one, two, or three had poorer cognition at phase five (adjusted β coefficient AH4 −4.3 95% CI −7.9, −0.7; phase two: −2.5 95% CI −4.7, −0.3; phase three: −2.3 95% CI −4.2, −0.5). The adjusted odds ratio (phase one) for diabetes and CIND was 4.0 (95% CI 1.4, 11.5) and dementia 0.61 (95% CI 0.07, 5.37). After adjustment, higher systolic blood pressure was the only component of the metabolic syndrome associated with worse cognitive outcomes. Diabetes in mid-life, but not MSND, is associated with impaired cognition and increased odds of CIND in later life. Show more
Keywords: Cognition disorders/epidemiology, cohort studies, diabetes mellitus Type 2/complications, metabolic syndrome X/epidemiology, risk factors
DOI: 10.3233/JAD-2011-111550
Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 931-939, 2012
Authors: Creavin, Sam | Fish, Mark | Bayer, Antony | Gallacher, John | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: Background: The merit of using baseline cognitive assessments in mid-life to help interpret cross-sectional cognitive tests scores in later life is uncertain. Objective: Evaluate how accuracy for diagnosing dementia is enhanced by comparing cross-sectional results to a midlife measure. Methods: Cohort study of 2,512 men with repeated measures of Mini-Mental State Examination (MMSE) over approximately 10 years. Index test MMSE at threshold of 24 indicating normal, as a cross-sectional measure and in combination with decline in MMSE score from mid-life. Reference standard consensus clinical diagnosis of dementia by two clinicians according to Diagnostic and Statistical Manual of Mental Disorders, Fourth …Edition (DSM-IV). Results: 1,150 men participated at phase 4 of whom 75 had dementia. A cross-sectional MMSE alone produced a sensitivity of 60% (50% to 70%) and specificity 95% (94% to 97%) with a threshold of≥24 points indicating normal. For lower-scoring men in late life, with cross sectional scores of < 22, combining cross-sectional AND a three-point or more decline over time had a sensitivity of 52% (39% to 64%) and specificity 99% (99% to 100%). For higher-scoring men in later life, with cross sectional scores < 26 combining cross-sectional OR decline of at least three points had a sensitivity of 98% (92% to 100%) and specificity 38% (32% to 44%). Conclusion: It may be helpful in practice to formally evaluate cognition in mid-life as a baseline to compare with if problems develop in future, as this may enhance diagnostic accuracy and classification of people in later life. Show more
Keywords: Cohort studies, cognitive dysfunction, dementia, epidemiologic studies, neurocognitive disorders, sensitivity and specificity
DOI: 10.3233/JAD-220345
Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1241-1248, 2022
Authors: Creavin, Samuel Thomas | Fish, Mark | Lawton, Michael | Cullum, Sarah | Bayer, Antony | Purdy, Sarah | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: Background: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown. Objective: Calculate diagnostic accuracy of brief cognitive tests in primary care. Methods: We did a diagnostic test accuracy study in general practice, in people over 70 years who had consulted their GP with cognitive symptoms but had no prior diagnosis of dementia. The reference standard was specialist assessment, adjudicated for difficult cases, according to ICD-10. We assessed 16 index tests at a research clinic, and additionally analyzed referring GPs clinical …judgement. Results: 240 participants had a median age of 80 years, of whom 126 were men and 132 had dementia. Sensitivity of individual tests at the recommended thresholds ranged from 56% for GP judgement (specificity 89%) to 100% for MoCA (specificity 16%). Specificity of individual tests ranged from 4% for Sniffin’ sticks (sensitivity 100%) to 91% for Timed Up and Go (sensitivity 23%). The 95% centile of test duration in people with dementia ranged from 3 minutes for 6CIT and Time and Change, to 16 minutes for MoCA. Combining tests with GP judgement increased test specificity and decreased sensitivity: e.g., MoCA with GP Judgement had specificity 87% and sensitivity 55%. Conclusions: Using GP judgement to inform selection of tests was an efficient strategy. Using IQCODE in people who GPs judge as having dementia and 6CIT in people who GPs judge as having no dementia, would be a time-efficient and accurate diagnostic assessment. The original protocol for the study is available at https://bmcfampract.biomedcentral.com/articles/10.1186/s12875-016-0475-2 Show more
Keywords: Alzheimer’s disease, dementia, general practice, sensitivity and specificity, symptom assessment
DOI: 10.3233/JAD-230320
Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1189-1200, 2023
Authors: Green, Christopher J. | Holly, Jeffrey M.P. | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Gallacher, John | Ben-Shlomo, Yoav
Article Type: Research Article
Abstract: Background: The increasing incidence of cognitive impairment and dementia in an aging population poses a significant burden on healthcare. Consequently, identifying modifiable physiological factors which may influence the onset of cognitive decline are becoming increasingly important. Previous studies have suggested an association between levels of insulin-like growth factors and cognitive function. Objective: To investigate whether low IGF-I, IGF-II, and IGF molar ratio is associated with greater cognitive decline and increased risk of dementia. Methods: We examined prospective associations between IGF-I, IGF-II, and IGFBP-3 and cognitive function in the Caerphilly Prospective Study (CaPS) (n = 746 men) from samples obtained around …1986, with assessment in around 2003 for clinical diagnosis of cognitive impairment but no dementia (CIND) or dementia, as well as with CAMCOG scores at three phases. Results: A one standard deviation increase in IGF-II was associated with a reduced odds ratio for CIND (0.76, 95% CI 0.60, 0.96) which hardly altered after further adjustment for confounders. A one standard deviation increase in IGFBP-3 among participants without dementia or CIND was associated with greater decline in cognition (p = 0.002) equivalent to 2.4 years difference in age. All the associations between IGF-I and our outcomes were consistent with chance. Conclusion: In this study of men, we found that both IGF-II and IGFBP-3 are associated with normal age-related cognitive decline and clinical pathology associated with CIND, but we failed to replicate previous associations with IGF-I. Assuming these findings are replicated, they may provide new insights into potential biological mechanisms that underlie age-related cognitive changes and development of dementia. Show more
Keywords: Dementia, insulin-like growth factors, mild cognitive impairment, prospective cohort study
DOI: 10.3233/JAD-132183
Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 867-875, 2014
Authors: Lawton, Michael | Baig, Fahd | Rolinski, Michal | Ruffman, Claudio | Nithi, Kannan | May, Margaret T. | Ben-Shlomo, Yoav | Hu, Michele T.M.
Article Type: Research Article
Abstract: Background: Within Parkinson’s there is a spectrum of clinical features at presentation which may represent sub-types of the disease. However there is no widely accepted consensus of how best to group patients. Objective: Use a data-driven approach to unravel any heterogeneity in the Parkinson’s phenotype in a well-characterised, population-based incidence cohort. Methods: 769 consecutive patients, with mean disease duration of 1.3 years, were assessed using a broad range of motor, cognitive and non-motor metrics. Multiple imputation was carried out using the chained equations approach to deal with missing data. We used an exploratory and then a confirmatory factor analysis to …determine suitable domains to include within our cluster analysis. K-means cluster analysis of the factor scores and all the variables not loading into a factor was used to determine phenotypic subgroups. Results: Our factor analysis found three important factors that were characterised by: psychological well-being features; non-tremor motor features, such as posture and rigidity; and cognitive features. Our subsequent five cluster model identified groups characterised by (1) mild motor and non-motor disease (25.4%), (2) poor posture and cognition (23.3%), (3) severe tremor (20.8%), (4) poor psychological well-being, RBD and sleep (18.9%), and (5) severe motor and non-motor disease with poor psychological well-being (11.7%). Conclusion: Our approach identified several Parkinson’s phenotypic sub-groups driven by largely dopaminergic-resistant features (RBD, impaired cognition and posture, poor psychological well-being) that, in addition to dopaminergic-responsive motor features may be important for studying the aetiology, progression, and medication response of early Parkinson’s. Show more
Keywords: Parkinson’s disease, Cohort studies, cluster analysis, factor analysis
DOI: 10.3233/JPD-140523
Citation: Journal of Parkinson's Disease, vol. 5, no. 2, pp. 269-279, 2015
Authors: Lord, Stephen R. | Bindels, Helen | Ketheeswaran, Mira | Brodie, Matthew A. | Lawrence, Andrew D. | Close, Jacqueline C.T. | Whone, Alan L. | Ben-Shlomo, Yoav | Henderson, Emily J.
Article Type: Research Article
Abstract: Background: Freezing of gait (FOG) is a common symptom of Parkinson’s disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework. Objective: Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG. Methods: 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and a FOG elicitation condition. …Video and accelerometry recordings were examined to document freezes and other gait disruptions. Results: Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis. Conclusion: The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation. Show more
Keywords: Parkinson’s disease, gait disorders, freezing of gait, dual task
DOI: 10.3233/JPD-191813
Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 631-640, 2020
