Abstract
Background
Early Alzheimer’s disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take ...place as a result of Alzheimer’s pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average ‘midpoint’ measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology.
Methods
In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ).
Results
We show an increase in T2 heterogeneity (T2σ;
p
< .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ;
p
= .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (
p
= .018), but midpoint (
p
= .132) and volume (
p
= .315) did not. Age affects T2, but the effects described here are significant even after correcting for age.
Conclusions
We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.
Functional cognitive disorder (FCD) is a relatively common cause of cognitive symptoms, characterised by inconsistency between symptoms and observed or self-reported cognitive functioning. We aimed ...to improve the clinical characterisation of FCD, in particular its differentiation from early neurodegeneration. Two patient cohorts were recruited from a UK-based tertiary cognitive clinic, diagnosed following clinical assessment, investigation and expert multidisciplinary team review: FCD, (n = 21), and neurodegenerative Mild Cognitive Impairment (nMCI, n = 17). We separately recruited a healthy control group (n = 25). All participants completed an assessment battery including: Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part B (TMT-B); Depression Anxiety and Stress Scale (DASS) and Minnesota Multiphasic Personality Inventory (MMPI-2RF). In comparison to healthy controls, the FCD and nMCI groups were equally impaired on trail making, immediate recall, and recognition tasks; had equally elevated mood symptoms; showed similar aberration on a range of personality measures; and had similar difficulties on inbuilt performance validity tests. However, participants with FCD performed significantly better than nMCI on HVLT-R delayed free recall and retention (regression coefficient −10.34, p = 0.01). Mood, personality and certain cognitive abilities were similarly altered across nMCI and FCD groups. However, those with FCD displayed spared delayed recall and retention, in comparison to impaired immediate recall and recognition. This pattern, which is distinct from that seen in prodromal neurodegeneration, is a marker of internal inconsistency. Differentiating FCD from nMCI is challenging, and the identification of positive neuropsychometric features of FCD is an important contribution to this emerging area of cognitive neurology.
Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation ...requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.
Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimer's disease is likely to be possible only in the earliest stages of disease, perhaps even before ...significant symptoms develop. Pathology in Alzheimer's disease accumulates for well over a decade before symptoms are detected giving a large potential window of opportunity for intervention. It is therefore important that imaging techniques detect subtle changes in brain tissue before significant macroscopic brain atrophy. Current diagnostic techniques often do not permit early diagnosis or are too expensive for routine clinical use. Magnetic Resonance Imaging (MRI) is the most versatile, affordable, and powerful imaging modality currently available, being able to deliver detailed analyses of anatomy, tissue volumes, and tissue state. In this mini-review, we consider how MRI might detect patients at risk of future dementia in the early stages of pathological change when symptoms are mild. We consider the contributions made by the various modalities of MRI (structural, diffusion, perfusion, relaxometry) in identifying not just atrophy (a late-stage AD symptom) but more subtle changes reflective of early dementia pathology. The sensitivity of MRI not just to gross anatomy but to the underlying "health" at the cellular (and even molecular) scales, makes it very well suited to this task.
In the UK, dementia affects 5% of the population aged over 65 years and 25% of those over 85 years. Frontotemporal dementia (FTD) represents one subtype and is thought to account for up to 16% of all ...degenerative dementias. Although the core of the diagnostic process in dementia rests firmly on clinical and cognitive assessments, a wide range of investigations are available to aid diagnosis.Regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) is an established clinical tool that uses an intravenously injected radiolabelled tracer to map blood flow in the brain. In FTD the characteristic pattern seen is hypoperfusion of the frontal and anterior temporal lobes. This pattern of blood flow is different to patterns seen in other subtypes of dementia and so can be used to differentiate FTD.It has been proposed that a diagnosis of FTD, (particularly early stage), should be made not only on the basis of clinical criteria but using a combination of other diagnostic findings, including rCBF SPECT. However, more extensive testing comes at a financial cost, and with a potential risk to patient safety and comfort.
To determine the diagnostic accuracy of rCBF SPECT for diagnosing FTD in populations with suspected dementia in secondary/tertiary healthcare settings and in the differential diagnosis of FTD from other dementia subtypes.
Our search strategy used two concepts: (a) the index test and (b) the condition of interest. We searched citation databases, including MEDLINE (Ovid SP), EMBASE (Ovid SP), BIOSIS (Ovid SP), Web of Science Core Collection (ISI Web of Science), PsycINFO (Ovid SP), CINAHL (EBSCOhost) and LILACS (Bireme), using structured search strategies appropriate for each database. In addition we searched specialised sources of diagnostic test accuracy studies and reviews including: MEDION (Universities of Maastricht and Leuven), DARE (Database of Abstracts of Reviews of Effects) and HTA (Health Technology Assessment) database.We requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies and used the related articles feature in PubMed to search for additional studies. We tracked key studies in citation databases such as Science Citation Index and Scopus to ascertain any further relevant studies. We identified 'grey' literature, mainly in the form of conference abstracts, through the Web of Science Core Collection, including Conference Proceedings Citation Index and Embase. The most recent search for this review was run on the 1 June 2013.Following title and abstract screening of the search results, full-text papers were obtained for each potentially eligible study. These papers were then independently evaluated for inclusion or exclusion.
We included both case-control and cohort (delayed verification of diagnosis) studies. Where studies used a case-control design we included all participants who had a clinical diagnosis of FTD or other dementia subtype using standard clinical diagnostic criteria. For cohort studies, we included studies where all participants with suspected dementia were administered rCBF SPECT at baseline. We excluded studies of participants from selected populations (e.g. post-stroke) and studies of participants with a secondary cause of cognitive impairment.
Two review authors extracted information on study characteristics and data for the assessment of methodological quality and the investigation of heterogeneity. We assessed the methodological quality of each study using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. We produced a narrative summary describing numbers of studies that were found to have high/low/unclear risk of bias as well as concerns regarding applicability. To produce 2 x 2 tables, we dichotomised the rCBF SPECT results (scan positive or negative for FTD) and cross-tabulated them against the results for the reference standard. These tables were then used to calculate the sensitivity and specificity of the index test. Meta-analysis was not performed due to the considerable between-study variation in clinical and methodological characteristics.
Eleven studies (1117 participants) met our inclusion criteria. These consisted of six case-control studies, two retrospective cohort studies and three prospective cohort studies. Three studies used single-headed camera SPECT while the remaining eight used multiple-headed camera SPECT. Study design and methods varied widely. Overall, participant selection was not well described and the studies were judged as having either high or unclear risk of bias. Often the threshold used to define a positive SPECT result was not predefined and the results were reported with knowledge of the reference standard. Concerns regarding applicability of the studies to the review question were generally low across all three domains (participant selection, index test and reference standard).Sensitivities and specificities for differentiating FTD from non-FTD ranged from 0.73 to 1.00 and from 0.80 to 1.00, respectively, for the three multiple-headed camera studies. Sensitivities were lower for the two single-headed camera studies; one reported a sensitivity and specificity of 0.40 (95% confidence interval (CI) 0.05 to 0.85) and 0.95 (95% CI 0.90 to 0.98), respectively, and the other a sensitivity and specificity of 0.36 (95% CI 0.24 to 0.50) and 0.92 (95% CI 0.88 to 0.95), respectively.Eight of the 11 studies which used SPECT to differentiate FTD from Alzheimer's disease used multiple-headed camera SPECT. Of these studies, five used a case-control design and reported sensitivities of between 0.52 and 1.00, and specificities of between 0.41 and 0.86. The remaining three studies used a cohort design and reported sensitivities of between 0.73 and 1.00, and specificities of between 0.94 and 1.00. The three studies that used single-headed camera SPECT reported sensitivities of between 0.40 and 0.80, and specificities of between 0.61 and 0.97.
At present, we would not recommend the routine use of rCBF SPECT in clinical practice because there is insufficient evidence from the available literature to support this.Further research into the use of rCBF SPECT for differentiating FTD from other dementias is required. In particular, protocols should be standardised, study populations should be well described, the threshold for 'abnormal' scans predefined and clear details given on how scans are analysed. More prospective cohort studies that verify the presence or absence of FTD during a period of follow up should be undertaken.
Background
Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression.
Objective
This study investigated whether taking ...the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo.
Design
A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months.
Setting
Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland.
Participants
Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions.
Intervention
The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months.
Main outcome measures
Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability.
Results
A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (
n
= 105) or placebo (
n
= 106) arms. Of the 197 people (93%) who completed the study, 81% (
n
= 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml;
p
= 0.19), and there was no evidence of benefit for any of the secondary outcome measures.
Limitations
Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes.
Conclusions
Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease.
Future work
Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis.
Trial registration
Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 8, No. 19. See the NIHR Journals Library website for further project information.
Abstract Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported ...genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio OR, 2.7; 95% CI, 1.9–3.8; P =2.4x10–8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P =9.7x10–9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P =4.8x10–9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P =7.1x10–9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.
Elucidating the material culture of early people in arid Australia and the nature of their environmental interactions is essential for understanding the adaptability of populations and the potential ...causes of megafaunal extinctions 50-40 thousand years ago (ka). Humans colonized the continent by 50 ka, but an apparent lack of cultural innovations compared to people in Europe and Africa has been deemed a barrier to early settlement in the extensive arid zone. Here we present evidence from Warratyi rock shelter in the southern interior that shows that humans occupied arid Australia by around 49 ka, 10 thousand years (kyr) earlier than previously reported. The site preserves the only reliably dated, stratified evidence of extinct Australian megafauna, including the giant marsupial Diprotodon optatum, alongside artefacts more than 46 kyr old. We also report on the earliest-known use of ochre in Australia and Southeast Asia (at or before 49-46 ka), gypsum pigment (40-33 ka), bone tools (40-38 ka), hafted tools (38-35 ka), and backed artefacts (30-24 ka), each up to 10 kyr older than any other known occurrence. Thus, our evidence shows that people not only settled in the arid interior within a few millennia of entering the continent, but also developed key technologies much earlier than previously recorded for Australia and Southeast Asia.
Background
Quantitative T2 and diffusion MRI indices inform about tissue state and microstructure, both of which may be affected by pathology before tissue atrophy.
Purpose
To evaluate the capability ...of both volumetric and quantitative MRI (qMRI) of the hippocampus and entorhinal cortex (EC) for classification of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD).
Study type
Retrospective cross‐sectional study.
Population
Consecutive cohorts of healthy age‐matched controls (n = 62), aMCI patients (n = 25), and ADD patients (n = 14).
Field strength/sequence
3T using T1‐weighted imaging, T2‐weighted imaging, T2 relaxometry and diffusion tensor imaging (DTI).
Assessment
Montreal Cognitive Assessment and paired associate learning tests for cognitive state. Hippocampal subfield volumes by the automated segmentation of hippocampal subfields system from structural brain images. T2 relaxation time and DTI indices quantified for hippocampal subfields. The fraction of voxels with high T2 values (>20 ms above subfield median) was calculated and regionalized for hippocampus and EC.
Statistical tests
Support vector machine and receiver operating characteristic analyses from cognitive and MRI data.
Results
qMRI classified aMCI and ADD with excellent sensitivity (79.0% and 94.5%, respectively) and specificity (85.6% and 86.1%, respectively), superior to volumes alone (70.0% and 84.5% for respective sensitivities; 82.2 and 91.1 for respective specificities) and similar to cognitive tests (61.7% and 87.5% for respective sensitivities; 88.2% and 90.7% for respective specificities). Regions of high T2 are dispersed throughout each hippocampal subfield in aMCI and ADD with higher concentration than controls, and was most pronounced in the EC. No other individual qMRI marker than EC volume can separate aMCI from ADD, however.
Data conclusion
qMRI markers of hippocampal and entorhinal tissue states are sensitive and specific classifiers of aMCI and ADD. They may serve as markers of a neurodegenerative state preceding volume loss.
Level of Evidence: 2
Technical Efficacy: Stage 3
J. Magn. Reson. Imaging 2019;49:445–455.
To test whether active management of urinary tract infections (UTI) in young children by general practitioners can reduce kidney scarring rates.
A comparison of two audits in Newcastle, of children ...aged <8 years, presenting with UTIs ; a retrospective audit of conventional management during 1992-1995 (1990s) versus a prospective audit of direct access management during 2004-2011 (2000s).
Kidney scarring rates, and their relationship with time-to-treat.
Children with a first UTI in the 2000s compared to those in the 1990s, were referred younger, were half as likely to have a renal scar (girls OR 0.47, 95% CI 0.29 to 0.76; boys 0.35, 0.16 to 0.81), and were about 12 times more likely to have vesicoureteric reflux without scarring (girls 11.9, 4.3 to 33.5; boys 14.4, 4.3 to 47.6). In the 2000s, general practitioners treated about half the children at first consultation. Children who were treated within 3 days of their symptoms starting were one-third as likely to scar as those whose symptoms lasted longer (0.33, 0.12 to 0.72).
Most kidney defects seen in children after UTIs, are acquired scars, and in Newcastle, active management in primary care has halved this rate.
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