Publications by authors named "Patrick G Kehoe"

126 Publications

Cognitive impact of COVID-19: looking beyond the short term.

Alzheimers Res Ther 2020 12 30;12(1):170. Epub 2020 Dec 30.

Dementia Research Group, Bristol Medical School (THS), University of Bristol, Learning & Research level 1, Southmead Hospital, Bristol, BS10 5NB, UK.

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE ε4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.
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http://dx.doi.org/10.1186/s13195-020-00744-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772800PMC
December 2020

Correction to: ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

Acta Neuropathol 2020 Nov;140(5):791

Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Level 1 Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.

Unfortunately, the acknowledgement section was not included in the original publication.
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http://dx.doi.org/10.1007/s00401-020-02229-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852865PMC
November 2020

Comparison of Antihypertensive Drug Classes for Dementia Prevention.

Epidemiology 2020 11;31(6):852-859

Dementia Research Group, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink.

Methods: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over.

Results: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that β-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, β-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives.

Conclusions: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.
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http://dx.doi.org/10.1097/EDE.0000000000001245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523578PMC
November 2020

Small RNA modifications in Alzheimer's disease.

Neurobiol Dis 2020 11 21;145:105058. Epub 2020 Aug 21.

Departments of Pharmacology, Physiology & Cell Biology, Center for Molecular & Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, School of Medicine, Reno, NV, USA. Electronic address:

Background While significant advances have been made in uncovering the aetiology of Alzheimer's disease and related dementias at the genetic level, molecular events at the epigenetic level remain largely undefined. Emerging evidence indicates that small non-coding RNAs (sncRNAs) and their associated RNA modifications are important regulators of complex physiological and pathological processes, including aging, stress responses, and epigenetic inheritance. However, whether small RNAs and their modifications are altered in dementia is not known. Methods We performed LC-MS/MS-based, high-throughput assays of small RNA modifications in post-mortem samples of the prefrontal lobe cortices of Alzheimer's disease (AD) and control individuals. We noted that some of the AD patients has co-occurring vascular cognitive impairment-related pathology (VaD). Findings We report altered small RNA modifications in AD samples compared with normal controls. The 15-25-nucleotide (nt) RNA fraction of these samples was enriched for microRNAs, whereas the 30-40-nt RNA fraction was enriched for tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). Interestingly, most of these altered RNA modifications were detected both in the AD and AD with co-occurring vascular dementia subjects. In addition, sequencing of small RNA in the 30-40-nt fraction from AD cortices revealed reductions in rsRNA-5S, tsRNA-Tyr, and tsRNA-Arg. Interpretation These data suggest that sncRNAs and their associated modifications are novel signals that may be linked to the pathogenesis and development of Alzheimer's disease. Fund NIH grants (R01HL122770, R01HL091905, 1P20GM130459, R01HD092431, P50HD098593, GM103440), AHA grant (17IRG33370128), Sigmund Gestetner Foundation Fellowship to P Kehoe.
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http://dx.doi.org/10.1016/j.nbd.2020.105058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572745PMC
November 2020

Evidence that the Kennedy and polyamine pathways are dysregulated in human brain in cases of dementia with Lewy bodies.

Brain Res 2020 09 22;1743:146897. Epub 2020 May 22.

Beaumont Research Institute, Royal Oak, MI 48073, USA; Oakland University-William Beaumont School of Medicine, Rochester, MI 48309, USA. Electronic address:

Disruptions of brain metabolism are considered integral to the pathogenesis of dementia, but thus far little is known of how dementia with Lewy bodies (DLB) impacts the brain metabolome. DLB is less well known than other neurodegenerative diseases such as Alzheimer's and Parkinson's disease which is perhaps why it is under-investigated. This exploratory study aimed to address current knowledge gaps in DLB research and search for potentially targetable biochemical pathways for therapeutics. It also aimed to better understand metabolic similarities and differences with other dementias. Combined metabolomic analyses of H NMR and tandem mass spectrometry of neocortical post-mortem brain tissue (Brodmann region 7) from autopsy confirmed cases of DLB (n = 15) were compared with age/gender-matched, non-cognitively impaired healthy controls (n = 30). Following correction for multiple comparisons, only 2 metabolites from a total of 219 measured compounds significantly differed. Putrescine was suppressed (55.4%) in DLB and O-phosphocholine was elevated (52.5%). We identified a panel of 5 metabolites (PC aa C38:4, O-Phosphocholine, putrescine, 4-Aminobutyrate, and SM C16:0) capable of accurately discriminating between DLB and control subjects. Deep Learning (DL) provided the best predictive model following 10-fold cross validation (AUROC (95% CI) = 0.80 (0.60-1.0)) with sensitivity and specificity equal to 0.92 and 0.88, respectively. Altered brain levels of putrescine and O-phosphocholine indicate that the Kennedy pathway and polyamine metabolism are perturbed in DLB. These are accompanied by a consistent underlying trend of lipid dysregulation. As yet it is unclear whether these are a cause or consequence of DLB onset.
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http://dx.doi.org/10.1016/j.brainres.2020.146897DOI Listing
September 2020

Baseline Results: The Association Between Cardiovascular Risk and Preclinical Alzheimer's Disease Pathology (ASCEND) Study.

J Alzheimers Dis 2020 ;75(1):109-117

Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Background: The rate of AD for African Americans (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress, and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs.

Objective: Our objective was to determine if in a healthy middle-aged cohort at risk for AD (1) AD biomarkers in CSF differ by race, (2) peripheral vascular dysfunction and cognition are related to a higher burden of CSF AD biomarkers, and (3) these relationships differ by race.

Methods: We enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Study procedures included lumbar puncture, vascular ultrasound, and cognitive testing.

Results: While participants were in overall good health, AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central MAP, and EndoPAT AI, a marker of arterial stiffness. AAs also had significantly less cerebrospinal fluid tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, race significantly modified the relationship between total tau, phospho-tau, and Trails B, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs.

Conclusion: In a healthy middle-aged cohort at risk for AD, AAs had worse peripheral vascular health and worse cognition than Whites. Despite lower tau burden overall, race modified the relationship between tau and cognition, such that small differences in tau between AAs was related to worse cognition when compared to Whites.
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http://dx.doi.org/10.3233/JAD-191103DOI Listing
May 2021

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

Acta Neuropathol 2020 03 25;139(3):485-502. Epub 2020 Jan 25.

Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Level 1 Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.
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http://dx.doi.org/10.1007/s00401-019-02098-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035243PMC
March 2020

Elevated cerebrospinal fluid sodium in hypertensive human subjects with a family history of Alzheimer's disease.

Physiol Genomics 2020 03 21;52(3):133-142. Epub 2020 Jan 21.

Departments of Pharmacology and Physiology & Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada.

High salt (sodium) intake leads to the development of hypertension despite the fact that plasma sodium concentration ([Na]) is usually normal in hypertensive human patients. Increased cerebrospinal fluid (CSF) sodium contributes to elevated sympathetic activity and high blood pressure (BP) in rodent models of hypertension. However, whether there is an increased accumulation of sodium in the CSF of humans with chronic hypertension is not well defined. Here, we investigated CSF [Na] from hypertensive and normotensive human subjects with family histories of Alzheimer's disease in samples collected in a clinical trial, as spinal tap is not a routine clinical procedure for hypertensive patients. The [Na] and osmolality in plasma and CSF were measured by flame photometry. Daytime ambulatory BP was monitored while individuals were awake. Participants were deidentified and data were analyzed in conjunction with a retrospective analysis of patient history and diagnosis. We found that CSF [Na] was significantly higher in participants with high BP compared with normotensive participants; there was no difference in plasma [Na], or plasma and CSF osmolality between groups. Subsequent multiple linear regression analyses controlling for age, sex, race, and body mass index revealed a significant positive correlation between CSF [Na] and BP but showed no correlation between plasma [Na] and BP. In sum, CSF [Na] was higher in chronic hypertensive individuals and may play a key role in the pathogenesis of human hypertension. Collectively, our findings provide evidence for the clinical significance of CSF [Na] in chronic hypertension in humans.
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http://dx.doi.org/10.1152/physiolgenomics.00093.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099411PMC
March 2020

Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-β-Induced Hypertension and Maintains Cerebral Perfusion.

J Alzheimers Dis 2020 ;73(3):1185-1199

Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Cerebral blood flow is reduced in Alzheimer's disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aβ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aβ40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aβ40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aβ caused progressive rise in blood pressure (p < 0.0001) (paired t-test: increase of 3 (0.1-5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aβ and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aβ40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion.
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http://dx.doi.org/10.3233/JAD-190630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081103PMC
May 2021

Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis.

Neurology 2020 01 11;94(3):e267-e281. Epub 2019 Dec 11.

From Neuroscience Research Australia (R.P., K.J.A.); University of New South Wales (R.P., C.A., H.B., J.C., P.S.S., K.J.A.), Sydney, Australia; Johns Hopkins University (S.Y., M.C.C.), Baltimore, MD; The George Institute for Global Health (C.A., J.C.), Sydney, Australia; The George Institute China at Peking University Health Sciences Center (C.A.), Beijing, China; Icahn School of Medicine at Mount Sinai (S.A.), New York, NY; Center for Life Course Health Research/Geriatrics (R.A., S.K.-K., S.S., E.V.), University of Oulu; Medical Research Center Oulu (R.A.), Oulu University Hospital; Oulu City Hospital (R.A.), Finland; Department of Preventive Medicine and Public Health (H.A.), Fukuoka University, Japan; Guys and St Thomas' NHS Foundation Trust (N.B.), London, UK; University of Pittsburgh (J.C.B., M.G.), PA; Leiden University Medical Centre (A.S.B., S.T.), the Netherlands; University of Sheffield (A.B., J.P.), UK; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology (M.v.B., S.K.), Maastricht University, the Netherlands; University of Cambridge (C.B.), UK; University of California (M.C., C.K.), Irvine; University of Florida (S.D.), Gainesville; Albert Einstein College of Medicine (C.D., M.K.), New York, NY; University of Alberta (R.A.D., G.P.M.), Edmonton, Canada; International Longevity Centre (F.F.), Paris, France; University of Amsterdam (W.A.v.G., E.P.M.v.C.), the Netherlands; Golgi Cenci Foundation (A.G., R.V.), Milan, Italy; Trinity College Dublin (A.H., R.A.K.), Ireland; University of Calgary (D.B.H.), Canada; Newcastle University (C.J., B.C.M.S.), Newcastle upon Tyne; University of Bristol (P.G.K., S.K.K.), UK; University of Eastern Finland (J.L.), Kuopio; Faculty of Sport and Health Sciences, University of Jyväskylä (J.L.), Finland; School of Pharmacy, University of Waterloo (C.M.), Ontario, Canada; Academic Medical Center (T.v.M., E.R.), Amsterdam; Donders Institute for Brain, Cognition and Behaviour (T.v.M., E.R.), Radboud University Medical Center, Nijmegen, the Netherlands; National University of Singapore (T.-P.N.); Sengkang General Hospital (I.R.), Singhealth Duke-NUS Academic Medical Centre, Singapore; Dalhousie University (K.R.), Halifax, Canada; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy (L.R., I.S.), and Department of Psychology (J.S.), Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Sweden; University of Leuven (J.A.S., L.T.), Belgium; Bordeaux Population Health Research Center (P.J.T., C.T.), UMR 1219, CHU Bordeaux, University of Bordeaux, Inserm, France; University of Adelaide (P.J.T.); Australian National University (E.W.), Canberra, Australia; and University of Warwick (J.W.), Coventry, UK.

Objective: High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data.

Methods: To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data.

Results: Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age.

Conclusion: Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.

Clinical Trials Registration: The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.
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http://dx.doi.org/10.1212/WNL.0000000000008732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108807PMC
January 2020

Cerebrospinal Fluid Changes in the Renin-Angiotensin System in Alzheimer's Disease.

J Alzheimers Dis 2019 ;72(2):525-535

Dementia Research Group, Clinical Neuroscience, Southmead Hospital, University of Bristol, Bristol, UK.

Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer's disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 (ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42, total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p = 0.008) and positively correlated with ACE2 in AD (r = 0.420, p = 0.007). CSF ACE1 weakly correlated with t-tau (r = 0.294, p = 0.066) and p-tau (r = 0.329, p = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r = 0.426, p = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r = 0.422, p = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD.
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http://dx.doi.org/10.3233/JAD-190721DOI Listing
November 2020

Repurposing antihypertensive drugs for the prevention of Alzheimer's disease: a Mendelian randomization study.

Int J Epidemiol 2020 08;49(4):1132-1140

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Background: Evidence concerning the potential repurposing of antihypertensives for Alzheimer's disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer's disease.

Methods: We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer's disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer's disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets.

Results: There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer's disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153).

Conclusions: Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer's disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer's disease, they may not do so via systolic blood pressure.
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http://dx.doi.org/10.1093/ije/dyz155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751008PMC
August 2020

Challenges to and Facilitators of Recruitment to an Alzheimer's Disease Clinical Trial: A Qualitative Interview Study.

J Alzheimers Dis 2019 ;69(4):1067-1075

Bristol Randomised Trials Collaboration, Bristol Trials Centre, University of Bristol, Bristol, UK.

Background: Low participation in clinical trials is a major challenge to advancing clinical Alzheimer's disease (AD) research and care. Factors influencing recruitment to AD trials are not fully understood.

Objective: To identify barriers to, and facilitators of, recruitment in a UK multi-center, secondary care AD trial (Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) trial) and implications for improving recruitment to AD trials.

Methods: Semi-structured qualitative telephone interviews with a purposive sample of 17 trial site staff explored the RADAR trial recruitment pathway and views and experiences of recruitment. Interviews were analyzed thematically.

Results: Diagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening. Research is not routinely embedded in AD care but facilitated recruitment when it was. Clinicians' and patients' favorable view of the trial purpose facilitated recruitment, although the complexity of participant information sheets and requirement for study companion created challenges.

Conclusion: These findings have important implications for the design of future AD trials and for planning how to best interface with clinical commitments to ensure sufficient and timely recruitment. Challenges to AD trial recruitment can occur at care pathway, clinician, and patient and companion levels. Recruitment can be facilitated by: improving diagnostic processes and systems for recording and sharing patient information, embedding research into routine patient care, collaborating with a range of services to identify and approach eligible patients, training and engaging trial staff, and providing patients with clear and concise study information.
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http://dx.doi.org/10.3233/JAD-190146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598018PMC
September 2020

Divergence in the activity of the N- and C- catalytic domains of ACE1 - implications for the role of the renin-angiotensin system in Alzheimer's disease.

Acta Neuropathol Commun 2019 04 24;7(1):57. Epub 2019 Apr 24.

Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Level 1 Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.

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http://dx.doi.org/10.1186/s40478-019-0718-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480511PMC
April 2019

The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer's Disease Risk.

J Alzheimers Dis 2019 ;68(4):1535-1547

Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.
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http://dx.doi.org/10.3233/JAD-181116DOI Listing
August 2020

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Evidence That Parietal Lobe Fatty Acids May Be More Profoundly Affected in Moderate Alzheimer's Disease (AD) Pathology Than in Severe AD Pathology.

Metabolites 2018 Oct 26;8(4). Epub 2018 Oct 26.

Institute for Global Food Security (IGFS), Queen's University Belfast, Stranmillis Road, Belfast BT9 6AG, Ireland.

Brain is a lipid-rich tissue, and fatty acids (FAs) play a crucial role in brain function, including neuronal cell growth and development. This study used GC-MS to survey all detectable FAs in the human parietal cortex (Brodmann area 7). These FAs were accurately quantified in 27 cognitively normal age-matched controls, 16 cases of moderate Alzheimer's disease (AD), 30 severe AD, and 14 dementia with Lewy bodies (DLB). A total of 24 FA species were identified. Multiple comparison procedures, using stepdown permutation tests, noted higher levels of 13 FAs but the majority of changes were in moderate AD and DLB, rather than severe AD. Subjects with moderate AD and DLB pathology exhibited significantly higher levels of a number of FAs (13 FAs and 12 FAs, respectively). These included nervonic, lignoceric, -13,16-docosadienoic, arachidonic, -11,14,17-eicosatrienoic, erucic, behenic, α-linolenic, stearic, oleic, -10-heptanoic, and palmitic acids. The similarities between moderate AD and DLB were quite striking-arachidic acid was the only FA which was higher in moderate AD than control, and was not similarly affected in DLB. Furthermore, there were no significant differences between moderate AD and DLB. The associations between each FA and a number of variables, including diagnosis, age, gender, Aβ plaque load, tau load, and frontal tissue pH, were also investigated. To conclude, the development of AD or DLB pathology affects brain FA composition but, intriguingly, moderate AD neuropathology impacts this to a much greater extent. Post-mortem delay is a potential confounding factor, but the findings here suggest that there could be a more dynamic metabolic response in the earlier stages of the disease pathology.
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http://dx.doi.org/10.3390/metabo8040069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316131PMC
October 2018

What is the impact of regulatory guidance and expiry of drug patents on dementia drug prescriptions in England? A trend analysis in the Clinical Practice Research Datalink.

Alzheimers Res Ther 2018 05 29;10(1):51. Epub 2018 May 29.

Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK.

Background: Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016.

Methods: We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer's disease, receiving their first prescription for each drug class-namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest.

Results: The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, - 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, - 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister's Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials.

Conclusions: Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively.
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http://dx.doi.org/10.1186/s13195-018-0379-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975499PMC
May 2018

Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.

Clin Sci (Lond) 2018 04 30;132(8):851-868. Epub 2018 Apr 30.

Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, U.K.

Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.
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http://dx.doi.org/10.1042/CS20171620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700732PMC
April 2018

Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial.

J Alzheimers Dis 2018 ;61(2):815-824

Dementia Research Group, Faculty of Health Sciences, University of Bristol, Learning and Research, Southmead Hospital, Bristol, UK.

Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.
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http://dx.doi.org/10.3233/JAD-161198DOI Listing
January 2019

The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial.

J Alzheimers Dis 2018 ;61(2):803-814

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression.

Objective: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR).

Methods: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables.

Results: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits.

Conclusion: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.
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http://dx.doi.org/10.3233/JAD-170101DOI Listing
January 2019

Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study.

Alzheimers Dement 2018 03 19;14(3):280-292. Epub 2017 Oct 19.

Translational Health Sciences, University of Bristol, Bristol, UK. Electronic address:

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2.

Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI.

Results: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging.

Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration.
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http://dx.doi.org/10.1016/j.jalz.2017.09.007DOI Listing
March 2018

Cerebral Aβ and systemic hypertension.

J Cereb Blood Flow Metab 2018 11 7;38(11):1993-2005. Epub 2017 Aug 7.

1 School of Clinical Sciences, University of Bristol, Bristol, UK.

Mid-life hypertension and cerebral hypoperfusion may be preclinical abnormalities in people who later develop Alzheimer's disease. Although accumulation of amyloid-beta (Aβ) is characteristic of Alzheimer's disease and is associated with upregulation of the vasoconstrictor peptide endothelin-1 within the brain, it is unclear how this affects systemic arterial pressure. We have investigated whether infusion of Aβ into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat. The Dahl salt-sensitive rat develops hypertension if given a high-salt diet. Intracerebroventricular infusion of Aβ induced a progressive rise in blood pressure in rats with pre-existing hypertension produced by a high-salt diet ( p < 0.0001), but no change in blood pressure in normotensive rats. The elevation in arterial pressure in high-salt rats was associated with an increase in low frequency spectral density in systolic blood pressure, suggesting autonomic imbalance, and reduced cardiac baroreflex gain. Our results demonstrate the potential for intracerebral Aβ to exacerbate hypertension, through modulation of autonomic activity. Present findings raise the possibility that mid-life hypertension in people who subsequently develop Alzheimer's disease may in some cases be a physiological response to reduced cerebral perfusion complicating the accumulation of Aβ within the brain.
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http://dx.doi.org/10.1177/0271678X17724930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259324PMC
November 2018

Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies.

Eur J Epidemiol 2017 11 27;32(11):947-959. Epub 2017 Jul 27.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

The renin-angiotensin system (RAS) represents an important target of antihypertensive medications. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), which are widely-used RAS inhibiting drugs, have been suggested to have beneficial effects on bone tissue. We aimed to assess the associations of use of ACEIs and/or ARBs with the risk of fractures using a population-based prospective cohort and a meta-analysis of published prospective cohort studies. Information on antihypertensive medication use (including both ACEIs and ARBs) were assessed in 1743 men and women of the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) [95% confidence intervals (CI)] of ACEIs or ARBs use with incident fractures were calculated. A total of 203 composite (hip, humeral, and wrist) fractures occurred during a median follow-up of 14.8 years. In multivariate adjusted analysis, the HR for composite fractures comparing users of ACEIs or ARBs with non-users was 1.00 (0.59-1.69). The corresponding adjusted HR for hip fractures comparing users versus non-users of ACEIs or ARBs was 0.89 (0.32-2.47). Including the current study, a total of 11 observational cohort studies involving 3526,319 participants and >323,355 fractures were included in a meta-analysis. Comparing ACEI users with non-users and ARB users with non-users, the HRs for composite fractures were 1.09 (0.89-1.33) and 0.87 (0.76-1.01) respectively. The corresponding HRs for hip fractures were 0.91 (0.86-0.95) and 0.80 (0.75-0.85) respectively. Use of RAS inhibitors was not associated with long-term risk of composite fractures in both primary and pooled analyses. Pooled evidence however suggests a beneficial effect of RAS blockers on hip fracture risk.
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http://dx.doi.org/10.1007/s10654-017-0285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684291PMC
November 2017

Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer's Disease.

Metabolites 2017 Jun 17;7(2). Epub 2017 Jun 17.

Advanced Asset Technology Centre, Institute for Global Food Security, Queen's University Belfast, Belfast BT9 5AG, UK.

Certain endogenous bile acids have been proposed as potential therapies for ameliorating Alzheimer's disease (AD) but their role, if any, in the pathophysiology of this disease is not currently known. Given recent evidence of bile acids having protective and anti-inflammatory effects on the brain, it is important to establish how AD affects levels of endogenous bile acids. Using LC-MS/MS, this study profiled 22 bile acids in brain extracts and blood plasma from AD patients (n = 10) and age-matched control subjects (n = 10). In addition, we also profiled brain/plasma samples from APP/PS1 and WT mice (aged 6 and 12 months). In human plasma, we detected significantly lower cholic acid (CA, p = 0.03) in AD patients than age-matched control subjects. In APP/PS1 mouse plasma we detected higher CA (p = 0.05, 6 months) and lower hyodeoxycholic acid (p = 0.04, 12 months) than WT. In human brain with AD pathology (Braak stages V-VI) taurocholic acid (TCA) were significantly lower (p = 0.01) than age-matched control subjects. In APP/PS1 mice we detected higher brain lithocholic acid (p = 0.05) and lower tauromuricholic acid (TMCA; p = 0.05, 6 months). TMCA was also decreased (p = 0.002) in 12-month-old APP/PS1 mice along with 5 other acids: CA (p = 0.02), β-muricholic acid (p = 0.02), Ω-muricholic acid (p = 0.05), TCA (p = 0.04), and tauroursodeoxycholic acid (p = 0.02). The levels of bile acids are clearly disturbed during the development of AD pathology and, since some bile acids are being proposed as potential AD therapeutics, we demonstrate a method that can be used to support work to advance bile acid therapeutics.
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http://dx.doi.org/10.3390/metabo7020028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487999PMC
June 2017

Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer's and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink.

BMJ Open 2016 12 13;6(12):e012044. Epub 2016 Dec 13.

School of Social and Community Medicine, University of Bristol, Bristol, UK.

Introduction: Current treatments for Alzheimer's and other neurodegenerative diseases have only limited effectiveness meaning that there is an urgent need for new medications that could influence disease incidence and progression. We will investigate the potential of a selection of commonly prescribed drugs, as a more efficient and cost-effective method of identifying new drugs for the prevention or treatment of Alzheimer's disease, non-Alzheimer's disease dementias, Parkinson's disease and amyotrophic lateral sclerosis. Our research will focus on drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all of which have previously been identified as potentially cerebroprotective and have variable levels of preclinical evidence that suggest they may have beneficial effects for various aspects of dementia pathology.

Methods And Analysis: We will conduct a hypothesis testing observational cohort study using data from the Clinical Practice Research Datalink (CPRD). Our analysis will consider four statistical methods, which have different approaches for modelling confounding. These are multivariable adjusted Cox regression; propensity matched regression; instrumental variable analysis and marginal structural models. We will also use an intention-to-treat analysis, whereby we will define all exposures based on the first prescription observed in the database so that the target parameter is comparable to that estimated by a randomised controlled trial.

Ethics And Dissemination: This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate.
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http://dx.doi.org/10.1136/bmjopen-2016-012044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168636PMC
December 2016

The Vascular Impairment of Cognition Classification Consensus Study.

Alzheimers Dement 2017 Jun 10;13(6):624-633. Epub 2016 Dec 10.

Dementia Research Group, Faculty of Health Sciences, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK. Electronic address:

Introduction: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment.

Methods: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines.

Results: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge.

Discussion: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.
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http://dx.doi.org/10.1016/j.jalz.2016.10.007DOI Listing
June 2017

Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment.

Brain 2016 11;139(11):2957-2969

Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Learning and Research Level 1, Southmead Hospital, Bristol, BS10 5NB, UK.

There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet's AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment.10.1093/brain/aww214_video_abstractaww214_video_abstract.
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http://dx.doi.org/10.1093/brain/aww214DOI Listing
November 2016

Is Extracorporeal Shockwave Therapy Combined With Isokinetic Exercise More Effective Than Extracorporeal Shockwave Therapy Alone for Subacromial Impingement Syndrome? A Randomized Clinical Trial.

J Orthop Sports Phys Ther 2016 Sep 31;46(9):714-25. Epub 2016 Jul 31.

Unlabelled: Study Design Single-blind randomized trial. Background Extracorporeal shockwave therapy (ESWT) has been shown to produce good results in the treatment of subacromial impingement syndrome (SAIS). The efficacy of a combined administration of ESWT and isokinetic exercise (IE) has not yet been studied. Objectives To evaluate the efficacy of focused ESWT combined with IE for the rotator cuff versus focused ESWT alone in the treatment of SAIS. The secondary objective was to assess the isokinetic torque recovery (external rotation at 210°/s, 180°/s, and 120°/s). Methods Thirty participants with SAIS were randomly assigned to a focused-ESWT group or focused ESWT-plus-IE group. Subjects of both groups received 3 treatment sessions of focused ESWT over a period of 10 days. Participants in the second group also received IE for 10 therapy sessions. Outcome measures were the Constant-Murley score (CMS), the visual analog scale (VAS), and isokinetic parameters (peak torque and total work calculated from 5 repetitions) measured with the isokinetic test. Subjects were assessed at baseline, 10 days after the last treatment session with focused ESWT, and after 2 months of follow-up. Results At 2 months posttreatment, participants in the focused ESWT-plus-IE group showed significantly less pain (focused-ESWT VAS, 3.4 ± 0.8 versus focused ESWT-plus-IE VAS, 1.5 ± 0.5; P<.001) and greater improvement in functionality (focused-ESWT CMS, 75.9 ± 6.7 versus focused ESWT-plus-IE CMS, 92.1 ± 6.3; P<.001) and muscle endurance than the subjects in the focused-ESWT group. Conclusion In subjects with SAIS, combined administration of focused ESWT and IE for the rotator cuff resulted in greater reduction of pain, as well as superior functional recovery and muscle endurance in the short to medium term, compared with ESWT alone. Level of evidence Therapy, 2b.

Trial Registration: unregistered 2011 trial. J Orthop Sports Phys Ther 2016;46(9):714-725. Epub 5 Aug 2016. doi:10.2519/jospt.2016.4629.
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http://dx.doi.org/10.2519/jospt.2016.4629DOI Listing
September 2016