Imperial College London

ProfessorPareshMalhotra

Faculty of MedicineDepartment of Brain Sciences

Professor of Clinical Neurology
 
 
 
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Contact

 

+44 (0)20 3313 5525p.malhotra

 
 
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Location

 

Lab BlockCharing Cross Campus

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Summary

 

Publications

Publication Type
Year
to

107 results found

Parkinson ME, Doherty R, Curtis F, Soreq E, Lai HHL, Serban A-I, Dani M, Fertleman M, Barnaghi P, Sharp DJ, UK Dementia Research Institute Care Research & Technology Research Group, Li LMet al., 2023, Using home monitoring technology to study the effects of traumatic brain injury in older multimorbid adults., Ann Clin Transl Neurol

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.

Journal article

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, 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.

Journal article

Crow J, Savage M, Gardner L, Hughes C, Corbett C, Wells M, Malhotra Pet 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.

Journal article

Parkinson M, Dani M, Fertleman M, Soreq E, Barnaghi P, Sharp D, Li LMet 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.

Journal article

Dounavi M-E, Mak E, Swann P, Low A, Muniz-Terrera G, McKeever A, Pope M, Williams GB, Wells K, Lawlor B, Naci L, Malhotra P, Mackay C, Koychev I, Ritchie K, Su L, Ritchie CW, O'Brien JTet al., 2023, Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife., J Cereb Blood Flow Metab

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.

Journal article

Loreto F, Gontsarova A, Scott G, Patel N, Win Z, Carswell C, Perry R, Malhotra Pet 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.

Journal article

David MCB, Kolanko M, Del Giovane M, Lai H, True J, Beal E, Li LM, Nilforooshan R, Barnaghi P, Malhotra PA, Rostill H, Wingfield D, Wilson D, Daniels S, Sharp DJ, Scott Get 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

Journal article

Newton C, Pope M, Rua C, Henson R, Ji Z, Burgess N, Rodgers CT, Stangl M, Dounavi M-E, Castegnaro A, Koychev I, Malhotra P, Wolbers T, Ritchie K, Ritchie CW, O'Brien J, Su L, Chan D, PREVENT Dementia Research Programmeet 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.

Journal article

Ng B, Rowland HA, Wei T, Arunasalam K, Hayes EM, Koychev I, Hedegaard A, Ribe EM, Chan D, Chessell T, Ffytche D, Gunn RN, Kocagoncu E, Lawson J, Malhotra PA, Ridha BH, Rowe JB, Thomas AJ, Zamboni G, Buckley NJ, Cader ZM, Lovestone S, Wade-Martins Ret al., 2022, Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability, BRAIN COMMUNICATIONS, Vol: 4

Journal article

Low A, Prats-Sedano MA, McKiernan E, Carter SF, Stefaniak JD, Nannoni S, Su L, Dounavi M-E, Muniz-Terrera G, Ritchie K, Lawlor B, Naci L, Malhotra P, Mackay C, Koychev I, Ritchie CW, Markus HS, O'Brien JTet 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

Journal article

Low A, Prats-Sedano M, Mckiernan E, Carter S, Stefaniak J, Nannoni S, Su L, Dounavi M-E, Muniz-Terrera G, Ritchie K, Lawlor B, Naci L, Malhotra P, Mackay C, Koychev I, Ritchie C, Markus H, O'Brien Jet 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

Conference paper

Soreq E, Kolanko M, Guruswamy Ravindran KK, Monica CD, Revell V, Lai H, Barnaghi P, Malhotra P, Dijk D-J, Sharp Det 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

Conference paper

Hoang K, Watt H, Golemme M, Perry R, Ritchie C, Wilson D, Pickett J, Fox C, Howard R, Malhotra Pet 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

Journal article

Inglese M, Patel N, Linton-Reid K, Loreto F, Win Z, Perry RJ, Carswell C, Grech-Sollars M, Crum WR, Lu H, Malhotra PA, Alzheimers Disease Neuroimaging Initiative, Aboagye EOet 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.

Journal article

Inglese M, Patel N, Linton-Reid K, Loreto F, Win Z, Perry R, Carswell C, Grech-Sollars M, Crum WR, Lu H, Malhotra PA, Aboagye Eet 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.

Journal article

David MCB, Del Giovane M, Liu KY, Gostick B, Rowe JB, Oboh I, Howard R, Malhotra PAet 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

Journal article

Loreto F, Fitzgerald A, Golemme M, Gunning S, Win Z, Patel N, Carswell C, Perry R, Kennedy A, Edison P, Malhotra Pet 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.

Journal article

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.

Journal article

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.

Journal article

Dounavi M-E, Newton C, Jenkins N, Mak E, Low A, Muniz-Terrera G, Williams GB, Lawlor B, Naci L, Malhotra P, Mackay CE, Koychev I, Ritchie K, Ritchie CW, Su L, O'Brien JTet 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

Journal article

Kapsetaki ME, Militaru IE, Sanguino I, Boccanera M, Zaara N, Zaman A, Loreto F, Malhotra PA, Russell Cet 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.

Journal article

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

Conference paper

Fitzgerald A, Loreto F, Golemme M, Win Z, Patel N, Carswell C, Perry R, Malhotra Pet al., 2021, HIGH PREVALENCE OF LIFETIME DEPRESSIVE SYMPTOMS IN PATIENTS REFERRED FOR CLINICAL AMYLOID-PET: A RETROSPECTIVE STUDY, British Neuropsychiatry Annual Meeting, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050

Conference paper

Loreto F, Gunning S, Golemme M, Watt H, Patel N, Win Z, Carswell C, Perry R, Malhotra Pet al., 2021, COGNITIVE PERFORMANCE AND AFFECTIVE SYMPTOMS IN PATIENTS UNDERGOING CLINICAL AMYLOID PET IMAGING, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 92, ISSN: 0022-3050

Journal article

Mallon DH, Malhotra P, Naik M, Edison P, Perry R, Carswell C, Win Zet al., 2021, The role of amyloid PET in patient selection for extra-ventricular shunt insertion for the treatment of idiopathic normal pressure hydrocephalus: A pooled analysis, JOURNAL OF CLINICAL NEUROSCIENCE, Vol: 90, Pages: 325-331, ISSN: 0967-5868

Journal article

Loreto F, Gunning S, Golemme M, Watt H, Patel N, Win Z, Carswell C, Perry R, Malhotra Pet al., 2021, Evaluating cognitive profiles of patients undergoing clinical Amyloid-PET Imaging, Brain Communications, Vol: 3, Pages: 1-12, ISSN: 2632-1297

Episodic memory impairment and brain amyloid-beta (Aβ) are two of the main hallmarks of Alzheimer’s Disease (AD). In patients with suspected AD, these are often evaluated through neuropsychological testing and amyloid PET imaging (API), respectively. Crucially, the use of amyloid PET in clinical practice is only indicated in patients with substantial diagnostic uncertainty due to atypical clinical presentation, multiple comorbidities and/or early age of onset. The relationship between Aβ and cognition has been previously investigated, but no study has examined how neuropsychological features relate to the presence of amyloid pathology in the clinical population meeting the appropriate use criteria for API.In this study, we evaluated a clinical cohort of patients (n=107) who presented at the Imperial Memory Clinic and were referred for clinical API and neuropsychological assessment as part of their diagnostic workup. We compared the cognitive performance of amyloid-positive patients (Aβ-pos, n=47) with that of stable amyloid-negative (stableAβ-neg, n=26) and progressive amyloid-negative (progAβ-neg, n=34) patients.The Aβ-pos group performed significantly worse than both the amyloid- negative groups in the visuospatial and working memory domains. Episodic memory performance, instead, effectively differentiated the Aβ-pos group from the stableAβ-neg but not the progAβ-neg group. On affective questionnaires, the stableAβ-neg group reported significantly higher levels of depression than the Aβ-pos group.In our clinical cohort, visuospatial dysfunction and working memory impairment were better indicators of amyloid positivity than episodic memory dysfunction. These findings highlight the limited value of isolated cognitive scores in patients with atypical clinical presentation, comorbidities and/or early age of onset.

Journal article

Kolanko M, Loreto F, Win Z, Patel N, Perry R, Carswell C, Gontsarova A, Malhotra Pet al., 2020, Amyloid PET imaging in clinical practice, Practical Neurology, Vol: 20, Pages: 451-462, ISSN: 1474-7766

The introduction of Amyloid PET imaging enables in vivo detection of brain beta-amyloid deposition, one of the neuropathological hallmarks of Alzheimer disease. There is increasing evidence in support of the clinical utility of Amyloid PET with major studies demonstrating that Amyloid PET improves diagnostic accuracy, increases diagnostic certainty, and results in therapeutic changes. Appropriate use criteria have been developed by the Amyloid Imaging Taskforce (AIT), to guide clinicians by predefining certain scenarios in which amyloid PET would be justified.In this review we aim to provide a practical guide on how and when to use Amyloid PET based on the available research and our own experience. We discuss three main appropriate indications for Amyloid PET and illustrate with them with clinical cases. We stress the importance of a multidisciplinary approach when deciding which patients would benefit from Amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in interpretation.

Journal article

Frost E, Porat T, Malhotra P, Picinali Let al., 2020, Collaborative design of a gamified application for auditory-cognitive training, JMIR Human Factors, Vol: 7, ISSN: 2292-9495

Background:Multiple gaming applications under the dementia umbrella for skills such as navigation exist, but there has yet to be an application designed specifically to investigate the role hearing loss may have in the process of cognitive decline. There is a demonstrable gap in utilising serious games to further the knowledge of the potential relationship between hearing loss and dementia.Objective:The aim of this study was to identify the needs, facilitators and barriers in designing a novel auditory-cognitive training gaming application.Methods:A participatory design approach was used to engage key stakeholders across audiology and cognitive disorders specialisms. Two rounds, including paired semi-structured interviews and focus groups were completed and thematically analysed.Results:18 stakeholders participated in total and 6 themes were identified to inform the next stage of the application’s development.Conclusions:The findings can now be implemented into the development of the beta-version of the application. The application will be evaluated against outcome measures of speech listening in noise, cognitive and attentional tasks, quality of life and usability.

Journal article

Patel NH, Perry L, Lilja J, Golemme M, McMeekin H, Alves L, Nijran KS, Malhotra P, Perry RJ, Win Zet al., 2020, Quantification of 18F-Florbetaben amyloid PET images in patients with Alzheimer's disease, 33rd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S166-S166, ISSN: 1619-7070

Conference paper

Kolanko M, Win Z, Patel N, Malik O, Carswell C, Gontsarova A, Nicholas R, Perry R, Malhotra Pet al., 2020, Using Amyloid PET imaging to diagnose Alzheimer’s disease in patients with Multiple Sclerosis, Journal of Neurology, Vol: 267, Pages: 3268-3273, ISSN: 0340-5354

BackgroundCognitive dysfunction affects 40–60% of individuals with multiple sclerosis (MS). The neuropsychological profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer’s disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis, especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET demonstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia.MethodsHere, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with 18F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team.ResultsTwo patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification of another potential cause of worsening cognitive impairment.ConclusionsThe experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.

Journal article

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