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1.  Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials 
BMJ Open  2014;4(7):e005122.
Objectives
To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane (123I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies.
Design
Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA).
Setting
Multicentre, open-label, non-randomised.
Participants
Patients with either a movement disorder or dementia, and healthy volunteers.
Interventions
Ioflupane (123I) was administered.
Outcome measures
Images were assessed by panels of 3–5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity.
Results
Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane (123I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%).
Conclusions
In this pooled analysis, the visual assessment of ioflupane (123I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane (123I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia.
Trial registration number
NCT00209456.
doi:10.1136/bmjopen-2014-005122
PMCID: PMC4091455  PMID: 24993764
2.  Memory Decline in Down Syndrome and Its Relationship to iPF2alpha, a Urinary Marker of Oxidative Stress 
PLoS ONE  2014;9(6):e97709.
Background
Lipid peroxidation may be a marker of free-radical-mediated injury associated with Alzheimer’s disease (AD). We aimed to investigate whether changes in lipid peroxidation is associated with cognitive decline in individuals with Down syndrome over a 4-year period.
Methods
Thirty-two adults with DS participated in a longitudinal study with urinary isoprostane 8,12-iso-iPF2alpha (iPF2alpha) assays at baseline and four years follow-up. Informants rated their functional ability and memory function and the adults with DS attempted assessments of language skills and memory. Twenty-six individuals completed assessments of memory (Modified Memory Object Task, MOMT), adaptive behavior (ABAS), and receptive vocabulary (British Picture vocabulary, BPVS) at both time-points.
Results
Overall change in iPF2alpha level was negatively correlated with change in the MOMT score (Spearman’s Rho = −0.576, p = 0.006), i.e., increased lipid peroxidation was correlated with worse memory functioning over time. An increase of ≥0.02 ng/mg creatinine iPF2α had good sensitivity (85.7%), positive predictive value (75%,), specificity (85.7%) and negative predictive value (92.3%) for memory decline.
Conclusion
Change in iPF2alpha over time may have potential as a biomarker for memory decline in Down syndrome and potentially also help to track progression of MCI to AD in the general population.
doi:10.1371/journal.pone.0097709
PMCID: PMC4046955  PMID: 24901945
3.  A complex multimodal activity intervention to reduce the risk of dementia in mild cognitive impairment–ThinkingFit: pilot and feasibility study for a randomized controlled trial 
BMC Psychiatry  2014;14:129.
Background
Dementia affects 35 million people worldwide and is currently incurable. Many cases may be preventable because regular participation in physical, mental and social leisure activities during middle age is associated with up to 47% dementia risk reduction. However, the majority of middle-aged adults are not active enough. MCI is therefore a clear target for activity interventions aimed at reducing dementia risk. An active lifestyle during middle age reduces dementia risk but it remains to be determined if increased activity reduces dementia risk when MCI is already evident. Before this can be investigated conclusively, complex multimodal activity programmes are required that (1) combine multiple health promoting activities, (2) engage people with MCI, and (3) result in sufficient adherence rates.
Methods
We designed the ThinkingFit programme to engage people with MCI in a complex intervention comprised of three activity components: physical activity, group-based cognitive stimulation (GCST) and individual cognitive stimulation (ICST). Engagement and adherence was promoted by applying specific psychological techniques to enhance behavioural flexibility in an early pre-phase and during the course of the intervention. To pilot the intervention, participants served as their own controls during a 6- to 12-week run-in period, which was followed by 12 weeks of activity intervention.
Results
Out of 212 MCI patients screened, 163 were eligible, 70 consented and 67 completed the intervention (mean age 74 years). Activity adherence rates were high: physical activity = 71%; GCST = 83%; ICST = 67%. Significant treatment effects (p < .05) were evident on physical health outcomes (decreased BMI and systolic blood pressure, [pre/post values of 26.3/25.9 kg/m2 and 145/136 mmHg respectively]), fitness (decreased resting and recovery heart rate [68/65 bpm and 75/69 bpm]), and cognition (improved working memory [5.3/6.3 items]).
Conclusions
We found satisfactory recruitment, retention and engagement rates, coupled with significant treatment effects in elderly MCI patients. It appears feasible to conduct randomized controlled trials of the dementia prevention potential of complex multimodal activity programmes like ThinkingFit.
Trial registration
ClinicalTrials.gov registration nr: NCT01603862; date: 17/5/2012.
doi:10.1186/1471-244X-14-129
PMCID: PMC4037760  PMID: 24886353
Mild cognitive impairment; Alzheimer’s dementia; Dementia prevention; Complex activity intervention; Physical activity; Cognitive stimulation; Social stimulation
4.  Microglia, Amyloid, and Glucose Metabolism in Parkinson's Disease with and without Dementia 
Neuropsychopharmacology  2013;38(6):938-949.
[11C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [11C]PIB-PET is a marker of amyloid, while [18F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [11C](R)PK11195, [18F]FDG, and [11C]PIB PET scans. Parametric maps of [11C](R)PK11195 binding potential, rCMRGlc, and [11C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [11C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression.
doi:10.1038/npp.2012.255
PMCID: PMC3629382  PMID: 23303049
Amyloid; Cognition; glucose metabolism; Imaging; Clinical or Preclinical; Microglia; Movement Disorders; Neurology; Parkinson's disease; Parkinson's disease dementia; PK11195; amyloid; microglia; Parkinson's disease; Parkinson's disease dementia; glucose metabolism
5.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Objectives
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
Design
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Setting
Patients were recruited from 40 European centres.
Participants
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
Results
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
Conclusions
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
doi:10.1136/bmjopen-2011-000380
PMCID: PMC3330257  PMID: 22318660
6.  Dementia with Lewy bodies: a comparison of clinical diagnosis, FP‐CIT single photon emission computed tomography imaging and autopsy 
Background
Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone.
Methods
A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]‐2beta‐carbometoxy‐3beta‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (FP‐CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls.
Results
Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP‐CIT scan for the diagnosis of DLB was 88% and specificity was 100%.
Conclusion
FP‐CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.
doi:10.1136/jnnp.2006.110122
PMCID: PMC2117602  PMID: 17353255
7.  Abuse of people with dementia by family carers: representative cross sectional survey 
Objective To determine the prevalence of abusive behaviours by family carers of people with dementia.
Design Representative cross sectional survey
Setting Community mental health teams in Essex and London.
Participants 220 family carers of people newly referred to secondary psychiatric services with dementia who were living at home.
Main outcome measure Psychological and physical abuse (revised modified conflict tactics scale).
Results 115 (52%, 95% confidence interval 46% to 59%) carers reported some abusive behaviour and 74 (34%, 27% to 40%) reported important levels of abuse. Verbal abuse was most commonly reported. Only three (1.4%) carers reported occasional physical abuse.
Conclusions Abusive behaviour by family carers towards people with dementia is common, with a third reporting important levels of abuse and half some abusive behaviour. We found few cases of physical or frequent abuse, although those with the most abusive behaviour may have been reluctant to report it.
doi:10.1136/bmj.b155
PMCID: PMC2769065  PMID: 19164392
8.  Do cerebral white matter lesions influence the rate of progression from mild cognitive impairment to dementia? 
Background: Cerebral white matter lesions (WML), evident on CT and MRI brain scans, are histopathologically heterogeneous but associated with vascular risk factors and thought mainly to indicate ischemic damage. There has been disagreement over their clinical prognostic value in predicting conversion from mild cognitive impairment (MCI) to dementia.
Methods: We scrutinised and rated CT and MRI brain scans for degree of WML in a memory clinic cohort of 129 patients with at least 1 year of follow-up. We examined the relationship between WML severity and time until conversion to dementia for all MCI patients and for amnestic (aMCI) and non-amnestic (naMCI) subgroups separately.
Results: Five-year outcome data were available for 87 (67%) of the 129 patients. The proportion of patients converting to dementia was 25% at 1 year and 76% at 5 years. Patients with aMCI converted to dementia significantly earlier than those with naMCI. WML severity was not associated with time to conversion to dementia for either MCI patients in general or aMCI patients in particular. Among naMCI patients, there was a tendency for those with a low degree of WML to survive without dementia for longer than those with a high degree of WML. However, this was not statistically significant.
Conclusions: MCI subtype is a significant independent predictor of conversion to dementia, with aMCI patients having higher risk than naMCI for conversion throughout the 5-year follow-up period. WML severity does not influence conversion to dementia for aMCI but might accelerate progression in naMCI.
doi:10.1017/S1041610212000932
PMCID: PMC3518278  PMID: 22874528
survival analysis; conversion; amnestic; non-amnestic; white matter lesions; dementia; Alzheimer's disease; cerebrovascular disease
9.  Cost effectiveness of a manual based coping strategy programme in promoting the mental health of family carers of people with dementia (the START (STrAtegies for RelaTives) study): a pragmatic randomised controlled trial 
Objective To assess whether the START (STrAtegies for RelatTives) intervention added to treatment as usual is cost effective compared with usual treatment alone.
Design Cost effectiveness analysis nested within a pragmatic randomised controlled trial.
Setting Three mental health and one neurological outpatient dementia service in London and Essex, UK.
Participants Family carers of people with dementia.
Intervention Eight session, manual based, coping intervention delivered by supervised psychology graduates to family carers of people with dementia added to usual treatment, compared with usual treatment alone.
Primary outcome measures Costs measured from a health and social care perspective were analysed alongside the Hospital Anxiety and Depression Scale total score (HADS-T) of affective symptoms and quality adjusted life years (QALYs) in cost effectiveness analyses over eight months from baseline.
Results Of the 260 participants recruited to the study, 173 were randomised to the START intervention, and 87 to usual treatment alone. Mean HADS-T scores were lower in the intervention group than the usual treatment group over the 8 month evaluation period (mean difference −1.79 (95% CI −3.32 to −0.33)), indicating better outcomes associated with the START intervention. There was a small improvement in health related quality of life as measured by QALYs (0.03 (−0.01 to 0.08)). Costs were no different between the intervention and usual treatment groups (£252 (−28 to 565) higher for START group). The cost effectiveness calculations suggested that START had a greater than 99% chance of being cost effective compared with usual treatment alone at a willingness to pay threshold of £30 000 per QALY gained, and a high probability of cost effectiveness on the HADS-T measure.
Conclusions The manual based coping intervention START, when added to treatment as usual, was cost effective compared with treatment as usual alone by reference to both outcome measures (affective symptoms for family carers, and carer based QALYs).
Trial Registration ISCTRN 70017938
doi:10.1136/bmj.f6342
PMCID: PMC3808080  PMID: 24162943
10.  Clinical effectiveness of a manual based coping strategy programme (START, STrAtegies for RelaTives) in promoting the mental health of carers of family members with dementia: pragmatic randomised controlled trial 
Objective To assess whether a manual based coping strategy compared with treatment as usual reduces depression and anxiety symptoms in carers of family members with dementia.
Design Randomised, parallel group, superiority trial.
Setting Three mental health community services and one neurological outpatient dementia service in London and Essex, UK.
Participants 260 carers of family members with dementia.
Intervention A manual based coping intervention comprising eight sessions and delivered by supervised psychology graduates to carers of family members with dementia. The programme consisted of psychoeducation about dementia, carers’ stress, and where to get emotional support; understanding behaviours of the family member being cared for, and behavioural management techniques; changing unhelpful thoughts; promoting acceptance; assertive communication; relaxation; planning for the future; increasing pleasant activities; and maintaining skills learnt. Carers practised these techniques at home, using the manual and relaxation CDs.
Main outcome measures Affective symptoms (hospital anxiety and depression total score) at four and eight months. Secondary outcomes were depression and anxiety caseness on the hospital anxiety and depression scale; quality of life of both the carer (health status questionnaire, mental health) and the recipient of care (quality of life-Alzheimer’s disease); and potentially abusive behaviour by the carer towards the recipient of care (modified conflict tactics scale).
Results 260 carers were recruited; 173 were randomised to the intervention and 87 to treatment as usual. Mean total scores on the hospital anxiety and depression scale were lower in the intervention group than in the treatment as usual group over the eight month evaluation period: adjusted difference in means −1.80 points (95% confidence interval −3.29 to −0.31; P=0.02) and absolute difference in means −2.0 points. Carers in the intervention group were less likely to have case level depression (odds ratio 0.24, 95% confidence interval 0.07 to 0.76) and there was a non-significant trend towards reduced case level anxiety (0.30, 0.08 to 1.05). Carers’ quality of life was higher in the intervention group (difference in means 4.09, 95% confidence interval 0.34 to 7.83) but not for the recipient of care (difference in means 0.59, −0.72 to 1.89). Carers in the intervention group reported less abusive behaviour towards the recipient of care compared with those in the treatment as usual group (odds ratio 0.47, 95% confidence interval 0.18 to 1.23), although this was not significant.
Conclusions A manual based coping strategy was effective in reducing affective symptoms and case level depression in carers of family members with dementia. The carers’ quality of life also improved.
Trial registration Current Controlled Trials ISCTRN70017938.
doi:10.1136/bmj.f6276
PMCID: PMC3808082  PMID: 24162942

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