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1.  The assessment of cognition in visually impaired older adults 
Age and ageing  2012;42(1):98-102.
Background
visual and cognitive impairments are common in later life. Yet there are very few cognitive screening tests for the visually impaired.
Objective
to screen for cognitive impairment in the visually impaired.
Methods
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.
Results
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).
Conclusion
visually impaired patients benefit from cognitive tests, which do not rely on vision. The more visually impaired the greater the benefit.
doi:10.1093/ageing/afs157
PMCID: PMC4153986  PMID: 23108164
visual impairment; cognitive impairment; cognitive testing
2.  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
3.  Single-Cell Expression Profiling of Dopaminergic Neurons Combined with Association Analysis Identifies Pyridoxal Kinase as Parkinson’s Disease Gene 
Annals of neurology  2009;66(6):792-798.
Objective
The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.
Methods
We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.
Results
We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44).
Interpretation
We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.
doi:10.1002/ana.21780
PMCID: PMC4034432  PMID: 20035503
4.  Alzheimer and Vascular Neuropathological Changes Associated with Different Cognitive States in a Non-Demented Sample 
The state between aging with no cognitive impairment and dementia has become a major focus for intervention. The neuropathological and neurobiological correlates of this intermediate state are therefore of considerable interest, particularly from population representative samples. Here we investigate the neuropathological profile associated with different cognitive ability levels measured using strata defined by Mini Mental State Examination (MMSE) scores. One hundred and fifty one individuals were stratified into three cognitive groups including: non-, mildly, and moderately impaired at death. Alzheimer’s disease, atrophy, and vascular pathologies were investigated. Mild impairment was associated with an increased risk of vascular pathologies including small vessel disease and lacunes. In contrast, the moderately impaired group showed a more extensive pattern of pathology, including tangles and neuritic plaques (entorhinal/hippocampus), atrophy (cortical and hippocampal), and vascular disease (small vessel disease, lacunes, and infarcts). In a population-based sample of older people, MMSE score defined strata are associated with multiple pathologies. The profile of AD and vascular changes becomes more complex with increased cognitive impairment and these changes are likely to constitute a major substrate for age associated cognitive impairment. The results highlight the need for rigorous investigation of both neurodegenerative and vascular risks factors in old age.
doi:10.3233/JAD-2011-110518
PMCID: PMC3975483  PMID: 22233761
Aging; Alzheimer’s disease; cognitive impairment; neuropathology; vascular pathology
5.  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.
doi:10.1038/jcbfm.2013.2
PMCID: PMC3618400  PMID: 23361395
Alzheimer's disease; differential diagnosis; dementia with Lewy bodies; perfusion; spatial covariance; SPECT
6.  A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies 
JAMA neurology  2013;70(6):10.1001/jamaneurol.2013.1925.
Importance
While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.
Objective
To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).
Design
We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.
Setting
Eleven centers from sites around the world performing genotyping.
Participants
Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.
Main Outcome Measures
Frequency of GBA1 mutations in cases and controls.
Results
We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78–14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53–15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P<.001), with higher disease severity scores.
Conclusions and Relevance
Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
doi:10.1001/jamaneurol.2013.1925
PMCID: PMC3841974  PMID: 23588557
7.  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.
Background:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1017/S1041610213001488
PMCID: PMC3819183  PMID: 24148774
attention; Alzheimer’s disease; single photon emission computed tomography; SPECT; imaging
8.  Diagnosing Mild Cognitive Impairment (MCI) in clinical trials: a systematic review 
BMJ Open  2013;3(2):e001909.
Objective
To describe how criteria for amnestic Mild Cognitive Impairment (aMCI) have been operationalised in randomised controlled clinical trials (RCTs).
Design
Systematic review.
Information sources
EMBASE, PubMed and PSYCHInfo were searched from their inception to February 2012. Electronic clinical trial registries were also searched (February 2012).
Study selection
RCTs were included where participant selection was made using Petersen et al-defined aMCI. There was no restriction on intervention type or the outcome tested.
Data extraction
For each trial, we extracted information on study design, demographics, exclusion criteria and the operationalisation strategy for the five aMCI diagnostic criteria including: (1) memory complaint, (2) normal general cognitive function, (3) memory impairment, (4) no functional impairment and (5) no dementia.
Results
223 articles and 278 registered trials were reviewed, of which 22 met inclusion criteria. Various methods were applied for operationalising aMCI criteria resulting in variability in participant selection. Memory complaint and assessment of general cognitive function were the most consistently measured criteria. There was large heterogeneity in the neuropsychological methods used to determine memory impairment. It was not possible to assess the impact of these differences on case selection accuracy for dementia prediction. Further limitations include selective and unclear reporting of how each of the criteria was measured.
Conclusions
The results highlight the urgent need for a standardised approach to map aMCI. Lack of uniformity in clinical diagnosis, however, is not exclusively a problem for MCI but also for other clinical states such as dementia including Alzheimer's disease, Lewy Body, frontotemporal or vascular dementia. Defining a uniform approach to MCI classification, or indeed for any classification concept within the field of dementia, should be a priority if further trials are to be undertaken in the older aged population based on these concepts.
doi:10.1136/bmjopen-2012-001909
PMCID: PMC3586181  PMID: 23386579
Mental Health; Neurology
9.  Supporting clinical research in the NHS in England: the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network 
Clinical research is best done when aligned with clinical care - that is, when the patient can be identified, recruited and, in many instances, researched in parallel with the delivery of clinical service. However, to achieve this effectively requires identification of the additional cost to the National Health Service clinical support services and the development of an appropriately skilled workforce. The National Institute for Health Research (NIHR) Cancer Research Network demonstrated the value of dedicated research support in terms of the number of patients recruited into clinical trials. Building on this model, the NIHR in England funded the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). DeNDRoN is now in its sixth year and has established a geographically widespread network of research support staff and research leadership managed by a central coordinating centre. Success can already be measured by a significant increase in the number of patients entering studies and the speed with which both commercial and noncommercial studies are completed. There are also early indications that the network will result in improved patient outcomes.
doi:10.1186/alzrt126
PMCID: PMC3506937  PMID: 22769969
10.  Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study 
The British Journal of Psychiatry  2012;200(6):491-498.
Background
Visual hallucinations and visuoperceptual deficits are common in dementia with Lewy bodies, suggesting that cortical visual function may be abnormal.
Aims
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.
Method
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).
Results
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.
Conclusions
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).
doi:10.1192/bjp.bp.111.099432
PMCID: PMC3365275  PMID: 22500014
11.  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
12.  Visual hallucinations in dementia with Lewy bodies: transcranial magnetic stimulation study 
The British Journal of Psychiatry  2011;199(6):492-500.
Background
The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism.
Aims
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.
Method
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.
Results
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).
Conclusions
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.
doi:10.1192/bjp.bp.110.090373
PMCID: PMC3227808  PMID: 22016436
13.  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
14.  Cholinesterase inhibitor use does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish Alzheimer's disease from dementia with Lewy bodies 
Background
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.
Objective
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).
Design
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.
Results
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).
Conclusions
Use of ChEi does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish AD from DLB.
doi:10.1136/jnnp.2006.111666
PMCID: PMC2117542  PMID: 17299017
15.  Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study 
PLoS Medicine  2009;6(11):e1000180.
Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation.
Background
Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).
Methods and Findings
A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).
Conclusions
Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Losing one's belongings and forgetting people's names is often a normal part of aging. But increasing forgetfulness can also be a sign of dementia, a group of symptoms caused by several disorders that affect the structure of the brain. The commonest form of dementia is Alzheimer disease. In this, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. Vascular dementia, in which problems with blood circulation deprive parts of the brain of oxygen, is also common. People with dementia have problems with two or more “cognitive” functions—thinking, language, memory, understanding, and judgment. As the disease progresses, they gradually lose their ability to deal with normal daily activities until they need total care, their personality often changes, and they may become agitated or aggressive. Dementia is rare before the age of 65 years but about a quarter of people over 85 years old have dementia. Because more people live to a ripe old age these days, the number of people with dementia is increasing. According to the latest estimates, about 35 million people now have dementia and by 2050, 115 million may have the disorder.
Why Was This Study Done?
There is no cure for dementia but many drugs designed to modulate specific abnormal (pathological) changes in the brain that can cause the symptoms of dementia are being developed. To assess the likely impact of these potentially expensive new therapies, experts need to know what proportion of dementia is associated with each type of brain pathology. Although some brain changes can be detected in living brains with techniques such as computed tomography brain scans, most brain changes can only be studied in brains taken from people after death (post mortem brains). In this study, which is part of the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), the researchers look for associations between dementia in elderly people and pathological changes in their post mortem brains and estimate the attributable-risk (AR) for dementia at death associated with specific pathological features in the brain. That is, they estimate the proportion of dementia directly attributable to each type of pathology.
What Did the Researchers Do and Find?
Nearly 20 years ago, the MRC CFAS interviewed more than 18,000 people aged 65 years or older recruited at six sites in England and Wales to determine their cognitive function and their ability to deal with daily activities. 20% of the participants, which included people with and without cognitive impairment, were then assessed in more detail and invited to donate their brains for post mortem examination. As of 2004, 456 individuals had donated their brains. The dementia status of these donors was established using data from their assessment interviews and death certificates, and from interviews with relatives and carers, and their brains were carefully examined for abnormal changes. The researchers then used statistical methods to estimate the AR for dementia at death associated with various abnormal brain changes. The main contributors to AR for dementia at death included age (18% of dementia at death was attributable to this factor), plaques (8%), and neurofibrillary tangles (11%) in a brain region called the neocortex, small blood vessel disease (12%), and multiple abnormal changes in blood vessels (9%).
What Do These Findings Mean?
These findings suggest that multiple abnormal brain changes determine the overall burden of dementia. Importantly, they also suggest that dementia is often associated with mixed pathological changes—many people with dementia had brain changes consistent with both Alzheimer disease and vascular dementia. Because people with dementia live for variable lengths of time during which the abnormal changes in their brain are likely to alter, it may be difficult to extrapolate these findings to living populations of elderly people. Furthermore, only a small percentage of the MRC CFAS participants have donated their brains so the findings of this study may not apply to the general population. Nevertheless, these findings suggest that the new therapies currently under development may do little to reduce the overall burden of dementia because most people's dementia involves multiple pathologies. Consequently, it may be necessary to develop a range of strategies and combination therapies to deal with the ongoing dementia epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000180.
The US National Institute on Aging provides information for patients and carers about forgetfulness and about Alzheimer disease (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides information about dementia (in English and Spanish)
The UK National Health Service Choices Web site also provides detailed information for patients and their carers about dementia and about Alzheimer disease
MedlinePlus provides links to additional resources about dementia and Alzheimer disease (in English and Spanish)
More information about the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is available
doi:10.1371/journal.pmed.1000180
PMCID: PMC2765638  PMID: 19901977
16.  DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease – a multicentre RCT 
Trials  2009;10:57.
Background
Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.
Method
DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.
Discussion
There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.
Trial registration
Current controlled trials ISRCTN49545035
doi:10.1186/1745-6215-10-57
PMCID: PMC2723100  PMID: 19630974
17.  Operationalisation of Mild Cognitive Impairment: A Graphical Approach 
PLoS Medicine  2007;4(10):e304.
A new online tool allows mapping of the different classifications of mild cognitive impairment.
doi:10.1371/journal.pmed.0040304
PMCID: PMC2043006  PMID: 17973571
18.  Dementia with Lewy bodies 
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people, accounting for 10% to 15% of all cases, it occupies part of a spectrum that includes Parkinson's disease and primary autonomic failure. All these diseases share a neuritic pathology based upon abnormal aggregation of the synaptic protein α-synuciein. It is important to identify DLB patients accurately because they have specific symptoms, impairments, and functional disabilities thai differ from other common dementia syndromes such as Alzheimer's disease, vascular cognitive impairment, and frontotemporal dementia. Clinical diagnostic criteria for DLB have been validated against autopsy, but fail to detect a substantial minority of cases with atypical presentations that are often due to the presence of mixed pathology. DLB patients frequently have severe neuroleptic sensitivity reactions, which are associated with significantly increased morbidity and mortality. Cholinesterase inhibitor treatment is usually well tolerated and substantially improves cognitive and neuropsychiatrie symptoms. Although virtually unrecognized 20 years ago, DLB could within this decade become one of the most treatable neurodegenerative disorders of late life.
PMCID: PMC3181810  PMID: 22033743
Lewy body; dementia; Parkinson's disease; α-synuclein; diagnosis; treatment; cholinesterase inhibitor
19.  Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial 
BMJ : British Medical Journal  2003;326(7380):73.
Objective
To determine the effectiveness of multifactorial intervention after a fall in older patients with cognitive impairment and dementia attending the accident and emergency department.
Design
Randomised controlled trial.
Participants
274 cognitively impaired older people (aged 65 or over) presenting to the accident and emergency department after a fall: 130 were randomised to assessment and intervention and 144 were randomised to assessment followed by conventional care (control group).
Setting
Two accident and emergency departments, Newcastle upon Tyne.
Main outcome measures
Primary outcome was number of participants who fell in year after intervention. Secondary outcomes were number of falls (corrected for diary returns), time to first fall, injury rates, fall related attendances at accident and emergency department, fall related hospital admissions, and mortality.
Results
Intention to treat analysis showed no significant difference between intervention and control groups in proportion of patients who fell during 1 year's follow up (74% (96/130) and 80% (115/144), relative risk ratio 0.92, 95% confidence interval 0.81 to 1.05). No significant differences were found between groups for secondary outcome measures.
Conclusions
Multifactorial intervention was not effective in preventing falls in older people with cognitive impairment and dementia presenting to the accident and emergency department after a fall.
What is already known on this topicMultifactorial intervention prevents falls in cognitively normal older people living in the community and in those who present to the accident and emergency department after a fallFall prevention strategies have not been tested by controlled trials in patients with cognitive impairment and dementia who fallWhat this study addsNo benefit was shown from multifactorial assessment and intervention after a fall in patients with cognitive impairment and dementia presenting to the accident and emergency departmentThe intervention was less effective in these patients than in cognitively normal older people
PMCID: PMC139930  PMID: 12521968
20.  Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease 
Journal of Neurochemistry  2012;123(2):298-309.
Lewy body disease (LBD) development is enhanced by mutations in the GBA gene coding for glucocerebrosidase (GCase). The mechanism of this association is thought to involve an abnormal lysosomal system and we therefore sought to evaluate if lysosomal changes contribute to the pathogenesis of idiopathic LBD. Analysis of post-mortem frontal cortex tissue from 7 GBA mutation carriers with LBD, 5 GBA mutation carriers with no signs of neurological disease and human neural stem cells exposed to a GCase inhibitor was used to determine how GBA mutation contributes to LBD. GBA mutation carriers demonstrated a significantly reduced level of GCase protein and enzyme activity and retention of glucocerebrosidase isoforms within the endoplasmic reticulum (ER). This was associated with enhanced expression of the lysosomal markers LAMP1 and LAMP2, though the expression of ATP13A2 and Cathepsin D was reduced, along with the decreased activity of Cathepsin D. The ER unfolded protein response (UPR) regulator BiP/GRP78 was reduced by GBA mutation and this was a general phenomenon in LBD. Despite elevation of GRP94 in LBD, individuals with GBA mutations showed reduced GRP94 expression, suggesting an inadequate UPR. Finally, human neural stem cell cultures showed that inhibition of GCase causes acute reduction of BiP, indicating that the UPR is affected by reduced glucocerebrosidase activity. The results indicate that mutation in GBA leads to additional lysosomal abnormalities, enhanced by an impaired UPR, potentially causing α-synuclein accumulation.
doi:10.1111/j.1471-4159.2012.07879.x
PMCID: PMC3494984  PMID: 22803570
dementia with Lewy bodies; endoplasmic reticulum; glucocerebrosidase; Lewy body disease; lysosome; Parkinson’s disease

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