Imperial College London

Chair in Neurology, Neuroepidemiology and Ageing

Faculty of MedicineSchool of Public Health

Chair in Clinical Neurology
 
 
 
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Contact

 

+44 (0)20 3311 7290l.middleton CV

 
 
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Assistant

 

Ms Naia Headland-Vanni +44 (0)20 3311 7290

 
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Location

 

Room 10L05 LaboratoryCharing Cross HospitalCharing Cross Campus

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Summary

 

Publications

Publication Type
Year
to

220 results found

Udeh-Momoh C, Watermeyer T, Sindi S, Giannakopoulou P, Robb C, Ahmadi Abhari S, Zheng B, Waheed A, McKeand E, Salman D, Beaney T, Loots C, Price G, Atchison C, Car J, Majeed A, McGregor A, Kivipelto M, Ward H, Middleton Let al., 2021, Health, lifestyle and psycho-social determinants of poor sleep quality during the Early Phase of the COVID-19 pandemic: a focus on UK older adults deemed clinically extremely vulnerable, Frontiers in Public Health, ISSN: 2296-2565

Journal article

Salman D, Beaney T, Robb C, Loots CADJ, Giannakopoulou P, Udeh-Momoh C, Ahmadi Abhari S, Majeed F, Middleton LT, McGregor AHet al., 2021, The impact of social restrictions during the COVID-19 pandemic on the physical activity levels of adults aged 50-92 years: a baseline survey of the CHARIOT COVID-19 Rapid Response prospective cohort study, BMJ Open, Vol: 11, Pages: 1-12, ISSN: 2044-6055

Objectives: Physical inactivity is more common in older adults, is associated with social isolation and loneliness, and contributes to increased morbidity and mortality. We examined the effect of social restrictions to reduce COVID-19 transmission in the UK (lockdown), on physical activity (PA) levels of older adults, and the social predictors of any change.Design: Baseline analysis of a survey-based prospective cohort study Setting: Adults enrolled in the Cognitive Health in Ageing Register for Investigational and Observational Trials (CHARIOT) cohort from General Practitioner (GP) practices in North West London were invited to participate from April to July 2020.Participants: 6,219 cognitively healthy adults aged 50 to 92 years completed the survey.Main outcome measures: Self-reported PA before and after the introduction of lockdown, as measured by Metabolic Equivalent of Task (MET) minutes. Associations of PA with demographic, lifestyle and social factors, mood and frailty.Results: Mean PA was significantly lower following the introduction of lockdown, from 3,519 MET minutes/week to 3,185 MET minutes/week (p<0.001). After adjustment for confounders and pre-lockdown PA, lower levels of PA after the introduction of lockdown were found in those who were over 85 years old (640 [95% CI: 246 to 1034] MET minutes/week less); were divorced or single (240 [95% CI: 120 to 360] MET minutes/week less); living alone (277 [95% CI: 152 to 402] MET minutes/week less); reported feeling lonely often (306 [95% CI: 60 to 552] MET minutes/week less); and showed symptoms of depression (1007 [95% CI: 1401 to 612] MET minutes/week less) compared to those aged 50-64 years, married, co-habiting, and not reporting loneliness or depression, respectively. Conclusions and Implications: Markers of social isolation, loneliness and depression were associated with lower PA following the introduction of lockdown in the UK. Targeted interventions to increase PA in these groups should be consid

Journal article

Zheng B, Su B, Price G, Tzoulaki I, Ahmadi-Abhari S, Middleton Let al., 2021, Glycemic control, diabetic complications, and risk of dementia in patients with diabetes: results from a large UK cohort study, Diabetes Care, Vol: 44, Pages: 1556-1563, ISSN: 0149-5992

OBJECTIVE Type 2 diabetes is an established risk factor for dementia. However, the roles of glycemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA1c levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes.RESEARCH DESIGN AND METHODS Data of eligible patients with diabetes, aged ≥50 years in the U.K. Clinical Practice Research Datalink from 1987 to 2018, were analyzed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% CIs for dementia risk.RESULTS Among 457,902 patients with diabetes, 28,627 (6.3%) incident dementia cases were observed during a median of 6 years’ follow-up. Patients with recorded hypoglycemic events or microvascular complications were at higher risk of dementia incidence compared with those without such complications (HR 1.30 [95% CI 1.22–1.39] and 1.10 [1.06–1.14], respectively). The HbA1c level, modeled as a time-varying exposure, was associated with increased dementia risk (HR 1.08 [95% CI 1.07–1.09] per 1% HbA1c increment) among 372,287 patients with diabetes with postdiagnosis HbA1c records. Similarly, a higher coefficient of variation of HbA1c during the initial 3 years of follow-up was associated with higher subsequent dementia risk (HR 1.03 [95% CI 1.01–1.04] per 1-SD increment).CONCLUSIONS Higher or unstable HbA1c levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycemia might have a significant role in maintaining cognitive health among older adults with diabetes.

Journal article

Ahmadi Abhari S, Bandosz P, Kivimaki M, Middleton Let al., 2021, Impact of COVID19 on years of life lost with and without disability across 18 European-countries, World Congress of Epidemiology (WCE)

Conference paper

Burns DK, Alexander RC, Welsh-Bohmer KA, Culp M, Chiang C, O'Neil J, Evans RM, Harrigan P, Plassman BL, Burke JR, Wu J, Lutz MW, Haneline S, Schwarz AJ, Schneider LS, Yaffe K, Saunders AM, Ratti Eet al., 2021, Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial, LANCET NEUROLOGY, Vol: 20, Pages: 537-547, ISSN: 1474-4422

Journal article

Udeh-Momoh CT, Watermeyer T, Price G, de Jager Loots CA, Reglinska-Matveyev N, Ropacki M, Ketter N, Fogle M, Raghavan N, Arrighi M, Brashear R, Di J, Baker S, Giannakopoulou P, Robb C, Bassil D, Cohn M, McLellan-Young H, Crispin J, Lakey K, Lisa C, Chowdary Seemulamoodi Y, Kafetsouli D, Perera D, Car J, Majeed A, Ward H, Ritchie K, Perneczky R, Kivipelto M, Scott D, Bracoud L, Saad Z, Novak G, Ritchie CW, Middleton Let al., 2021, Protocol of the cognitive health in ageing register: investigational, observational and trial studies in dementia research (CHARIOT): prospective readiness cOhort (PRO) SubStudy., BMJ Open, Vol: 11, Pages: 1-12, ISSN: 2044-6055

INTRODUCTION: The Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer's disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline. METHODS AND ANALYSIS: CPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60-85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment-Alzheimer's disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer's Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required. ETHICS AND DISSEMINATION: CPSS received ethical approvals from the London-Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therape

Journal article

Vamos EP, Lai H, Sharabiani M, Valabhji J, Middleton L, Majeed A, Millett C, Bottle Aet al., 2021, 20-year trajectories of cardiometabolic factors among patients with type 2 diabetes before diagnosis of dementia in England, DUK, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Nalder L, Zheng B, Chiandet G, Middleton L, Loots CAet al., 2021, Vitamin B12 and folate status in cognitively healthy older adults and associations with cognitive performance, Journal of Nutrition, Health and Aging, Vol: 25, Pages: 287-294, ISSN: 1279-7707

Objectives: To determine prevalence of vitamin B12 and folate deficiency and associations with cognitive performance in participants recruited for the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies in Dementia Research: Prospective Readiness cOhort Study (CHARIOTPRO) SubStudy (CPRO-SS). Design: Cross-sectional analysis of data collected in the screening phase for the CPRO-SS. Setting: Participants were recruited from the Chariot Register at Imperial College London comprising approximately 39,000 community dwelling volunteers. Participants: Community dwelling individuals aged 60-85 years with B vitamin biomarker measures available were included (n=1946). After medical history and other exclusions, 1347 cognitively healthy participants were included for analysis of cognitive data. Measurements: Cognitive status was assessed with the Repeatable Battery for Neuropsychological Status (RBANS). Assays included vitamin B12 and folate, followed by serum methylmalonic acid and homocysteine levels for those with low vitamin B12. Gender-specific linear regression analysis was performed for associations between cognition and biomarkers. Non-gender specific regression for groups graded by B vitamin deficiency severity were also performed. Results: Vitamin B12 deficiency (<148pmol/L) was found in 17.2% of individuals and folate deficiency (<10nmol/L) in 1% of our participants. Low vitamin B12 was associated with poorer memory (p<0.03) in men. A high BMI predicted poorer attention and visuospatial indices (p<0.05). A regression analysis by B12 level revealed associations with poorer attention (β -6.46; p=0.004) for the deficient group and with immediate memory (β -2.99; p=0.019) for those categorised as severely deficient. Conclusion: Older men and women are pro

Journal article

Wilson H, Politis M, Rabiner E, Middleton LTet al., 2020, Novel PET biomarkers to disentangle molecular pathways across age-related neurodegenerative diseases, Cells, Vol: 9, ISSN: 2073-4409

There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

Journal article

Peters S, Broberg K, Gallo V, Levi M, Kippler M, Vineis P, Veldink J, van den Berg L, Middleton L, Travis RC, Bergmann MM, Palli D, Grioni S, Tumino R, Elbaz A, Vlaar T, Mancini F, Kuehn T, Katzke V, Agudo A, Goni F, Gomez J-H, Rodriguez-Barranco M, Merino S, Barricarte A, Trichopoulou A, Jenab M, Weiderpass E, Vermeulen Ret al., 2020, Blood metal levels and amyotrophic lateral sclerosis risk: a prospective cohort, Annals of Neurology, Vol: 89, Pages: 125-133, ISSN: 0364-5134

ObjectiveMetals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality.MethodsA nested ALS case–control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma–mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models.ResultsThe study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08–3.87) and lead (OR = 1.89, 95% CI = 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27–0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers.InterpretationThis is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a–n/a

Journal article

Ford J, Zheng B, Hurtado B, de Jager CA, Udeh-Momoh C, Middleton L, Price Get al., 2020, Strategy or symptom: semantic clustering and risk of Alzheimer's disease-related impairment, Journal of Clinical and Experimental Neuropsychology, Vol: 42, Pages: 849-856, ISSN: 1380-3395

Alzheimer's disease (AD) is the most common form of dementia, impacting global cognitive performance, including episodic memory. Semantic clustering is a learning strategy involving grouping words of similar meaning and can improve episodic memory performance, e.g., list learning. As the APOE ε4 allele is the most validated genetic risk factor for AD, we predicted that its presence would be associated with poorer list learning performance, and we hypothesized that semantic clustering moderates or mediates this association. The sample comprised 699 healthy older adults participating in the CHARIOT PRO Main Study, 169 of whom were APOE ε4 carriers. Participants' ability to form groups of related stimuli (assessed via a categorization task, CAT), and their use of semantic clustering during list learning, were investigated using the Neuropsychological Assessment Battery (NAB). CAT scores predicted the use of semantic clustering in, and performance on, the list learning task. CAT scores were not significantly lower in APOE ε4 carriers, suggesting that the ability to categorize was preserved. However, APOE ε4 carriers made less use of semantic clustering in list learning. Semantic clustering use partially mediated the relationship between CAT scores and list learning performance, and, in women only, moderated the impact of APOE ε4 on list learning performance. The results suggest that better categorization ability is associated with greater use of mnemonic strategies and better performance on memory tasks regardless of genetic risk, but that APOE ε4 carriers make less use of such strategies. Furthermore, female APOE ε4 carriers may benefit more than their non-carriers from using semantic clustering to aid list learning. Thus, semantic clustering may be a contributing factor of their "cognitive reserve", compensating for potential deficits in episodic memory.

Journal article

Zheng B, Tal R, Yang Z, Middleton L, Udeh-Momoh Cet al., 2020, Cortisol hypersecretion and the risk of Alzheimer’s disease: A systematic review and meta-analysis, Ageing Research Reviews, Vol: 64, Pages: 1-11, ISSN: 1568-1637

BackgroundMorning cortisol levels have been reported to be elevated among patients with Alzheimer’s disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD.MethodsPubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity.Results17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I2 = 48.5 %), saliva (g = 0.540, P < 0.001; I2 = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I2 = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I2 = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent.ConclusionsMorning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD.

Journal article

Robb C, Loots C, Ahmadi-Abhari S, Giannakopoulou P, Udeh-Momoh C, McKeand J, Price G, Car J, Majeed A, Ward H, Middleton Let al., 2020, Associations of social isolation with anxiety and depression during the early COVID-19 Pandemic: a survey of older adults in London, UK, Frontiers in Psychiatry, Vol: 11, Pages: 1-12, ISSN: 1664-0640

The COVID-19 pandemic is imposing a profound negative impact on the health and wellbeing of societies and individuals, worldwide. One concern is the effect of social isolation as a result of social distancing on the mental health of vulnerable populations, including older people.Within six weeks of lockdown, we initiated the CHARIOT COVID-19 Rapid Response Study, a bespoke survey of cognitively healthy older people living in London,to investigate the impact of COVID-19 and associated social isolation on mental and physical wellbeing. The sample was drawn from CHARIOT, a register of people over 50 who have consented to be contacted for ageing related research. A total of 327,127 men and women (mean age=70.7 [SD=7.4]) participated in the baseline survey, May-July 2020. Participants were asked about changes to the 14 components of the Hospital Anxiety Depression scale (HADS) after lockdown was introduced in the UK,on 23rd March. A total of 12.8% of participants reported feeling worse on the depression components of HADS (7.8% men and 17.3% women) and 3612.3% reported feeling worse on the anxiety components (7.8% men and 16.5% women). Fewer participants reported feeling improved (1.5% for depression and 4.9% for anxiety). Women, younger participants, those single/widowed/divorced, reporting poor sleep, feelings of loneliness and who reported living alone were more likely to indicate feeling worse on both the depression and/or anxiety components of the HADS. There was a significant negative association between subjective loneliness and worsened components of both depression (OR 17.24, 95% CI 13.20, 22.50) and anxiety (OR 10.85, 95% CI 8.39, 14.03). Results may inform targeted interventions and help guide policy recommendations in reducing the effects of social isolation related to the pandemic, and beyond, on the mental health of older people.

Journal article

Wilson H, Pagano G, de Natale ER, Mansur A, Caminiti SP, Polychronis S, Middleton LT, Price G, Schmidt KF, Gunn RN, Rabiner EA, Politis Met al., 2020, Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson's Disease, Movement Disorders, Vol: 35, Pages: 1416-1427, ISSN: 0885-3185

BackgroundDysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross‐sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug‐naive PD patients.MethodsTwelve early drug‐naive PD patients and 16 healthy controls underwent a 3‐Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB‐J, [11C]SA‐4503, and [18F]BCPP‐EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1‐year follow‐up assessments.ResultsReduced [11C]UCB‐J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug‐naive PD patients compared with healthy controls. [11C]UCB‐J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA‐4503 and [18F]BCPP‐EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB‐J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow‐up compared with baseline.ConclusionsOur findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug‐naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow‐up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, In

Journal article

Udeh-Momoh C, Loots C, Price G, Middleton Let al., 2020, Transition from physical to virtual visit format for a longitudinal brain ageing study, in response to the Covid-19 pandemic. Operationalising adaptive methods and challenges, Alzheimer's and Dementia: Translational Research and Clinical Interventions, Vol: 6, Pages: 1-7, ISSN: 2352-8737

The COVID-19 pandemic necessitated adaptations to standard operations and management of clinical studies, following lockdown measures put in place by several governments to reduce SARS-COV-2 spread. In this paper, we describe our telehealth strategy developed for transitioning our dementia prevention clinical observational prospective study from face-to-face visits to virtual visits, to ensure the ongoing collection of longitudinal data. We share the lessons learned in terms of challenges experienced and solutions implemented to achieve successful administration of study assessments. Our methods will be useful for informing longitudinal observational or interventional studies that require a feasible model for remote data collection, in cognitively unimpaired adults.

Journal article

Peters S, Gallo V, Vineis P, Middleton LT, Forsgren L, Sacerdote C, Sieri S, Kyrozis A, Chirlaque M-D, Zamora-Ros R, Hansson O, Petersson J, Katzke V, Kuehn T, Mokoroa O, Masala G, Ardanaz E, Panico S, Bergmann MM, Key TJ, Weiderpass E, Ferrari P, Vermeulen Ret al., 2020, Alcohol consumption and risk of Parkinson's disease: data from a large prospective European cohort, Movement Disorders, Vol: 35, Pages: 1258-1263, ISSN: 0885-3185

BackgroundParkinson's disease (PD) etiology is not well understood. Reported inverse associations with smoking and coffee consumption prompted the investigation of alcohol consumption as a risk factor, for which evidence is inconclusive.ObjectiveTo assess the associations between alcohol consumption and PD risk.MethodsWithin NeuroEPIC4PD, a prospective European population‐based cohort, 694 incident PD cases were ascertained from 209,998 PD‐free participants. Average alcohol consumption at different time points was self‐reported at recruitment. Cox regression hazard ratios were estimated for alcohol consumption and PD occurrence.ResultsNo associations between baseline or lifetime total alcohol consumption and PD risk were observed. Men with moderate lifetime consumption (5–29.9 g/day) were at ~50% higher risk compared with light consumption (0.1–4.9 g/day), but no linear exposure–response trend was observed. Analyses by beverage type also revealed no associations with PD.ConclusionOur data reinforce previous findings from prospective studies showing no association between alcohol consumption and PD risk. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Journal article

Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H, Baker L, Belleville S, Brodaty H, Brucki SM, Calandri I, Caramelli P, Chen C, Chertkow H, Chew E, Choi SH, Chowdhary N, Crivelli L, De La Torre R, Du Y, Dua T, Espeland M, Feldman HH, Hartmanis M, Hartmann T, Heffernan M, Henry CJ, Hong CH, Hakansson K, Iwatsubo T, Jeong JH, Jimenez-Maggiora G, Koo EH, Launer LJ, Lehtisalo J, Lopera F, Martinez-Lage P, Martins R, Middleton L, Molinuevo JL, Montero-Odasso M, Moon SY, Morales-Perez K, Nitrini R, Nygaard HB, Park YK, Peltonen M, Qiu C, Quiroz YT, Raman R, Rao N, Ravindranath V, Rosenberg A, Sakurai T, Salinas RM, Scheltens P, Sevlever G, Soininen H, Sosa AL, Suemoto CK, Tainta-Cuezva M, Velilla L, Wang Y, Whitmer R, Xu X, Bain LJ, Solomon A, Ngandu T, Carrillo MCet al., 2020, World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia, ALZHEIMERS & DEMENTIA, Vol: 16, Pages: 1078-1094, ISSN: 1552-5260

Journal article

Bauermeister S, Orton C, Thompson S, Barker RA, Bauermeister JR, Ben-Shlomo Y, Brayne C, Burn D, Campbell A, Calvin C, Chandran S, Chaturvedi N, Chene G, Chessell IP, Corbett A, Davis DHJ, Denis M, Dufouil C, Elliott P, Fox N, Hill D, Hofer SM, Hu MT, Jindra C, Kee F, Kim C-H, Kim C, Kivimaki M, Koychev I, Lawson RA, Linden GJ, Lyons RA, Mackay C, Matthews PM, McGuiness B, Middleton L, Moody C, Moore K, Na DL, O'Brien JT, Ourselin S, Paranjothy S, Park K-S, Porteous DJ, Richards M, Ritchie CW, Rohrer JD, Rossor MN, Rowe JB, Scahill R, Schnier C, Schott JM, Seo SW, South M, Steptoe M, Tabrizi SJ, Tales A, Tillin T, Timpson NJ, Toga AW, Visser P-J, Wade-Martins R, Wilkinson T, Williams J, Wong A, Gallacher JEJet al., 2020, The Dementias Platform UK (DPUK) data portal, European Journal of Epidemiology, Vol: 35, Pages: 601-611, ISSN: 0393-2990

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

Journal article

Ververis A, Dajani R, Koutsou P, Aloqaily A, Nelson-Williams C, Loring E, Arafat A, Mubaidin AF, Horany K, Bader MB, Al-Baho Y, Ali B, Muhtaseb A, DeSpenza T, Al-Qudah AA, Middleton LT, Zamba-Papanicolaou E, Lifton R, Christodoulou Ket al., 2020, Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation, Journal of Medical Genetics, Vol: 57, Pages: 178-186, ISSN: 0022-2593

BACKGROUND: Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. METHODS: We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. RESULTS: A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. CONCLUSION: In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

Journal article

Mansur A, Rabiner EA, Comley RA, Lewis Y, Middleton LT, Huiban M, Passchier J, Tsukada H, Gunn RNet al., 2020, Characterization of 3 PET tracers for Quantification of Mitochondrial and Synaptic function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, Journal of Nuclear Medicine, Vol: 61, Pages: 96-103, ISSN: 1535-5667

Mitochondrial complex 1 (MC1) is involved in maintaining brain bioenergetics, the sigma 1 receptor (σ1R) responds to neuronal stress and synaptic vesicle protein 2A (SV2A) reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here we characterise the kinetic behaviour of three positron emission tomography (PET) radioligands 18F-BCPP-EF, 11C-SA-4503 and 11CUCB- J, for the measurement of MC1, σ1R and SV2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans including associated arterial blood sampling with each radioligand. A range of kinetic models were investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All three radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution (VT) were multilinear analysis 1 (MA1) and the 2-tissue compartment (2TC) model for 18F-BCPP-EF, MA1 for 11C-SA- 4503, and both MA1 and the 1-tissue compartment (1TC) model for 11C-UCB-J. Acquisition times of 70, 80 and 60 minutes for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional VT values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

Journal article

Takousis P, Sadlon A, Schulz J, Wohlers I, Dobricic V, Middleton L, Lill CM, Perneczky R, Bertram Let al., 2019, Differential expression of microRNAs in Alzheimer's disease brain, blood, and cerebrospinal fluid, Alzheimers & Dementia, Vol: 15, Pages: 1468-1477, ISSN: 1552-5260

INTRODUCTION: Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. METHODS: A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty. RESULTS: Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10-4) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles. DISCUSSION: Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.

Journal article

McRae-McKee K, Chinedu T, Udeh-Momoh CT, Price G, Sumali Bajaj S, de Jager CA, Scott D, Hadjichrysanthou C, McNaughton E, Bracoud L, Ahmadi-Abhari S, De Wolf F, Anderson R, Middleton Let al., 2019, Perspective: Clinical relevance of the dichotomous classification of Alzheimer’s disease biomarkers: Should there be a “grey zone”?, Alzheimers & Dementia, Vol: 15, Pages: 1348-1356, ISSN: 1552-5260

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

Journal article

Udeh-Momoh C, Su B, Evans S, Zheng B, Sindi S, Tzoulaki I, Perneczky R, Middleton Let al., 2019, Cortisol, Amyloid- , and Reserve Predicts Alzheimer's disease progression for cognitively normal older adults, Journal of Alzheimer's Disease, Vol: 70, Pages: 551-560, ISSN: 1387-2877

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer’s disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aβ+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aβ42. High reserve reduces the associated AD progression risk in these high-risk individuals.

Journal article

Mansur A, Rabiner EA, Comley RA, Lewis Y, Middleton LT, Huiban M, Passchier J, Tsukada H, Gunn RNet al., 2019, Characterization of [18F]BCPP-EF, [11C]SA-4503 and [11C]UCB-J for the quantification of mitochondrial and synaptic function in the healthy human brain, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 109-110, ISSN: 0271-678X

Conference paper

Ward H, McLellan H, Udeh-Momoh C, Giannakopoulou P, Robb C, Wark P, Middleton Let al., 2019, Use of online dietary recalls among older UK adults: A feasibility study of an online dietary assessment tool, Nutrients, Vol: 11, ISSN: 2072-6643

This study examined the feasibility of including myfood24, an online 24-hour dietary recall tool, in a cohort studies of older adults. Participants (n = 319) were recruited during follow-up visits for the CHARIOT-Pro Sub-study, a prospective study of cognitively healthy adults aged 60–85 years at baseline. Email invitations were sent over three consecutive months, with weekly reminders. Multivariable regression models were applied to examine the number of recalls completed in relation to technology readiness (TR) scores and demographic characteristics. Ninety-four percent of people agreed to participate. Among participants, 67% completed at least one recall, and 48% completed two or more. Participants who completed multiple recalls reported higher self-confidence with technology and received a higher TR score than those who did not complete any recalls. A one-point higher TR score was associated with higher odds of completing three recalls compared to zero recalls (OR 1.70, 95% CI 0.96–3.01); this association was further attenuated after adjustment for demographic and other TR-related covariates (OR 1.35, 95% CI 0.63–2.88). This study demonstrates reasonable participation rates for a single myfood24 recall among older adults participating in a cohort study but suggests that further support may be required to obtain multiple recalls in this population.

Journal article

Schulz J, Takousis P, Wohlers I, Itua IOG, Dobricic V, Rücker G, Binder H, Middleton L, Ioannidis JPA, Perneczky R, Bertram L, Lill CMet al., 2019, Meta-analyses identify differentially expressed microRNAs in Parkinson's disease, Annals of Neurology, Vol: 85, Pages: 835-851, ISSN: 0364-5134

Objective: MicroRNA-mediated (dys)regulation of gene expression has been implicated in Parkinson's disease (PD), although results of microRNA expression studies remain inconclusive. We aimed to identify microRNAs that show consistent differential expression across all published expression studies in PD.Mathods: We performed a systematic literature search on microRNA expression studies in PD and extracted data from eligible publications. After stratification for brain, blood, and cerebrospinal fluid (CSF)-derived specimen we performed meta-analyses across microRNAs assessed in three or more independent datasets. Meta-analyses were performed using effect-size and p-value based methods, as applicable.Results: After screening 599 publications we identified 47 datasets eligible for meta-analysis. On these, we performed 160 meta-analyses on microRNAs quantified in brain (n=125), blood (n=31), or CSF samples (n=4). Twenty-one meta-analyses were performed using effect sizes. We identified 13 significantly (Bonferroni-adjusted α=3.13x10-4 ) differentially expressed microRNAs in brain (n=3) and blood (n=10) with consistent effect directions across studies. The most compelling findings were with hsa-miR-132-3p (p=6.37x10-5 ), hsa-miR-497-5p (p=1.35x10-4 ), and hsa-miR-133b (p=1.90x10-4 ) in brain, and with hsa-miR-221-3p (p=4.49x10-35 ), hsa-miR-214-3p (p=2.00x10-34 ), and hsa-miR-29c-3p (p=3.00x10-12 ) in blood. No significant signals were found in CSF. Analyses of GWAS data for target genes of brain microRNAs showed significant association (α=9.40x10-5 ) of genetic variants in nine loci.Interpretation: We identified several microRNAs that showed highly significant differential expression in PD. Future studies may assess the possible role of the identified brain miRNAs in pathogenesis and disease progression as well as the potential of the top blood microRNAs as biomarkers for diagnosis, progression or prediction of PD.

Journal article

Gallo V, Vineis P, Cancellieri M, Chiodini P, Barker RA, Brayne C, Pearce N, Vermeulen R, Panico S, Bueno-de-Mesquita B, Vanacore N, Forsgren L, Ramat S, Ardanaz E, Arriola L, Peterson J, Hansson O, Gavrila D, Sacerdote C, Sieri S, Kühn T, Katzke VA, van der Schouw YT, Kyrozis A, Masala G, Mattiello A, Perneczky R, Middleton L, Saracci R, Riboli Eet al., 2019, Exploring causality of the association between smoking and Parkinson's disease, International Journal of Epidemiology, Vol: 48, Pages: 912-925, ISSN: 1464-3685

Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

Journal article

Riso L, Kaaks R, Kühn T, Sookthai D, Forsgren L, Trupp M, Trichopoulou A, La Vecchia C, Karakatsani A, Gavrila D, Ferrari P, Freisling H, Petersson J, Lewan S, Vermeulen RC, Panico S, Masala G, Ardanaz E, Krogh V, Perneczky RG, Middleton LT, Mokoroa O, Sacerdote C, Sieri S, Hayat SA, Brayne C, Riboli E, Vineis P, Gallo V, Katzke VAet al., 2019, General and abdominal adiposity and the risk of parkinson's disease.A prospective chort study, Parkinsonism and Related Disorders, Vol: 62, Pages: 98-104, ISSN: 1353-8020

IntroductionDue to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD.MethodsIn 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking.ResultsWe found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD.ConclusionOur data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

Journal article

Woerman AL, Oehler A, Kazmi SA, Lee J, Halliday GM, Middleton LT, Gentleman SM, Mordes DA, Spina S, Grinberg LT, Olson SH, Prusiner SBet al., 2019, Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines, Acta Neuropathologica, Vol: 137, Pages: 437-454, ISSN: 1432-0533

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/−, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P+/+)Nbm, and Tg(SNCA*A53T+/+)Nbm]. In contrast to studies using TgM83+/− mice, motor deficits were not observed by 330–400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. However, using a cell-based bioassay to measure α-synuclein prions, we found brain homogenates from Tg(SNCA*A53T+/+)Nbm mice inoculated with MSA patient samples contained α-synuclein prions, whereas control mice did not. Moreover, these α-synuclein aggregates retained the biological and biochemical characteristics of the α-synuclein prions in MSA patient samples. Intriguingly, Tg(SNCA*A53T+/+)Nbm mice developed α-synuclein pathology in neurons and astrocytes throughout the limbic system. This finding is in contrast to MSA-inoculated TgM83+/− mice, which develop exclusively neuronal α-synuclein aggregates in the hindbrain that cause motor deficits with advanced disease. In a crossover experiment, we inoculated TgM83+/− mice with brain homogenate from two MSA patient samples or one control sample first inoculated, or passaged, in Tg(SNCA*A53T+/+)Nbm animals. Additionally, we performed the reverse experiment by inoculating Tg(SNCA*A53T+/+)Nbm mice with brain homogenate from the same two MSA samples and one control sample first passaged in TgM83+/− animals. The TgM83+/− mice inoculated wit

Journal article

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