94 results found
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
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, ISSN: 0022-3050
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.
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
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., . 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
Fitzgerald A, Loreto F, Golemme M, et 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
Loreto F, Gunning S, Golemme M, et al., 2021, COGNITIVE PERFORMANCE AND AFFECTIVE SYMPTOMS IN PATIENTS UNDERGOING CLINICAL AMYLOID PET IMAGING, British Neuropsychiatry Annual Meeting, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Mallon DH, Malhotra P, Naik M, et 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
Loreto F, Gunning S, Golemme M, et 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.
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.
Frost E, Porat T, Malhotra P, et 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.
Patel NH, Perry L, Lilja J, et 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
Kolanko M, Win Z, Patel N, et 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.
Li K, Bentley P, Nair A, et al., 2020, Reward sensitivity predicts dopaminergic response in spatial neglect, Cortex, Vol: 122, Pages: 213-224, ISSN: 0010-9452
It has recently been revealed that spatial neglect can be modulated by motivational factors including anticipated monetary reward. A number of dopaminergic agents have been evaluated as treatments for neglect, but the results have been mixed, with no clear anatomical or cognitive predictors of dopaminergic responsiveness. Given that the effects of incentive motivation are mediated by dopaminergic pathways that are variably damaged in stroke, we tested the hypothesis that the modulatory influences of reward and dopaminergic drugs on neglect are themselves related.We employed a single-dose, double-blind, crossover design to compare the effects of Co-careldopa and placebo on a modified visual cancellation task in patients with neglect secondary to right hemisphere stroke. Whilst confirming that reward improved visual search in this group, we showed that dopaminergic stimulation only enhances visual search in the absence of reward. When patients were divided into REWARD-RESPONDERs and REWARD-NON-RESPONDERs, we found an interaction, such that only REWARD-NON-RESPONDERs showed a positive response to reward after receiving Co-careldopa, whereas REWARD-RESPONDERs were not influenced by drug. At a neuroanatomical level, responsiveness to incentive motivation was most associated with intact dorsal striatum.These findings suggest that dopaminergic modulation of neglect follows an ‘inverted U’ function, is dependent on integrity of the reward system, and can be measured as a behavioural response to anticipated reward.
Malhotra P, 2019, Impairments of attention in Alzheimer’s disease, Current Opinion in Psychology, Vol: 29, Pages: 41-48, ISSN: 2352-250X
Alzheimer’s Disease (AD) is characteristically perceived as primarily being a disorder of episodic memory, with prominent attentional impairments more typically being associated with other neurodegenerative conditions, such as Dementia with Lewy Bodies. However, attention is also affected early on in Alzheimer’s, particularly in individuals with young onset and atypical syndromes. In addition, some initial symptoms that are apparently due to episodic memory loss may be secondary to failures of attentional processes.This review describes the various attentional impairments that can be observed in patients with AD, and addresses them through the conceptual framework of attention proposed by Posner and Petersen. It also explains how current knowledge of the development of AD has influenced our understanding of how these deficits arise. Finally, there is a brief summary of the effects of current AD treatments on attentional deficits, and how future pharmacological approaches might better target these deficits.
Fakhry-Darian D, Patel NH, Khan S, et al., 2019, Optimisation and usefulness of quantitative analysis of 18F-florbetapir PET, British Journal of Radiology, Vol: 92, ISSN: 0007-1285
OBJECTIVES: This study investigates the usefulness of quantitative SUVR thresholds on sub types of typical (type A) and atypical (non-type A) positive (Aβ+) and negative (Aβ-) 18F-florbetapir scans and aims to optimise the thresholds. METHODS: Clinical 18F-florbetapir scans (n = 100) were categorised by sub type and visual reads were performed independently by three trained readers. Inter-reader agreement and reader-to-reference agreement were measured. Optimal SUVR thresholds were derived by ROC analysis and were compared with thresholds derived from a healthy control group and values from published literature. RESULTS: Sub type division of 18F-florbetapir PET scans improves accuracy and agreement of visual reads for type A: accuracy 90%, 96% and 70% and agreement κ > 0.7, κ ≥ 0.85 and -0.1 < κ < 0.9 for all data, type A and non-type A respectively. Sub type division also improves quantitative classification accuracy of type A: optimum mcSUVR thresholds were found to be 1.32, 1.18 and 1.48 with accuracy 86%, 92% and 76% for all data, type A and non-type A respectively. CONCLUSIONS: Aβ+/Aβ- mcSUVR threshold of 1.18 is suitable for classification of type A studies (sensitivity = 97%, specificity = 88%). Region-wise SUVR thresholds may improve classification accuracy in non-type A studies. Amyloid PET scans should be divided by sub type before quantification. ADVANCES IN KNOWLEDGE: We have derived and validated mcSUVR thresholds for Aβ+/Aβ- 18F-florbetapir studies. This work demonstrates that division into sub types improves reader accuracy and agreement and quantification accuracy in scans with typical presentation and highlights the atypical presentations not suited to global SUVR quantification.
Dumba M, Khan S, Patel N, et al., 2019, Clinical 18F-FDG and amyloid brain positron emission tomography/CT in the investigation of cognitive impairment: where are we now?, British Journal of Radiology, Vol: 92, ISSN: 0007-1285
The number of people living with dementia is increasing, but as yet there remains no cure or disease-modifying treatment. This review aims to help readers understand the role of 18F-FDG PET/CT imaging in the investigation of cognitive impairment and how the advent of amyloid PET/CT imaging may hold the key to radically changing management of the most common form of dementia - Alzheimer's disease. The indications for 18F-FDG PET/CT and amyloid PET/CT imaging in cognitive impairment are outlined. Additionally, the mechanisms of action, technique, patient preparation and acquisition parameters for both are detailed. We conclude by providing a framework for interpreting 18F-FDG PET/CT and amyloid PET/CT imaging in the more common conditions that lead to cognitive impairment conditions with tips on avoiding pitfalls in interpretation.
Curry S, Patel N, Fakhry-Darian D, et al., 2019, Quantitative evaluation of beta-amyloid brain PET imaging in dementia: a comparison between two commercial software packages and the clinical report, British Journal of Radiology, Vol: 92, ISSN: 0007-1285
OBJECTIVE: To compare commercially available image analysis tools Hermes BRASS and Siemens Syngo.VIA with clinical assessment in 18F-Florbetapir PET scans. METHODS: 225 scans were reported by clinicians and quantified using two software packages. Scans were classified into Type A (typical features) or non-Type A (atypical features) for both positive and negative scans. For BRASS, scans with z-score ≥ 2 in 2 ≥ region of interest were classed positive. For Syngo.VIA a positive scan was indicated when mean cortical standardized uptake value ratio (mcSUVR) ≥ 1.17. RESULTS: 81% scans were Type A, and 19% scans were non-Type A. The sensitivity of BRASS and Syngo.VIA for Type A scans was 98.8 and 96.3%, specificity was 73 and 92%, respectively. Sensitivity for non-Type A scans was 95.8 and 79.2%, specificity was 36.8 and 57.9%, respectively. A third threshold of identifiable levels of plaque (1.08 ≤ mcSUVR ≤ 1.17) was recommended for Syngo.VIA to increase detection of false negative scans. The false positive rate of BRASS significantly decreased when an alternative positive threshold value of mcSUVR ≥ 1.18. Introduction of alternative criteria did not improve prediction outcome for non-Type A scans. More complex solutions are recommended. CONCLUSION: Hermes criteria for a positive scan leads to a high sensitivity but a low specificity. Siemens Syngo.VIA criteria gives a high sensitivity and specificity and agrees better with the clinical report. Alternative thresholds and classifications may help to improve agreement with the clinical report. ADVANCES IN KNOWLEDGE: Software packages may assist with clinical reporting of more difficult to interpret cases that require a more experienced read.
Koychev I, Lawson J, Chessell T, et al., 2019, Deep and frequent phenotyping study protocol: an observational study in prodromal Alzheimer's disease., BMJ Open, Vol: 9, ISSN: 2044-6055
INTRODUCTION: Recent failures of potential novel therapeutics for Alzheimer's disease (AD) have prompted a drive towards clinical studies in prodromal or preclinical states. However, carrying out clinical trials in early disease stages is extremely challenging-a key reason being the unfeasibility of using classical outcome measures of dementia trials (eg, conversion to dementia) and the lack of validated surrogate measures so early in the disease process. The Deep and Frequent Phenotyping (DFP) study aims to resolve this issue by identifying a set of markers acting as indicators of disease progression in the prodromal phase of disease that could be used as indicative outcome measures in proof-of-concept trials. METHODS AND ANALYSIS: The DFP study is a repeated measures observational study where participants will be recruited through existing parent cohorts, research interested lists/databases, advertisements and memory clinics. Repeated measures of both established (cognition, positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) markers of pathology, structural MRI markers of neurodegeneration) and experimental modalities (functional MRI, magnetoencephalography and/or electroencephalography, gait measurement, ophthalmological and continuous smartphone-based cognitive and other assessments together with experimental CSF, blood, tear and saliva biomarkers) will be performed. We will be recruiting male and female participants aged >60 years with prodromal AD, defined as absence of dementia but with evidence of cognitive impairment together with AD pathology as assessed using PET imaging or CSF biomarkers. Control participants without evidence of AD pathology will be included at a 1:4 ratio. ETHICS AND DISSEMINATION: The study gained favourable ethical opinion from the South Central-Oxford B NHS Research Ethics Committee (REC reference 17/SC/0315; approved on 18 August 2017; amendment 13 February 2018). Data will be shared with the scientific commu
Dahdaleh S, Malhotra P, 2019, Treatment of central nervous system complications of renal dialysis and transplantation, Current Treatment Options in Neurology, Vol: 21, ISSN: 1092-8480
Purpose of reviewMost clinical neurologists will have come across individuals receiving renal replacement therapy who have developed a neurological complication, and neurologists working in, or close to, hospitals with a Renal Unit will be very aware of the range of central nervous system (CNS) complications that may develop in these patients. These can often be difficult to differentiate from disorders relating to renal failure or systemic conditions leading to kidney disease and can in fact arise from the interaction between underlying disease and the side effects of treatment. Patients with renal disease frequently have multiple comorbidities, and it is necessary to take a generally inclusive approach to diagnosis and treatment.Recent findingsUnfortunately, there is a lack of specific high-quality evidence for a number of CNS complications of renal replacement therapy. Here, we review the major CNS complications of dialysis and transplantation, discussing evidence for treatments where available and detailing standard management approaches where evidence is scarce.SummaryGiven the lack of specific evidence for interventions in the treatment of CNS complications of renal replacement therapy, it is often necessary to take an individualised approach based on comorbidities and applying findings from the general population. In these complex patients, we must stress the importance of collaborative working between neurologists and renal physicians when treating this complex patient group.
Russell C, Davies S, Li K, et al., 2019, Self-perspective in episodic memory after parietal damage and in healthy ageing, Neuropsychologia, Vol: 124, Pages: 171-181, ISSN: 0028-3932
Although there is strong support from functional imaging studies for lateral parietal lobe involvement in episodic memory, patients with damage to these regions do not appear to suffer from severe deficits in this cognitive domain. As such there has been no definitive explanation of this area's precise involvement. Here, we hypothesised that parietal regions play a crucial role in episodic memory - specifically in recollecting details from an egocentric perspective. In order to test this hypothesis systematically, we designed a novel experimental task utilising a head-mounted camera to record images from the participant's perspective, enabling us to evaluate the integrity of memory from the individual's own point of view. In the first study we examined patients with parietal damage and in a second study, using fMRI, we examined young and older healthy participants. Right-hemisphere patients with parietal damage were able to recall information accurately when recollecting what items had been present and where these items had been. However, patients were significantly impaired when attempting to judge from which perspective they had viewed the scenes. Critically, the patient group showed no evidence of impairment on standard tests of episodic and working memory. Examination of healthy participants in the second study utilised multi-voxel pattern analysis on neural activity during the recognition phase of a similar task. This revealed sensitivity to be highest around the angular gyrus of the lateral parietal cortex for our critical comparison - that is, when viewing stimuli that were the same as their egocentric view during encoding versus the identical scene but presented from an alternative angle. Our results provide important evidence that parietal cortex is directly involved in egocentric spatial perspective aspects of episodic memory and demonstrate for the first time a specific deficit in episodic memory in patients with right parietal damage.
Koychev I, Galna B, Zetterberg H, et al., 2019, A beta 42/A beta 40 and A beta 42/A beta 38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study (vol 65, pg 1377, 2018), JOURNAL OF ALZHEIMERS DISEASE, Vol: 72, Pages: 359-359, ISSN: 1387-2877
Venkataraman A, Perry R, Malhotra P, 2018, Young Onset Dementia
Carswell C, Malhotra P, 2018, Rapidly Progressive Dementia, Reference Module in Neuroscience and Biobehavioral Psychology, Editors: Husain
Rapidly Progressive Dementia describes those patients with a Major Neurocognitive Disorder (DSM V) which progresses over a period of weeks or months and occasionally over days. In addition to the diseases which cause more insidious cognitive impairment, a number of pathological processes can lead to much more rapid decline. As a number of these conditions are potentially treatable, rapid and accurate diagnosis is critical. There have been a number of recent diagnostic advances in the field, especially in relation to prion disease and autoimmune encephalitis. Brain biopsy may still need to be considered in some cases, particularly where there is cerebrospinal fluid pleocytosis.
Kolanko MA, Malhotra PA, 2018, Exploring Alzheimer's disease subtypes at the prodromal stage, Brain, Vol: 141, Pages: 3285-3287, ISSN: 1460-2156
This scientific commentary refers to ‘Atrophy subtypes in prodromal Alzheimer’s disease are associated with cognitive decline', by ten Kate et al. (doi:10.1093/brain/awy264).
Koychev I, Galna B, Zetterberg H, et al., 2018, A beta(42)/A beta(40) and A beta(42)/A beta(38 ) ratios are associated with measures of gait variability and activities of daily living in mild Alzheimer's disease: a pilot study, Journal of Alzheimer's Disease, Vol: 65, Pages: 1377-1383, ISSN: 1387-2877
Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.
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