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ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Background: There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).Aims: To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification.Results: There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p<0.001) and AD (all p<0.03). DLB showed impairment of parasympathetic function (all p<0.05) and one of the sympathetic tests in comparison with controls (orthostasis; p = 0.02). PDD had significantly more impairment than DLB in some autonomic parameters (Valsalva ratio: p = 0.024; response to isometric exercise: p = 0.002). Patients with VAD showed impairment in two parasympathetic tests (orthostasis: p = 0.02; Valsalva ratio: p = 0.08) and one sympathetic test (orthostasis: p = 0.04). These results were in contrast with AD patients who only showed impairment in one sympathetic response (orthostasis: p = 0.004). The prevalence of orthostatic hypotension and autonomic neuropathies was higher in all dementias than in controls (all p<0.05).Conclusion: Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications. [ABSTRACT FROM AUTHOR]

Background: Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease.Objective: To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor.Methods: 32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation.Results: Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.Conclusion: Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases. [ABSTRACT FROM AUTHOR]

Background: 123I-labelled 2beta-carbomethoxy-3beta-(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. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M 1 /M 4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123 I-iodo-quinuclidinyl-benzilate (M 1 /M 4 receptor assessment) and 99m Tc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M 1 /M 4 and perfusion spatial covariance patterns associated with patients. A discreet M 1 /M 4 pattern that distinguished patients from controls (W 1,19.7 = 16.7, P  = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M 1 /M 4 pattern that correlated with a positive change in mini-mental state examination ( r  = 0.52, P  = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M 1 /M 4 pattern that correlated with a positive change in neuropsychiatric inventory score ( r  = 0.77, P  = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M 1 /M 4 receptor expression within attentional/executive and ventral visual network hubs, respectively., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series., Aims: This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences., Method: We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions., Results: The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs., Conclusions: Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid-β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML- and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non-demented and AD brains and was not associated with the burden of AD-associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non-demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology., (© 2018 International Society of Neuropathology.)

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

Background: Complex visual hallucinations are common in Lewy body dementia (LBD) and can cause significant patient and caregiver distress. Current treatments are primarily pharmacological in nature and have limited efficacy and associated side effects. The objective of this study was to assess the effects of consecutive sessions of transcranial direct current stimulation (tDCS) on visual hallucination frequency and severity in LBD, at short-term and long-term follow-up stages., Methods: The study was a randomised, double-blind, placebo-controlled trial involving 40 participants with LBD (M age  = 75.52 years, SD age  = 8.69 years) which was conducted at a single site between November 2013 and December 2017. Participants received two consecutive 20-min sessions of active (0.048 mA/cm 2 ) or placebo tDCS, separated by a 30-min break, over 5 consecutive days. The anodal electrode was applied to the right parietal cortex (P4) and the cathodal electrode was applied to the occipital cortex (O z ). The primary outcome measure was the Neuropsychiatric Inventory (NPI) hallucinations subscale, as completed by a caregiver/informant at baseline and day 5 (short-term) follow-up, and month 1 and month 3 (long-term) follow-up. Secondary outcome measures included visual cortical excitability, as measured using transcranial magnetic stimulation, computerised attentional and visuoperceptual tasks, and measures of global cognition and cognitive fluctuations., Results: Complete study data were obtained from 36 participants. There was an overall improvement in visual hallucinations (NPI) for both groups at day 5 relative to baseline, with a medium-to-large effect size; however, compared to placebo, active tDCS did not result in any improvements in visual hallucinations (NPI) at day 5 relative to baseline, or at month 1 or month 3 follow-up time points. Additionally, comparisons of secondary outcome measures showed that active tDCS did not result in any improvements on any measure (visual cortical excitability, attentional and visuoperceptual tasks or cognitive measures) at any time point., Conclusions: Repeated consecutive sessions of parietal anodal tDCS, and occipital cathodal tDCS, do not improve visual hallucinations or visuoperceptual function, or alter visual cortical excitability in LBD., Trial Registration: ISRCTN, ISRCTN40214749 . Registered on 25 October 2013.

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer&rsquo;s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer&rsquo;s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65&ndash;105; 58&percnt; female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66&ndash;107; 63&percnt; female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-&beta;40 and amyloid-&beta;42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer&rsquo;s disease processes.10.1093/brain/awy215&#95;video1awy215media15824729224001.

Background: The prevalence of dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) in routine clinical practice is unclear. Prevalence rates observed in clinical and population-based cohorts and neuropathological studies vary greatly. Small sample sizes and methodological factors in these studies limit generalisability to clinical practice., Methods: We investigated prevalence in a case series across nine secondary care services over an 18-month period, to determine how commonly DLB and PDD cases are diagnosed and reviewed within two regions of the UK., Results: Patients with DLB comprised 4.6% (95% CI 4.0-5.2%) of all dementia cases. DLB was represented in a significantly higher proportion of dementia cases in services in the North East (5.6%) than those in East Anglia (3.3%; χ 2 = 13.6, p < 0.01). DLB prevalence in individual services ranged from 2.4 to 5.9%. PDD comprised 9.7% (95% CI 8.3-11.1%) of Parkinson's disease cases. No significant variation in PDD prevalence was observed between regions or between services., Conclusions: We found that the frequency of clinical diagnosis of DLB varied between geographical regions in the UK, and that the prevalence of both DLB and PDD was much lower than would be expected in this case series, suggesting considerable under-diagnosis of both disorders. The significant variation in DLB diagnostic rates between these two regions may reflect true differences in disease prevalence, but more likely differences in diagnostic practice. The systematic introduction of more standardised diagnostic practice could improve the rates of diagnosis of both conditions.

Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration., (© 2016 International Society of Neuropathology.)

Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia following Alzheimer's disease (AD). DLB is clinically and pathologically related to Parkinson's disease (PD) and PD dementia, and the three disorders can be viewed as existing on a spectrum of Lewy body disease. In recent years there has been a concerted effort to establish the phenotypes of AD and PD in the prodromal phase (before the respective syndromes of cognitive and motor impairment are expressed). Evidence for the prodromal presentation of DLB is also emerging. This paper briefly reviews what is known about the clinical presentation of prodromal DLB before discussing the pathology of Lewy body disease and how this relates to potential biomarkers of prodromal DLB. The presenting features of DLB can be broadly placed in three categories: cognitive impairment (particularly nonamnestic cognitive impairments), behavioural/psychiatric phenomena (for example, hallucinations, rapid eye movement sleep behaviour disorder (RBD)) and physical symptoms (for example, parkinsonism, decreased sense of smell, autonomic dysfunction). Some noncognitive symptoms such as constipation, RBD, hyposmia and postural dizziness can predate the onset of memory impairment by several years in DLB. Pathological studies of Lewy body disease have found that the earliest sites of involvement are the olfactory bulb, the dorsal motor nucleus of the vagal nerve, the peripheral autonomic nervous system, including the enteric nervous system, and the brainstem. Some of the most promising early markers for DLB include the presence of RBD, autonomic dysfunction or hyposmia, (123)I-metaiodobenzylguanidine cardiac scintigraphy, measures of substantia nigra pathology and skin biopsy for α-synuclein in peripheral autonomic nerves. In the absence of disease-modifying therapies, the diagnosis of prodromal DLB is of limited use in the clinic. That said, knowledge of the prodromal development of DLB could help clinicians identify cases of DLB where the diagnosis is uncertain. Prodromal diagnosis is of great importance in research, where identifying Lewy body disease at an earlier stage may allow researchers to investigate the initial phases of dementia pathophysiology, develop treatments designed to interrupt the development of the dementia syndrome and accurately identify the patients most likely to benefit from these treatments.

Objectives: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane ((123)I)) 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 ((123)I) 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 ((123)I) 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 ((123)I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane ((123)I) 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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

We examined (99m)Tc-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 (F(1,64)=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 (F(1,61)=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.

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.

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.

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.

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).

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.

The potential protective role of education for dementia is an area of major interest. Almost all older people have some pathology in their brain at death but have not necessarily died with dementia. We have explored these two observations in large population-based cohort studies (Epidemiological Clinicopathological Studies in Europe; EClipSE) in an investigation of the relationships of brain pathology at death, clinical dementia and time in education, testing the hypothesis that greater exposure to education reduces the risk of dementia. EClipSE has harmonized longitudinal clinical data and neuropathology from three longstanding population-based studies that included post-mortem brain donation. These three studies started between 1985 and 1991. Number of years of education during earlier life was recorded at baseline. Incident dementia was detected through follow-up interviews, complemented by retrospective informant interviews, death certificate data and linked health/social records (dependent on study) after death. Dementia-related neuropathologies were assessed in each study in a comparable manner based on the Consortium to Establish a Registry for Alzheimer's Disease protocol. Eight hundred and seventy-two brain donors were included, of whom 56% were demented at death. Longer years in education were associated with decreased dementia risk and greater brain weight but had no relationship to neurodegenerative or vascular pathologies. The associations between neuropathological variables and clinical dementia differed according to the 'dose' of education such that more education reduced dementia risk largely independently of severity of pathology. More education did not protect individuals from developing neurodegenerative and vascular neuropathology by the time they died but it did appear to mitigate the impact of pathology on the clinical expression of dementia before death. The findings suggest that an understanding of the mechanisms leading to functional protection in the presence of pathology may be of considerable value to society.

Background: (123)I-FP-CIT SPECT (single photon emission computed tomography) can help in the differential diagnosis of probable dementia with Lewy bodies (Lewy body dementia) and Alzheimer's disease., Aims: Our aim was to determine the accuracy of (123)I-FP-CIT SPECT in diagnosing people with possible dementia with Lewy bodies., Method: We undertook a 12-month follow-up of 325 individuals with probable or possible Lewy body or non-Lewy body dementia who had previously undergone (123)I-FP-CIT SPECT. A consensus panel, masked to SPECT findings, established diagnosis at 12 months in 264 people., Results: Of 44 people with possible dementia with Lewy bodies at baseline, at follow-up the diagnosis for 19 people was probable dementia with Lewy bodies (43%), in 7 people non-Lewy body dementia (16%) and for 18 individuals it remained possible dementia with Lewy bodies (41%). Of the 19 who at follow-up were diagnosed with probable dementia with Lewy bodies, 12 had abnormal scans at baseline (sensitivity 63%); all 7 individuals with a possible diagnosis who were diagnosed as having Alzheimer's disease at follow-up had normal scans (specificity 100%)., Conclusions: Our findings confirm the diagnostic accuracy of (123)I-FP-CIT SPECT in distinguishing Lewy body from non-Lewy body dementia and also suggest a clinically useful role in diagnostically uncertain cases, as an abnormal scan in a person with possible dementia with Lewy bodies is strongly suggestive of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is characterized by progressive dementia with two of three core symptoms; Parkinsonism, visual hallucinations or disturbances of consciousness/fluctuating attention. Dementia in Parkinson's disease (PDD) has similar neuropsychiatric characteristics. Reduced nigrothalamic dopamine and altered thalamic D2 receptors may mediate some of the non-motor symptoms of DLB and PDD. The study aims were to ascertain whether thalamic D2 density was altered in Parkinson's disease (PD), PDD and DLB, and whether D2 density was related to core symptoms. Thalamic D2 receptor binding was measured by post-mortem autoradiography in 18 cases of DLB, 13 PDD, 6 PD and 14 normal elderly controls. Highest D2 density in control cases was in the intralaminar, midline, anterior and mediodorsal nuclei. In PD without dementia D2 binding was elevated above controls in all thalamic regions, significantly in reticular, laterodorsal, centromedian, ventral centromedian, parafascicular, paraventricular, ventroposterior, ventrolateral posterior, and ventrointermedius nuclei. Compared to controls, DLB cases with Parkinsonism (DLB+EPS) had significantly elevated D2 receptor density in laterodorsal and ventrointermedius nuclei; PDD cases had significantly raised density in the ventrointermedius, and DLB cases without Parkinsonism (DLB-EPS) did not show increased D2 density in any areas. In DLB and PDD cases with disturbances of consciousness, cases treated with neuroleptics had higher D2 binding in all thalamic regions, significantly in the mediodorsal and ventrolateral posterior nuclei. D2 receptor binding did not vary with cognitive decline (MMSE) or visual hallucinations, but was significantly higher with increased extrapyramidal symptoms.

Background: Levodopa (L-dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L-dopa use in patients with parkinsonism and dementia. Therefore, the effect of L-dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear., Aim: To ascertain the acute and long-term effects of L-dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease., Method: Baseline cognitive and motor function was assessed off L-dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard "bedside" measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L-dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L-dopa to assess the prolonged effect., Results: Acute L-dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L-dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L-dopa treatment., Conclusion: The use of L-dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.

Background: A previous cross sectional study found over-representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD)., Aims: (1) To examine rates of cognitive and motor decline over two years in PD (n=40), PDD (n=42) and DLB (n=41) subjects, compared with age matched controls (n=41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype., Results: Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non-demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE -4.5 and -3.9, respectively), compared with PD (-0.2) and controls (-0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (chi2=6.7, Fisher's exact test p<0.05)., Conclusion: A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.

Background: Brain perfusion deficits have been reported previously in subjects with Parkinson's disease in comparison with healthy controls., Objective: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year., Methods: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum., Results: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year., Conclusions: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.

Background: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms., Aim: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD)., Method: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa., Results: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p < 0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion., Conclusion: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.

Neurodegeneration in Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) affect cortical and subcortical networks involved in saccade generation. We therefore expected impairments in saccade performance in both disorders. In order to improve the pathophysiological understanding and to investigate the usefulness of saccades for differential diagnosis, saccades were tested in age- and education-matched patients with PDD (n = 20) and DLB (n = 20), Alzheimer's disease (n = 22) and Parkinson's disease (n = 24), and controls (n = 24). Reflexive (gap, overlap) and complex saccades (prediction, decision and antisaccade) were tested with electro-oculography. PDD and DLB patients had similar impairment in all tasks (P > 0.05, not significant). Compared with controls, they were impaired in both reflexive saccade execution (gap and overlap latencies, P < 0.0001; gains, P < 0.004) and complex saccade performance (target prediction, P < 0.0001; error decisions, P < 0.003; error antisaccades: P < 0.0001). Patients with Alzheimer's disease were only impaired in complex saccade performance (Alzheimer's disease versus controls, target prediction P < 0.001, error decisions P < 0.0001, error antisaccades P < 0.0001), but not reflexive saccade execution (for all, P > 0.05). Patients with Parkinson's disease had, compared with controls, similar complex saccade performance (for all, P > 0.05) and only minimal impairment in reflexive tasks, i.e. hypometric gain in the gap task (P = 0.04). Impaired saccade execution in reflexive tasks allowed discrimination between DLB versus Alzheimer's disease (sensitivity > or =60%, specificity > or =77%) and between PDD versus Parkinson's disease (sensitivity > or =60%, specificity > or =88%) when +/-1.5 standard deviations was used for group discrimination. We conclude that impairments in reflexive saccades may be helpful for differential diagnosis and are minimal when either cortical (Alzheimer's disease) or nigrostriatal neurodegeneration (Parkinson's disease) exists solely; however, they become prominent with combined cortical and subcortical neurodegeneration in PDD and DLB. The similarities in saccade performance in PDD and DLB underline the overlap between these conditions and underscore differences from Alzheimer's disease and Parkinson's disease.

Dementia with Lewy bodies (DLB) accounts for 15-20% of all autopsy confirmed dementias in old age. Characteristic histopathological changes are intracellular Lewy bodies and Lewy neurites, with abundant senile plaques but sparse neurofibrillary tangles. Core clinical features are fluctuating cognitive impairment, persistent visual hallucinations and extrapyramidal motor symptoms (parkinsonism). One of these core features has to be present for a diagnosis of possible DLB, and two for probable DLB. Supportive features are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions and hallucinations in other modalities. DLB is clinically under-diagnosed and frequently misclassified as systemic delirium or dementia due to Alzheimer's disease or cerebrovascular disease. Therapeutic approaches to DLB can pose difficult dilemmas in pharmacological management. Neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, which is associated with increased morbidity and mortality. Antiparkinsonian medication has the potential to exacerbate psychotic symptoms and may be relatively ineffective at relieving extrapyramidal motor symptoms. Recently there is converging evidence that treatment with cholinesterase inhibitors can offer a safe alternative for the symptomatic treatment of cognitive and neuropsychiatric features in DLB. This review will focus on the clinical characteristics of DLB, its differential diagnosis and on possible management strategies.

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.

Background: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70% loss of striatal dopamine., Objective: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life., Methods: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, (123)I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method., Results: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen., Conclusion: FP-CIT SPET provides a means of distinguishing DLB from AD during life.