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1.  Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? 
Two methods of non-invasive brain stimulation, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrable positive effects on cognition and can ameliorate neuropsychiatric symptoms such as depression. Less is known about the efficacy of these approaches in common neurodegenerative diseases. In this review, we evaluate the effects of TMS and tDCS upon cognitive and neuropsychiatric symptoms in the major dementias, including Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and frontotemporal dementia (FTD), as well as the potential pre-dementia states of Mild Cognitive Impairment (MCI) and Parkinson’s disease (PD).
PubMed (until 7 February 2014) and PsycINFO (from 1967 to January Week 3 2014) databases were searched in a semi-systematic manner in order to identify relevant treatment studies. A total of 762 studies were identified and 32 studies (18 in the dementias and 14 in PD populations) were included.
No studies were identified in patients with PDD, FTD or VaD. Of the dementias, 13 studies were conducted in patients with AD, one in DLB, and four in MCI. A total of 16 of the 18 studies showed improvements in at least one cognitive or neuropsychiatric outcome measure. Cognitive or neuropsychiatric improvements were observed in 12 of the 14 studies conducted in patients with PD.
Both TMS and tDCS may have potential as interventions for the treatment of symptoms associated with dementia and PD. These results are promising; however, available data were limited, particularly within VaD, PDD and FTD, and major challenges exist in order to maximise the efficacy and clinical utility of both techniques. In particular, stimulation parameters vary considerably between studies and are likely to subsequently impact upon treatment efficacy.
PMCID: PMC4255638  PMID: 25478032
2.  Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study 
The British Journal of Psychiatry  2012;200(6):491-498.
Visual hallucinations and visuoperceptual deficits are common in dementia with Lewy bodies, suggesting that cortical visual function may be abnormal.
To investigate: (1) cortical visual function using functional magnetic resonance imaging (fMRI); and (2) the nature and severity of perfusion deficits in visual areas using arterial spin labelling (ASL)-MRI.
In total, 17 participants with dementia with Lewy bodies (DLB group) and 19 similarly aged controls were presented with simple visual stimuli (checkerboard, moving dots, and objects) during fMRI and subsequently underwent ASL-MRI (DLB group n = 15, control group n = 19).
Functional activations were evident in visual areas in both the DLB and control groups in response to checkerboard and objects stimuli but reduced visual area V5/MT (middle temporal) activation occurred in the DLB group in response to motion stimuli. Posterior cortical perfusion deficits occurred in the DLB group, particularly in higher visual areas.
Higher visual areas, particularly occipito-parietal, appear abnormal in dementia with Lewy bodies, while there is a preservation of function in lower visual areas (V1 and V2/3).
PMCID: PMC3365275  PMID: 22500014
3.  Covariant perfusion patterns provide clues to the origin of cognitive fluctuations and attentional dysfunction in Dementia with Lewy bodies 
International Psychogeriatrics / Ipa  2013;25(12):1917-1928.
Fluctuating cognition (FC), particularly in attention, is a core and defining symptom in dementia with Lewy bodies (DLB) but is seen much less frequently in Alzheimer's dementia (AD). However, its neurobiological origin is poorly understood. The aim of our study was therefore to characterize perfusion patterns in DLB patients that are associated with the severity and frequency of FC as measured both clinically and using objective neuropsychological assessments.
Spatial covariance analyses were applied to data derived from single photon emission computed tomography (SPECT) HMPAO brain imaging in 19 DLB and 23 AD patients. Patients underwent clinical assessment of their FC and cognitive function as well as objective testing of their attention.
Covariant perfusion principal components (PCs) were not associated with either FC or cognitive or attentional measures in AD. However, in DLB patients, the second PC (defined as DLB-cognitive motor pattern, DLB-PCI2) which was characterized by bilateral relative increases in cerebellum, basal ganglia, and supplementary motor areas and widespread bilateral decreases in parietal regions, positively correlated with poorer cognitive function, increased FC and worse attentional function measured both clinically and neurophysiologically (p < 0.05) as well as with the severity of bradykinesia (p = 0.04).
FC in DLB appears distinct from those seen in AD, and likely to be driven by internal neurobiological perturbations in brain circuitry as evidenced using spatial covariance analyses of cerebral perfusion. FC and certain aspects of attentional dysfunction in DLB may, in part, depend upon both distributed motor and non-motor networks.
PMCID: PMC3819183  PMID: 24148774
attention; Alzheimer’s disease; single photon emission computed tomography; SPECT; imaging
4.  Cholinesterase inhibitor use does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish Alzheimer's disease from dementia with Lewy bodies 
123I‐labelled 2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (123I‐FP‐CIT) imaging is a diagnostic tool to help differentiate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, in animals, cholinesterase inhibitors (ChEi) have been reported to reduce radioligand binding to the striatal dopamine transporter. As ChEi are frequently used in people with dementia, it is important to determine whether their use affects 123I‐FP‐CIT uptake in the striatum.
To clarify whether chronic ChEi therapy modulates striatal dopamine transporter binding measured by 123I‐FP‐CIT in patients with AD, DLB and Parkinson's disease with dementia (PDD).
Cross sectional study in 99 patients with AD (nine on ChEi, 25 not on ChEi), DLB (nine on ChEi, 19 not on ChEi) and PDD (six on ChEi, 31 not on ChEi) comparing 123I‐FP‐CIT striatal binding (caudate, anterior and posterior putamen) in patients receiving compared with those not receiving ChEi, correcting for key clinical variables including diagnosis, age, sex, Mini‐Mental State Examination score, severity of parkinsonism and concurrent antidepressant use.
As previously described, 123I‐FP‐CIT striatal uptake was lower in DLB and PDD subjects compared with those with AD. Median duration of ChEi use was 180 days. 123I‐FP‐CIT uptake was not significantly reduced in subjects receiving ChEi compared those not receiving ChEi (mean percentage reduction: AD 4.3%; DLB 0.7%; PDD 6.1%; p = 0.40). ChEi use did not differentially affect striatal 123FP‐CIT uptake between patient groups (p = 0.83).
Use of ChEi does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish AD from DLB.
PMCID: PMC2117542  PMID: 17299017
5.  Quantitative electroencephalogram utility in predicting conversion of mild cognitive impairment to dementia with Lewy bodies☆ 
Neurobiology of Aging  2015;36(1):434-445.
Mild cognitive impairment (MCI) as a precursor of dementia with Lewy bodies (DLB) is the focus of recent research, trying to explore the early mechanisms and possible biomarkers of DLB. Quantitative electroencephalogram (QEEG) methods are able to differentiate early DLB from Alzheimer's disease (AD). The aim of the present study was to assess whether QEEG abnormalities, characterized by dominant frequency <8 Hz and dominant frequency variability >1.5 Hz, typical of early DLB, are already present at the stage of MCI and to evaluate whether EEG abnormalities can predict the development of DLB. Forty-seven MCI subjects were followed for 3 years. EEG recordings were obtained at admission and at the end of the study. At the end of follow-up, 20 subjects had developed probable DLB (MCI-DLB), 14 had probable AD (MCI-AD), 8 did not convert to dementia, 5 developed a non-AD/DLB dementia. One hundred percent of MCI-DLB showed EEG abnormalities at admission. Ninety three percent of MCI-AD maintained a normal EEG throughout the study. QEEG may represent a powerful tool to predict the progression from MCI to DLB with a sensitivity and specificity close to 100%.
•We studied in mild cognitive impairment (MCI) subjects the predictive value of electroencephalogram (EEG) alterations for the development of dementia with Lewy bodies (DLB).•One hundred percent of MCI subjects converted to DLB already had EEG alterations typical of DLB (dominant frequency <8 Hz and dominant frequency variability ≥1.5 Hz) at admission to the study.•Quantitative EEG may represent a powerful tool to predict the progression from MCI to DLB.
PMCID: PMC4270449  PMID: 25129239
Mild cognitive impairment; Dementia with Lewy bodies; Quantitative EEG
6.  Visual hallucinations in dementia with Lewy bodies: transcranial magnetic stimulation study 
The British Journal of Psychiatry  2011;199(6):492-500.
The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism.
To determine visual cortical excitability in people with dementia with Lewy bodies compared with aged-matched controls and also the relationship between visual cortical excitability and visual hallucinations in dementia with Lewy bodies.
Visual cortical excitability was determined by using transcranial magnetic stimulation (TMS) applied to the occiput to elicit phosphenes (transient subjective visual responses) in 21 patients with dementia with Lewy bodies and 19 age-matched controls.
Phosphene parameters were similar between both groups. However, in the patients with dementia with Lewy bodies, TMS measures of visual cortical excitability correlated strongly with the severity of visual hallucinations (P = 0.005). Six patients with dementia with Lewy bodies experienced visual hallucination-like phosphenes (for example, seeing people or figures on stimulation) compared with none of the controls (P = 0.02).
Increased visual cortical excitability in dementia with Lewy bodies does not appear to explain visual hallucinations but it may be a marker for their severity.
PMCID: PMC3227808  PMID: 22016436
7.  Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life 
Parkinsonism & Related Disorders  2014;20(10):1071-1075.
Poor quality of life (QoL) is a feature of people with Parkinson's disease (PD) who develop dementia. The relationship between mild cognitive impairment in PD (PD-MCI) and QoL is less clear. To address this, we studied the impact of varying severities of cognitive impairment on QoL in a cohort of non-demented patients with early PD.
Patients with newly diagnosed PD (n = 219) and age and sex matched healthy controls (n = 99) completed a schedule of neuropsychological tests, in addition to scales assessing QoL (PDQ-39), depression, sleep, neuropsychiatric symptoms and a clinical examination. The Movement Disorder Society criteria were used to define and classify PD-MCI.
Participants with PD-MCI were significantly older than those with normal cognition, had more severe motor symptoms, scored higher for depression and had poorer quality of life. Logistic regression showed that mild cognitive impairment, independent of other factors, was an indicator of poorer QoL. Using cognitive performance 2.0 standard deviations (SD) below normative data as a cut-off to define PD-MCI, there was a significant difference in QoL scores between patients with PD-MCI and those classified as having normal cognition. Subjects with less severe mild cognitive impairment did not exhibit significant differences in QoL.
PD-MCI is a significant, independent factor contributing to poorer QoL in patients with newly diagnosed PD. Those classified with greatest impairment (2.0 SD below normal values) have lower QoL. This has implications for clinical practice and future interventions targeting cognitive impairments.
•Quality of life declines with increased severity of cognitive impairment in PD.•Mild cognitive impairment in PD (PD-MCI) independently contributes to poorer QoL.•PD-MCI at 2 standard deviations below controls had the greatest impact on QoL.•The optimal operational cut-off for PD-MCI may be 2 standard deviations.
PMCID: PMC4194347  PMID: 25074728
Parkinson's disease; Mild cognitive impairment; Quality of life
8.  Challenges for the cataract surgeon treating people with dementia: a qualitative study exploring anesthetic choices 
In light of the growing number of people with dementia and age-related cataract, as well as changing anesthetic practices for cataract surgery, this study aimed to explore the experiences of cataract surgeons in managing patients with dementia and making anesthetic decisions.
This was a qualitative study using semistructured interviews with senior cataract surgeons from two centers in England. Fourteen surgeons were interviewed, and a thematic approach informed by grounded theory was used for the analysis.
Choice of anesthesia for people with dementia was a central theme arising from the data. Surgeons varied in their thresholds for using general anesthesia. Decisions about suitability for local anesthesia were limited by time constraints and generally made rapidly and based on instinct; dementia was not always apparent at the point of preassessment. Surgeons used a variety of topical, sub-Tenon’s, and sharp needle blocks for people with dementia. Surgeons discussed techniques to help patients tolerate local anesthesia, such as clear communication, a primary nurse, hand-holding, and support from an anesthetist. However, within our sample, some surgeons had had negative experiences of operating on people with dementia, where an incorrect judgment had been made that they could tolerate local anesthetic cataract surgery.
This study highlights the differing practices of cataract surgeons when making anesthetic choices for people with dementia and the challenges they face. In order to avoid the situation of a patient with dementia becoming distressed during awake surgery, increased time at preassessment and anesthetic support may be beneficial.
PMCID: PMC4196883  PMID: 25328382
dementia; cataract extraction; anesthesiology; qualitative research
9.  The assessment of cognition in visually impaired older adults 
Age and ageing  2012;42(1):98-102.
visual and cognitive impairments are common in later life. Yet there are very few cognitive screening tests for the visually impaired.
to screen for cognitive impairment in the visually impaired.
case–control study including 150 elderly participants with visual impairment (n = 74) and a control group without visual impairment (n = 76) using vision-independent cognitive tests and cognitive screening tests (MMSE and clock drawing tests (CDT)) which are in part vision dependent.
the scoring of the two groups did not differ in the vision-independent cognitive tests. Visually impaired patients performed poorer than controls in the vision-dependent items of the MMSE (T = 7.3; df: 148; P < 0.001) and in CDT (T = 3.1; df: 145; P = 0.003). No group difference was found when vision-independent items were added to MMSE and CDT. The test score gain by the use of vision-independent items correlated with the severity of visual impairment (P < 0.002).
visually impaired patients benefit from cognitive tests, which do not rely on vision. The more visually impaired the greater the benefit.
PMCID: PMC4153986  PMID: 23108164
visual impairment; cognitive impairment; cognitive testing
10.  Advances in the treatment of visual hallucinations in neurodegenerative diseases 
Future neurology  2013;8(4):433-444.
Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any single one may be of limited efficacy. Reducing medication, with the careful introduction of antidementia medication if needed, is the mainstay of current management. Antipsychotic medication leads to excessive morbidity and mortality and should only be used in cases of high distress that do not otherwise respond. Education, reduction of risk factors and psychological treatments have limited evidence of efficacy, but are unlikely to cause harm.
PMCID: PMC3717328  PMID: 23882162
Alzheimer’s disease; amyloidopathy; Lewy body; Parkinson’s disease; synucleinopathy; tauopathy; treatment; visual hallucination
12.  Cohort study of prevalence and phenomenology of tremor in dementia with Lewy bodies 
Journal of Neurology  2013;260(7):1731-1742.
To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p < 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p < 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-013-6853-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3705145  PMID: 23400498
Dementia with Lewy bodies; Parkinson’s disease; Tremor; EMG
13.  Multivariate spatial covariance analysis of 99mTc-exametazime SPECT images in dementia with Lewy bodies and Alzheimer's disease: utility in differential diagnosis 
We examined 99mTc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F1,64=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F1,61=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD.
PMCID: PMC3618400  PMID: 23361395
Alzheimer's disease; differential diagnosis; dementia with Lewy bodies; perfusion; spatial covariance; SPECT
14.  fMRI resting state networks and their association with cognitive fluctuations in dementia with Lewy bodies 
NeuroImage : Clinical  2014;4:558-565.
Cognitive fluctuations are a core symptom in dementia with Lewy bodies (DLB) and may relate to pathological alterations in distributed brain networks. To test this we analysed resting state fMRI changes in a cohort of fluctuating DLB patients (n = 16) compared with age matched controls (n = 17) with the aim of finding functional connectivity (FC) differences between these two groups and whether these associate with cognitive fluctuations in DLB. Resting state networks (RSNs) were estimated using independent component analysis and FC between the RSN maps and the entirety of the brain was assessed using dual regression. The default mode network (DMN) appeared unaffected in DLB compared to controls but significant cluster differences between DLB and controls were found for the left fronto-parietal, temporal, and sensory–motor networks. Desynchronization of a number of cortical and subcortical areas related to the left fronto-parietal network was associated with the severity and frequency of cognitive fluctuations. Our findings provide empirical evidence for the potential role of attention–executive networks in the aetiology of this core symptom in DLB.
•We report resting state network (RSN) alterations in dementia with Lewy bodies (DLB).•The default mode network was intact in DLB compared to healthy controls (HC).•Fronto-parietal, temporal, and sensory–motor RSNs showed differences (DLB < HC).•The left fronto-parietal network (FPN) correlated with cognitive fluctuations in DLB.•The FPN therefore may be a potential marker for cognitive fluctuations in DLB.
PMCID: PMC3984441  PMID: 24818081
Cognitive fluctuations; Visual hallucinations; Resting state network; Lewy bodies; Dementia
15.  The impact of visual impairment on Mini-Mental State Examination Scores in the Newcastle 85+ study 
Age and Ageing  2012;41(4):565-568.
Background: cognitive test scores and visual acuity are strongly associated in older people. This may be due to poor vision limiting performance on cognitive tasks specifically requiring vision, or an association between visual and neurodegenerative disorders.
Objective: to explore, using data from the Newcastle 85+ cohort study, the impact of sight impairment (SI) on Mini-Mental State Examination (MMSE) scores and whether reduced scores among SI participants are limited to tasks requiring vision.
Results: of 839 participants aged 85 years, 44 (5.2%) were registered SI. Median (inter-quartile range) sMMSE scores were 25 (22–29) for SI and 28 (25–29) for non-SI participants (P = 0.006). SI participants had lower subscale scores on tasks requiring vision (P < 0.001 for each) but also for some subscale scores not obviously requiring vision: orientation (P = 0.018) and repetition (P = 0.030). Excluding visual items, there was no significant difference in MMSE scores between those with/without SI.
Conclusion: SI may be an obstacle to older people completing cognitive assessments including tasks requiring vision. People with SI also scored lower on some tasks not obviously requiring vision. An association between cognitive impairment and SI may exist beyond simply being unable to see the test material in cognitive tests.
PMCID: PMC3377132  PMID: 22431154
visually impaired persons; memory disorders; cognition; elderly
16.  Driving and dementia: a clinical decision pathway 
This study aimed to develop a pathway to bring together current UK legislation, good clinical practice and appropriate management strategies that could be applied across a range of healthcare settings.
The pathway was constructed by a multidisciplinary clinical team based in a busy Memory Assessment Service. A process of successive iteration was used to develop the pathway, with input and refinement provided via survey and small group meetings with individuals from a wide range of regional clinical networks and diverse clinical backgrounds as well as discussion with mobility centres and Forum of Mobility Centres, UK.
We present a succinct clinical pathway for patients with dementia, which provides a decision-making framework for how health professionals across a range of disciplines deal with patients with dementia who drive.
By integrating the latest guidance from diverse roles within older people's health services and key experts in the field, the resulting pathway reflects up-to-date policy and encompasses differing perspectives and good practice. It is potentially a generalisable pathway that can be easily adaptable for use internationally, by replacing UK legislation for local regulations. A limitation of this pathway is that it does not address the concern of mild cognitive impairment and how this condition relates to driving safety. © 2014 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.
PMCID: PMC4305213  PMID: 24865643
driving; dementia; pathway; ageing

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