Publications
116 results found
Olgiati E, Violante IR, Xu S, et al., 2024, Targeted non-invasive brain stimulation boosts attention and modulates contralesional brain networks following right hemisphere stroke, NeuroImage: Clinical, Pages: 103599-103599, ISSN: 2213-1582
Newton C, Pope M, Rua C, et al., 2024, Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease., Alzheimers Dement
INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.
Buller-Peralta I, Gregory S, Low A, et al., 2024, Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults., Sci Rep, Vol: 14
To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.
Shah SN, Dounavi M-E, Malhotra PA, et al., 2024, Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study., Brain Commun, Vol: 6
A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dement
Mak E, Dounavi M-E, Operto G, et al., 2024, APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure., Brain Commun, Vol: 6
The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.
Loreto F, Verdi S, Kia SM, et al., 2024, Alzheimer's disease heterogeneity revealed by neuroanatomical normative modeling., Alzheimers Dement (Amst), Vol: 16, ISSN: 2352-8729
INTRODUCTION: Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD-related atrophy. METHODS: We applied neuroanatomical normative modeling to magnetic resonance imaging from a real-world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual- and group-levels. RESULTS: The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non-amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION: Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo-clinical correlations in individual patients.
Raposo de Lima M, Vaidyanathan R, Barnaghi P, 2023, Discovering behavioural patterns using conversational technology for in-home health and well-being monitoring, IEEE Internet of Things Journal, Vol: 10, Pages: 18537-18552, ISSN: 2327-4662
Advancements in conversational AI have createdunparalleled opportunities to promote the independence andwell-being of older adults, including people living with dementia(PLWD). However, conversational agents have yet to demonstratea direct impact in supporting target populations at home,particularly with long-term user benefits and clinical utility. Weintroduce an infrastructure fusing in-home activity data capturedby Internet of Things (IoT) technologies with voice interactionsusing conversational technology (Amazon Alexa). We collect 3103person-days of voice and environmental data across 14 households with PLWD to identify behavioural patterns. Interactionsinclude an automated well-being questionnaire and 10 topics ofinterest, identified using topic modelling. Although a significantdecrease in conversational technology usage was observed afterthe novelty phase across the cohort, steady state data acquisitionfor modelling was sustained. We analyse household activitysequences preceding or following Alexa interactions throughpairwise similarity and clustering methods. Our analysis demonstrates the capability to identify individual behavioural patterns,changes in those patterns and the corresponding time periods.We further report that households with PLWD continued usingAlexa following clinical events (e.g., hospitalisations), which offersa compelling opportunity for proactive health and well-beingdata gathering related to medical changes. Results demonstratethe promise of conversational AI in digital health monitoringfor ageing and dementia support and offer a basis for trackinghealth and deterioration as indicated by household activity, whichcan inform healthcare professionals and relevant stakeholdersfor timely interventions. Future work will use the bespokebehavioural patterns extracted to create more personalised AIconversations.
Parkinson M, Doherty R, Curtis F, et al., 2023, Using home monitoring technology to study the effects of traumatic brain injury in older multimorbid adults, Annals of Clinical and Translational Neurology, Vol: 10, Pages: 1688-1694, ISSN: 2328-9503
Internet of things (IOT) based in-home monitoring systems can passively collect high temporal resolution data in the community, offering valuable insight into the impact of health conditions on patients' day-to-day lives. We used this technology to monitor activity and sleep patterns in older adults recently discharged after traumatic brain injury (TBI). The demographics of TBI are changing, and it is now a leading cause of hospitalisation in older adults. However, research in this population is minimal. We present three cases, showcasing the potential of in-home monitoring systems in understanding and managing early recovery in older adults following TBI.
Crow J, Savage M, Gardner L, et al., 2023, What follow-up interventions, programmes and pathways exist for minor stroke survivors after discharge from the acute setting? A scoping review., BMJ Open, Vol: 13, Pages: 1-14, ISSN: 2044-6055
OBJECTIVE: To identify the breadth and range of follow-up interventions currently provided to people after minor stroke with a focus on the definitions used for minor stroke, intervention components, intervention theory and outcomes used. These findings will inform the development and feasibility testing of a pathway of care. DESIGN: Scoping review. SEARCH STRATEGY: The final search was run in January 2022. Five databases were searched-EMBASE, MEDLINE, CINAHL, British Nursing Index and PsycINFO. Grey literature was also searched. Title and abstract screening and full-text reviews were conducted by two researchers and a third was involved when differences of opinion existed. A bespoke data extraction template was created, refined and then completed. The Template for Intervention Description and Replication (TIDieR) checklist was used to describe interventions. RESULTS: Twenty-five studies, using a range of research methodologies were included in the review. A range of definitions were used for minor stroke. Interventions focused largely on secondary prevention and management of increased risk of further stroke. Fewer focused on the management of hidden impairments experienced after minor stroke. Limited family involvement was reported and collaboration between secondary and primary care was seldom described. The intervention components, content, duration and delivery were varied as were the outcome measures used. CONCLUSION: There is an increasing volume of research exploring how best to provide follow-up care to people after minor stroke. Personalised, holistic and theory-informed interdisciplinary follow-up is needed that balances education and support needs with adjustment to life after stroke.
Parkinson M, Dani M, Fertleman M, et al., 2023, Using home monitoring technology to study the effects of traumatic brain Injury in older multimorbid adults: protocol for a feasibility study, BMJ Open, Vol: 13, ISSN: 2044-6055
Introduction:The prevalence of Traumatic Brain Injury (TBI) among older adults is increasing exponentially. The sequelae can be severe in older adults and interacts with age-related conditions such a multimorbidity. Despite this, TBI research in older adults, is sparse. Minder, an in-home monitoring system using developed by the UK DRI Centre for Care Research and Technology, uses infra-red sensors and a bed mat to passively collect sleep and activity data. Similar systems have been used to monitor the health of older adults living with dementia. We will assess the feasibility of using this system to study changes in the health status of older adults in the early period post TBI.Methods and analysis:The study will recruit 15 inpatients (>60 years) with a moderate-severe TBI, who will have their daily activity and sleep patterns monitored using passive and wearable sensors over 6 months. Participants will report on their health during weekly calls, which will be used to validate sensor data. Physical, functional, and cognitive assessments will be conducted across the duration of the study. Activity levels and sleep patterns derived from sensor data will be calculated and visualised using activity maps. Within participant analysis will be performed to determine if participants are deviating from their own routines. We will apply machine learning approaches to activity and sleep data to assess whether these changes in these data can predict clinical events. Qualitative analysis of interviews conducted with participants, carers, and clinical staff will assess acceptability and utility of the system.Ethics and dissemination:Ethical approval for this study has been granted by the London - Camberwell St Giles Research Ethics Committee (REC number: 17/LO/2066). Results will be submitted for publication in peer review journals, presented at conferences and inform the design of a larger trial assessing recovery after TBI.
Dounavi M-E, Mak E, Swann P, et al., 2023, Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, ISSN: 0271-678X
Loreto F, Gontsarova A, Scott G, et al., 2023, Visual atrophy rating scales and amyloid PET status in an Alzheimer's disease clinical cohort, Annals of Clinical and Translational Neurology, Vol: 10, Pages: 619-631, ISSN: 2328-9503
Objectives:Visual rating scales (VRS) are the quantification method closest to the approach used in routine clinical practice to assess brain atrophy. Previous studies have suggested that the medial temporal atrophy (MTA) rating scale is a reliable diagnostic marker for AD, equivalent to volumetric quantification, while others propose a higher diagnostic utility for the Posterior Atrophy (PA) scale in early-onset AD.Methods:Here, we reviewed 14 studies that assessed the diagnostic accuracy of PA and MTA, we explored the issue of cut-off heterogeneity, and assessed 9 rating scales in a group of patients with biomarker-confirmed diagnosis. A neuroradiologist blinded to all clinical information rated the MR images of 39 amyloid-positive and 38 amyloid-negative patients using 9 validated VRS assessing multiple brain regions. Automated volumetric analyses were performed on a subset of patients (n = 48) and on a group of cognitively normal individuals (n = 28).Results:No single VRS could differentiate amyloid-positive from amyloid-negative patients with other neurodegenerative conditions. 44% of amyloid-positive patients were deemed to have age-appropriate levels of MTA. In the amyloid-positive group, 18% had no abnormal MTA or PA scores. These findings were substantially affected by cut-off selection. Amyloid-positive and amyloid-negative patients had comparable hippocampal and parietal volumes, and MTA but not PA scores correlated with the respective volumetric measures.Interpretation:Consensus guidelines are needed before VRS can be recommended for use in the diagnostic workup of AD. Our data are suggestive of high intragroup variability and non-superiority of volumetric quantification of atrophy over visual assessment.
David MCB, Kolanko M, Del Giovane M, et al., 2023, Remote monitoring of physiology in people living with dementia: an observational cohort study, JMIR Aging, Vol: 6, Pages: 1-14, ISSN: 2561-7605
BACKGROUND: Internet of Things (IoT) technology enables physiological measurements to be recorded at home from people living with dementia and monitored remotely. However, measurements from people with dementia in this context have not been previously studied. We report on the distribution of physiological measurements from 82 people with dementia over approximately 2 years. OBJECTIVE: Our objective was to characterize the physiology of people with dementia when measured in the context of their own homes. We also wanted to explore the possible use of an alerts-based system for detecting health deterioration and discuss the potential applications and limitations of this kind of system. METHODS: We performed a longitudinal community-based cohort study of people with dementia using "Minder," our IoT remote monitoring platform. All people with dementia received a blood pressure machine for systolic and diastolic blood pressure, a pulse oximeter measuring oxygen saturation and heart rate, body weight scales, and a thermometer, and were asked to use each device once a day at any time. Timings, distributions, and abnormalities in measurements were examined, including the rate of significant abnormalities ("alerts") defined by various standardized criteria. We used our own study criteria for alerts and compared them with the National Early Warning Score 2 criteria. RESULTS: A total of 82 people with dementia, with a mean age of 80.4 (SD 7.8) years, recorded 147,203 measurements over 958,000 participant-hours. The median percentage of days when any participant took any measurements (ie, any device) was 56.2% (IQR 33.2%-83.7%, range 2.3%-100%). Reassuringly, engagement of people with dementia with the system did not wane with time, reflected in there being no change in the weekly number of measurements with respect to time (1-sample t-test on slopes of linear fit, P=.45). A total of 45% of people with dementia met criteria for hypertension. People with dem
Newton C, Pope M, Rua C, et al., 2023, Path integration selectively predicts midlife risk of Alzheimer's disease., bioRxiv
The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.
Sri S, Greenstein A, Granata A, et al., 2023, A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia., Cereb Circ Cogn Behav, Vol: 5
Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.
Loreto F, Mills R, Duvnjak A, et al., 2022, ASSOCIATION BETWEEN THALAMIC ATROPHY AND DEPRESSION HISTORY IN AN ALZHEIMER'S DISEASE CLINICAL COHORT, Annual Meeting of the British-Neuropsychiatry-Association (BNPA), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Ng B, Rowland HA, Wei T, et al., 2022, Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability, BRAIN COMMUNICATIONS, Vol: 4
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Low A, Prats-Sedano MA, McKiernan E, et al., 2022, Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study, ALZHEIMERS RESEARCH & THERAPY, Vol: 14
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Low A, Prats-Sedano M, Mckiernan E, et al., 2022, SEX DIFFERENCES IN MODIFIABLE AND NON-MODIFIABLE RISK FACTORS ON MIDLIFE CEREBRAL SMALL VESSEL DISEASE: THE PREVENT-DEMENTIA STUDY, Publisher: SAGE PUBLICATIONS LTD, Pages: 27-28, ISSN: 1747-4930
Soreq E, Kolanko M, Guruswamy Ravindran KK, et al., 2022, Longitudinal assessment of sleep/wake behaviour in dementia patients living at home, Association-of-British-Neurologists (ABN) Annual Meeting, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Hoang K, Watt H, Golemme M, et al., 2022, Noradrenergic add-on therapy with extended-release guanfacine in alzheimer’s disease: study protocol for a randomised clinical trial (NorAD) and COVID-19 amendments, Trials, Vol: 23, ISSN: 1745-6215
Background:Guanfacine is a α2A adrenergic receptor agonist approved for treating Attention Deficit Hyperactivity Disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s Disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect in symptomatic AD. The primary objective of the NorAD trial is to evaluate change in cognition with 12 weeks treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s Disease.Methods/Design:NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s Disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include change in additional cognitive measures of attention (Tests of Attention: Trails A and B, Digit-symbol substitution, Test of Everyday attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020 observation of change following cessation
Dounavi M-E, Newton C, Jenkins N, et al., 2022, Macrostructural brain alterations at midlife are connected to cardiovascular and not inherited risk of future dementia: the PREVENT-Dementia study, JOURNAL OF NEUROLOGY, Vol: 269, Pages: 4299-4309, ISSN: 0340-5354
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Inglese M, Patel N, Linton-Reid K, et al., 2022, A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer's disease., Commun Med (Lond), Vol: 2
BACKGROUND: Alzheimer's disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. METHODS: We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called "Alzheimer's Predictive Vector" (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). RESULTS: The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer's related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype. CONCLUSIONS: This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.
Inglese M, Patel N, Linton-Reid K, et al., 2022, A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease, Communications Medicine, Vol: 2, ISSN: 2730-664X
Background:Alzheimer’s disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care.Methods:We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO).Results:The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer’s related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype.Conclusions:This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.
David MCB, Del Giovane M, Liu KY, et al., 2022, Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 93, Pages: 1080-1090, ISSN: 0022-3050
Background Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice.Objective To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer’s disease.Methods The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses.Results We included 19 randomised controlled trials (1811 patients), of which six were judged as ‘good’ quality, seven as ‘fair’ and six ‘poor’. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: −0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies.Discussion Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer’s disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to min
Loreto F, Fitzgerald A, Golemme M, et al., 2022, Prevalence of depressive symptoms in a memory clinic cohort: a retrospective study, Journal of Alzheimer's Disease, Vol: 88, ISSN: 1387-2877
Background Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer’s disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. Objective To examine the prevalence, features and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging.Methods We included 300 patients from a single-centre memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. Results One-hundred-and-forty-two (47%) patients had a history of significant depressive symptoms (‘D+’). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients.Conclusions Approximately half of patients who meet appropriate use criteria for amyloid PET had a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.
Olgiati E, Malhotra P, 2022, Using non-invasive transcranial direct current stimulation for neglect and associated attentional deficits following stroke, Neuropsychological Rehabilitation, Vol: 32, Pages: 732-763, ISSN: 0960-2011
Neglect is a disabling neuropsychological syndrome that is frequently observed following right-hemispheric stroke. Affected individuals often present with multiple attentional deficits, ranging from reduced orienting towards contralesional space to a generalized impairment in maintaining attention over time. Although a degree of spontaneous recovery occurs in most patients, in some individuals this condition can be treatment-resistant with prominent ongoing non-spatial deficits. Further, there is a large inter-individual variability in response to different therapeutic approaches. Given its potential to alter neuronal excitability and affect neuroplasticity, non-invasive brain stimulation is a promising tool that could potentially be utilized to facilitate recovery. However, there are many outstanding questions regarding its implementation in this heterogeneous patient group. Here we provide a critical overview of the available evidence on the use of non-invasive electrical brain stimulation, focussing on transcranial direct current stimulation (tDCS), to improve neglect and associated attentional deficits after right-hemispheric stroke. At present, there is insufficient robust evidence supporting the clinical use of tDCS to alleviate symptoms of neglect. Future research would benefit from careful study design, enhanced precision of electrical montages, multi-modal approaches exploring predictors of response, tailored dose-control applications and increased efforts to evaluate standalone tDCS versus its incorporation into combination therapy.
David M, Malhotra P, 2022, New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer’s disease, Annals of Clinical and Translational Neurology, Vol: 9, ISSN: 2328-9503
There is clear, early noradrenergic dysfunction in Alzheimer’s disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms.Despite the strong evidence of noradrenergic involvement in Alzheimer’s, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof-of-principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin-sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone.Here we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer’s disease.
Kapsetaki ME, Militaru IE, Sanguino I, et al., 2022, Type of encoded material and age modulate the relationship between episodic recall of visual perspective and autobiographical memory, Journal of Cognitive Psychology, Vol: 34, Pages: 142-159, ISSN: 2044-5911
Episodic memory enables us to form a bank of autobiographical memories across our lifespan. The relationship between autobiographical memory and laboratory-measures of episodic memory is complicated and these processes might be differentially affected by ageing (e.g. Diamond et al., [2020]. Different patterns of recollection for matched real-world and laboratory-based episodes in younger and older adults. Cognition, 202, 104309.). Here, we examine whether the ability to recall one’s own visual perspective relates to richness of autobiographical recall, and how this relationship is affected by age. Memory of perspective at encoding, was assessed in younger (18–35 years) and older adults (65–85 years). Participants, wearing head cameras, viewed arrays of objects. Later they were asked which images represented earlier scenes, and if the image was taken from their perspective (i.e. from their camera). Performance was compared with autobiographical memory. Accuracy in identifying their own perspective correlated with autobiographical scores. Age-group was a moderating factor in this relationship. Subsequently, new participants encoded photographs of objects and were later asked whether they recognised the images. Visual perspective was manipulated in these photographs. In this task there was no relationship between performance and autobiographical memory. In younger adults only 3-D encoding of scenes relates directly to autobiographical memory but ability to complete these two tasks appears to operate independently in the older group.
Crow J, Malhotra P, 2021, AN OCCUPATIONAL THERAPY LED TWO-WEEK POST MINOR STROKE TELEPHONE REVIEW WITH ONLINE COGNITIVE ASSESSMENT - WHAT DID THIS REVEAL?, Publisher: SAGE PUBLICATIONS LTD, Pages: 26-26, ISSN: 1747-4930
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