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Significance: Accurate and objective identification of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is of major clinical importance due to the current lack of low-cost and noninvasive diagnostic tools to differentiate between the two. Developing an approach for such identification can have a great impact in the field of dementia diseases as it would offer physicians a routine objective test to support their diagnoses. The problem is especially acute because these two dementias have some common symptoms and characteristics, which can lead to misdiagnosis of DLB as AD and vice versa, mainly at their early stages. Aim: The aim is to evaluate the potential of mid-infrared (IR) spectroscopy in tandem with machine learning algorithms as a sensitive method to detect minor changes in the biochemical structures that accompany the development of AD and DLB based on a simple peripheral blood test, thus improving the diagnostic accuracy of differentiation between DLB and AD. Approach: IR microspectroscopy was used to examine white blood cells and plasma isolated from 56 individuals: 26 controls, 20 AD patients, and 10 DLB patients. The measured spectra were analyzed via machine learning. Results: Our encouraging results show that it is possible to differentiate between dementia (AD and DLB) and controls with an ∼86% success rate and between DLB and AD patients with a success rate of better than 93%. Conclusions: The success of this method makes it possible to suggest a new, simple, and powerful tool for the mental health professional, with the potential to improve the reliability and objectivity of diagnoses of both AD and DLB.

BackgroundPotentially modifiable risk factors for developing dementia have been identified. However, risk factors for increased mortality in patients with diagnosed dementia are not well understood. Identifying factors that influence prognosis would help clinicians plan care and address unmet needs.AimsTo investigate diagnosed depression and sociodemographic factors as predictors of mortality in patients with dementia in UK secondary clinical care services.MethodWe conducted a cohort study of patients with a dementia diagnosis in an electronic health records database in a UK National Health Service mental health trust.ResultsIn 3374 patients with 10 856 person-years of follow-up, comorbid depression was not associated with mortality (adjusted hazard ratio 0.94; 95% CI 0.71–1.24). Single patients had higher mortality than those who were married (adjusted hazard ratio 1.25; 95% CI 1.03–1.50). Patients of Asian ethnicity had lower mortality rates than White British patients (adjusted hazard ratio 0.50; 95% CI 0.34–0.73).ConclusionsClinically diagnosed depression does not increase mortality in patients with dementia. Patients who are single are a potential high-mortality risk group. Lower mortality rates in Asian patients with dementia that have been reported in the USA also apply in the UK.Declaration of interestNone.

Background Trials of psychological interventions for reducing agitation in people with dementia living at home have been unsuccessful. Aims To inform future interventions by identifying successful strategies of family carers with relatives with dementia and agitation living at home. Method Qualitative in-depth individual interviews were performed with 18 family carers. We used thematic analysis to identify emerging themes. Results Carers described initial surprise and then acceptance that agitation is a dementia symptom and learned to respond flexibly. Their strategies encompassed: prevention of agitation by familiar routine; reduction of agitation by addressing underlying causes and using distraction; prevention of escalation by risk enablement, not arguing; and control of their emotional responses by ensuring their relative’s safety then walking away, carving out some time for themselves and using family and services for emotional and practical help. Conclusions These strategies can be manualised and tested in future randomised controlled trials for clinical effectiveness in reducing agitation in people with dementia living at home. Declaration of interest None. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

BACKGROUND: Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). AIMS: To compare cognitive decline and survival after diagnosis of Alzheimer's disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. METHOD: Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer's disease diagnosis. RESULTS: In the 9 months after Alzheimer's disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. CONCLUSIONS: In people with Alzheimer's disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. DECLARATION OF INTEREST: R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson’s disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits.

Objective: Our aim was to evaluate clinical and neuropsychological features to identify pre-dementia Alzheimer’s disease (PAD) among mild cognitive impairment (MCI) patients. Methods: A longitudinal prospective study of 89 consecutive patients affected with MCI was conducted. Clinical evaluation consisted of a clinical interview protocol, neuropsychological evaluation, standard laboratory tests, and CT scan. A 6-month clinical check-up was made to determine whether patients remained in MCI, improved or progressed to AD or another dementia. Results: At 3-year follow-up, 47% patients developed AD dementia. Seventeen variables were significant and were evaluated by logistic regression analysis to identify the remaining optimal diagnostic criteria: age, gender, repeating comments, difficulties in understanding explanations, time of symptom evolution, history of depression, and word fluency (with animals) were identified with a sensitivity of 100% and a specificity of 93%. A computer application was developed with all these variables which we have named Clinical Approach to Diagnosis of PAD (CAD-PAD). Conclusions: These results suggest that CAD-PAD can help in the clinical diagnosis of PAD.

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 [ 123 I]-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.

Background: Cognitive impairment plays a role in Parkinson’s disease (PD) and has important consequences for patient management. However, many aspects of cognitive impairment in PD remain unclear because of the use of different and often invalid measurement instruments. In this study, a reliable and valid instrument, the SCales for Outcomes in PArkinson’s disease-COGnition (SCOPA-COG), was used. Aim: To evaluate cognitive functioning in a large cohort of patients with Parkinson’s disease and to assess the relations with demographic, disease related and clinical variables. Methods: A cohort of 400 patients with PD was evaluated for cognition, motor and non-motor domains, as well as for demographic and disease related characteristics. Results were compared with 150 controls matched for overall age, sex and education distribution. Results: Patients with PD scored significantly lower on all cognitive subdomains compared with controls, with the largest differences for executive functioning and memory. After correction for age and years of education, 22% of patients had impaired cognition, as measured by the total SCOPA-COG score, compared with controls. Across all patients, more severe cognitive impairment was associated with significantly more impairment in motor, autonomic, depressive and psychotic domains. Patients with the postural instability gait difficulty (PIGD) dominant phenotype showed more cognitive impairment compared with patients with the tremor dominant phenotype. Contrary to tremor scores, PIGD scores significantly worsened with increasing disease severity. Conclusions: Cognition is an important domain of the clinical spectrum of PD and poorer cognitive performance is associated with greater impairment in motor and non-motor domains in PD. The difference in cognitive scores between PIGD dominant patients and tremor dominant patients likely reflects more advanced disease.

Background: Identifying quantitative gait markers of preclinical dementia may lead to new insights into early disease stages, improve diagnostic assessments and identify new preventive strategies. Objective: To examine the relationship of quantitative gait parameters to decline in specific cognitive domains as well as the risk of developing dementia in older adults. Methods: We conducted a prospective cohort study nested within a community based ageing study. Of the 427 subjects aged 70 years and older with quantitative gait assessments, 399 were dementia-free at baseline. Results: Over 5 years of follow-up (median 2 years), 33 subjects developed dementia. Factor analysis was used to reduce eight baseline quantitative gait parameters to three independent factors representing pace, rhythm and variability. In linear models, a 1 point increase on the rhythm factor was associated with further memory decline (by 107%), whereas the pace factor was associated with decline on executive function measured by the digit symbol substitution (by 29%) and letter fluency (by 92%) tests. In Cox models adjusted for age, sex and education, a 1 point increase on baseline rhythm (hazard ratio (HR) 1.48; 95% CI 1.03 to 2.14) and variability factor scores (HR 1.37; 95% CI 1.05 to 1.78) was associated with increased risk of dementia. The pace factor predicted the risk of developing vascular dementia (HR 1.60; 95% CI 1.06 to 2.41). Conclusion: Our findings indicate that quantitative gait measures predict future risk of cognitive decline and dementia in initially non-demented older adults.

Background: Patients with Alzheimer’s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer’s disease has been demonstrated. Several studies have investigated whether the exon 4 e2/e3/e4 haplotype of the apolipoprotein E ( APOE ) gene is associated with BPSD, with variable results. Objective: We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene. Methods: Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD. Results: We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A-491T with irritability, T-427C with agitation/aggression and appetite disturbances, and T-219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings. Conclusions: Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.

Objective: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson’s disease (PDD). Methods: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. Results: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score ⩾4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson’s disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson’s Disease Rating Scale and care giver distress scores. Conclusion: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

Objective: To investigate in a longitudinal cohort of people with Alzheimer’s disease whether taking antipsychotics is associated with more rapid cognitive deterioration. Method: From a sample of 224 people with Alzheimer’s disease recruited as epidemiologically representative, those taking antipsychotic drugs for more than 6 months were compared with those who were not, in terms of change in three measures of cognition. The effects of potential mediators and confounders (demographic factors, neuropsychiatric symptoms, cognitive severity and cholinesterase inhibitors) were also examined. Results: No significant difference was observed in cognitive decline between those taking antipsychotics (atypical or any) and others on any measure of cognition. The only predictor of more cognitive decline was greater baseline cognitive severity (B = 3.3, 95% confidence interval 0.6 to 6.1, t = 2.4, p Conclusions: In this, the first cohort study investigating the effects of atypical antipsychotics on cognitive outcome in Alzheimer’s disease, those taking antipsychotics were no more likely to decline cognitively over 6 months. Although clinicians should remain cautious when prescribing antipsychotic drugs to people with Alzheimer’s disease, any increase in cognitive deterioration is not of the magnitude previously reported. There is a need for cohort studies that follow up patients from first prescription in clinical practice for a period of months rather than weeks to determine “real-life” risks and benefits.

Marina Buswell, et al, 'Difference between how ambulance service personnel use paper and electronic patient care records when attending older people at home', letter to European Journal of Emergency Medicine, Vol. 22 (2), published on 1 April 2015. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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).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.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 p0.001) and AD (all p0.03). DLB showed impairment of parasympathetic function (all p0.05) 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 p0.05).Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications.

Objective: To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI). Methods: Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc-HMPAO. Clinical outcome after a 5-year follow-up period was heterogeneous. Results: Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer’s disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer’s disease within the follow-up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer’s disease were also included for purposes of comparison. The group of patients with Alzheimer’s disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion. Conclusions: These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.

Background: Dementia is common in Parkinson’s disease, but the underlying brain pathology is not yet fully understood. Aim: To examine the changes in the brain of patients with Parkinson’s disease with mild cognitive impairment (MCI) and dementia, using structural magnetic resonance imaging. Methods: Using voxel-based morphometry, the grey matter atrophy on brain images of patients with Parkinson’s disease and dementia (PDD; n = 16) and Parkinson’s disease without dementia (PDND; n = 20), and healthy elderly subjects (n = 20) was studied. In the PDND group, 12 subjects had normal cognitive status and 8 had MCI. Standardised rating scales for motor, cognitive and psychiatric symptoms were used. Results: Widespread areas of cortical atrophy were found in patients with PDD compared with normal controls (in both temporal and frontal lobes and in the left parietal lobe). Grey matter reductions were found in frontal, parietal, limbic and temporal lobes in patients with PDD compared with those with PDND. In patients with PDND with MCI, areas of reduced grey matter in the left frontal and both temporal lobes were found. Conclusion: These findings show that dementia in Parkinson’s disease is associated with structural neocortical changes in the brain, and that cognitive impairment in patients with PDND may be associated with structural changes in the brain. Further studies with larger groups of patients are needed to confirm these findings.

Aim: To assess the long-term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson’s disease, with a 5-year follow-up after surgery. Methods: 11 patients with Parkinson’s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on. Results: A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini-Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven’s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy. Conclusion: The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson’s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5-year follow-up, when selection criteria for neurosurgery are strict.

To explore the driving problems associated with Parkinson's disease (PD) and to ascertain whether any clinical features or tests predict driver safety.The driving ability of 154 individuals with PD referred to a driving assessment centre was determined by a combination of clinical tests, reaction times on a test rig and an in-car driving test.The majority of cases (104, 66%) were able to continue driving although 46 individuals required an automatic transmission and 10 others needed car modifications. Ability to drive was predicted by the severity of physical disease, age, presence of other associated medical conditions, particularly dementia, duration of disease, brake reaction, time on a test rig and score on a driving test (all p0.001). The level of drug treatment and the length of driving history were not correlated. Discriminant analysis revealed that the most important features in distinguishing safety to drive were severe physical disease (Hoehn and Yahr stage 3), reaction time, moderate disease associated with another medical condition and high score on car testing.Most individuals with PD are safe to drive, although many benefit from car modifications or from using an automatic transmission. A combination of clinical tests and in-car driving assessment will establish safety to drive, and a number of clinical correlates can be shown to predict the likely outcome and may assist in the decision process. This is the largest series of consecutive patients seen at a driving assessment centre reported to date, and the first to devise a scoring system for on-road driving assessment.

The diagnosis of mild cognitive impairment (MCI) is clinically unhelpful, as many patients with MCI develop dementia but many do not.To identify clinical instruments easily applicable in the clinical routine that might be useful to predict progression to dementia in patients with MCI assessed in the outpatient facility of a memory clinic.52 dementia-free patients (mean (standard deviation) age 70 (6) years; 56% women) with MCI, and 65 healthy controls (age 69 (6) years; 54% women) underwent brain magnetic resonance scan with standardised visual assessment of medial temporal atrophy (MTA) and subcortical cerebrovascular lesions (SVLs). Follow-up assessment occurred 15.4 (SD 3.4) months after baseline to detect incident dementia and improvement, defined as normal neuropsychological performance on follow-up.Patients were classified into three groups according to the presence of memory disturbance only (MCI Mem), other neuropsychological deficits (MCI Oth) or both (MCI Mem+). MCI Mem and Mem+ showed MTA more frequently (31% and 47% v 5% and 14% of controls and MCI Oth, p0.001). 11 patients developed dementia (annual rate 16.5%) and 7 improved on follow-up. The only independent predictor of progression was MTA (odds ratio (OR) 7.1, 95% confidence interval (CI) 1.4 to 35.0), whereas predictors of improvement were the absence of memory impairment (OR 18.5, 95% CI 2.0 to 171.3) and normal MRI scan (OR 10.0, 95% CI 1.7 to 60.2).Neuropsychological patterns identify groups of patients with MCI showing specific clinical features and risk of progression to dementia. MTA clinically rated with a visual scale is the most relevant predictor of progression and improvement.

Objective: To study the ability of patients with semantic dementia to understand actions, in order to examine the contribution of semantic memory to action comprehension. Methods: The ability to comprehend symbolic and instrumental actions was assessed in 6 patients with semantic dementia and 10 healthy controls. The patients were also given the imitation test of meaningful and meaningless actions. Results: In all patients with semantic dementia, comprehension of both symbolic and instrumental actions was defective. The comprehension of symbolic actions was more impaired than that of instrumental actions. Their ability to imitate other’s actions was well preserved. Conclusion: This study showed that comprehension of action was impaired in semantic dementia, suggesting that semantic memory has an important role in comprehension of human action.

Background: Attentional dysfunction is believed to be a prominent and distinguishing neuropsychological feature of dementia with Lewy bodies (DLB); yet, the specific nature of the attentional deficit and factors that can potentially influence attentional processing in DLB have not been fully defined. Aims: To clarify the nature of the attentional deficit in early-stage DLB relative to patients with early-stage dementia of the Alzheimer’s type (DAT) and elderly controls, and examine the effect of task complexity and type of cognitive load on attentional processing in DLB. Methods: Attentional impairment and fluctuating attention were investigated in three groups of subjects—patients with clinical features of early probable DLB (n = 20), a group with early probable DAT (n = 19) and healthy elderly controls (n = 20)—using an experimental computerised reaction time paradigm. Results: Patients with DLB showed greater attentional impairment and fluctuations in attention relative to patients with DAT and elderly controls. The attentional deficit was generalised in nature but increased in magnitude as greater demands were placed on attentional selectivity. Attentional deficits in DLB were most pronounced under task conditions that required more active recruitment of executive control and visuospatial cognitive processes. Conclusions: Attentional deficits in DLB are widespread and encompass all aspects of attentional function. Deficits in higher cortical function influence the degree of attentional impairment and fluctuating attention, suggesting that attentional processing in DLB is mediated by interacting cortical and subcortical mechanisms. These findings serve to clarify the nature of the attentional deficit in DLB and have potentially important ramifications for our understanding of the neurocognitive underpinnings of fluctuations.

Objective: To determine the earliest symptoms of anosognosia in people with Alzheimer’s disease and to validate a criteria-guided strategy to diagnose anosognosia in dementia. Methods: A consecutive series of 750 patients with very mild or probable Alzheimer’s disease attending a memory clinic, as well as their respective care givers, was assessed using a comprehensive psychiatric evaluation. Results: The factors of anosognosia for (1) basic activities of daily living (bADL), (2) instrumental activities of daily living (iADL), (3) depression and (4) disinhibition were produced by a principal component analysis on the differential scores (ie, caregiver score minus patient score) on the anosognosia questionnaire for dementia. A discrepancy of two or more points in the anosognosia-iADL factor was found to have a high sensitivity and specificity to identify clinically diagnosed anosognosia in people with Alzheimer’s disease. By logistic regression analysis, the severity of dementia and apathy were both shown to be noticeably associated with anosognosia in people with Alzheimer’s disease. Conclusion: Anosognosia in those with Alzheimer’s disease is manifested as poor awareness of deficits in iADL and bADL, depressive changes and behavioural disinhibition. The frequency of anosognosia is found to increase considerably with the severity of dementia. The validity of a specific set of criteria to diagnose anosognosia in people with Alzheimer’s disease was shown, which may contribute to the early identification of this condition.

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 (χ 2 = 6.7, Fisher’s exact test p 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: Apathy is usually defined as reduced interest and participation in various activities. It is a frequent consequence of neurological and psychiatric disorders. Although various scoring methods have been proposed, there is a lack of validated, standardised instruments for detecting apathy and assessing its severity. Objective: To develop an apathy rating scale using a structured standardised interview capable of distinguishing between the condition’s various features. Methods: The Lille Apathy Rating Scale (LARS) is based on a structured interview. It includes 33 items, divided into nine domains. Responses are scored on a dichotomous scale. The participants used to validate the scale consisted of 159 patients with probable Parkinson’s disease and 58 healthy control subjects. The Marin Apathy Scale, the Montgomery and Asberg Depression Rating Scale, and the Mattis Dementia Rating Scale were also administered. Results: Principal component analysis showed that the LARS probed a single construct which forms the root of an oblique factor structure reflecting four dimensions: intellectual curiosity, self awareness, emotion, and action initiation. The main psychometric properties of the LARS (internal consistency, inter-rater and test-retest reliability) were satisfactory. Concurrent validity was evaluated by reference to the Marin scale and to judgements provided by expert clinicians. Conclusions: Standard validity indices showed that the LARS is sensitive and capable of distinguishing between apathy and depression. As a screening tool, the scale is able to support dichotomous judgements accurately and, when greater measurement sensitivity is required, also determine the severity of apathy within a four category classification.

Background: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer’s disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). Objective: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer’s disease, using volumetry and a visual rating scale. Methods: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer’s disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. Results: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer’s disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer’s disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. Conclusions: Hippocampal atrophy is not only a characteristic of Alzheimer’s disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.

Background: Falls and fractures contribute to morbidity and mortality in bradykinetic rigid syndromes. Methods: The authors performed a retrospective case notes review at the Queen Square Brain Bank for Neurological Disorders and systematically explored the relation between clinical features and falls and fractures in 782 pathologically diagnosed cases (474 with Parkinson’s disease (PD); 127 progressive supranuclear palsy (PSP); 91 multiple system atrophy (MSA); 46 dementia with Lewy bodies (DLB); 27 vascular parkinsonism; nine Alzheimer’s disease; eight corticobasal degeneration). Results: Falls were recorded in 606 (77.5%) and fractures in 134 (17.1%). In PD, female gender, symmetrical onset, postural instability, and autonomic instability all independently predicted time to first fall. In PD, PSP, and MSA latency to first fall was shortest in those with older age of onset of disease. Median latency from disease onset to first fall was shortest in Richardson’s syndrome (12 months), MSA (42), and PSP-parkinsonism (47), and longest in PD (108). In all patients fractures of the hip were more than twice as common as wrist and forearm fractures. Fractures of the skull, ribs, and vertebrae occurred more frequently in PSP than in other diseases. Conclusion: Measures to prevent the morbidity associated with falls and fractures in bradykinetic rigid syndromes may be best directed at patients with the risk factors identified in this study.

Objective: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. Methods: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. Results: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. Conclusion: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

Apathy and depression are the most frequent behavioural and psychiatric disorders in Alzheimer's disease, and may both have a negative impact on the progression of the illness.To examine the clinical correlates of apathy in Alzheimer's disease (AD), and to determine whether apathy is a significant predictor of more rapid cognitive, functional and emotional decline.Using a structured psychiatric evaluation, we examined a consecutive series of 354 subjects meeting clinical criteria for AD. Apathy was assessed by the Apathy Scale, and diagnosed using standardised criteria. Additional measurements included scales for depression, functional impairment, and global cognitive functions. A follow up evaluation was carried out in 247 patients (70% of the total sample) between 1 and 4 years after the baseline evaluation.Apathy was significantly associated with older age (p = 0.009), and a higher frequency of minor and major depression (p0.0001). Apathy at baseline was a significant predictor of depression at follow up (p = 0.01), and was associated with a faster cognitive (p = 0.0007) and functional decline (p = 0.006).Apathy in AD is a behavioural marker of a more aggressive dementia, characterised by a faster progression of cognitive, functional, and emotional impairment.

disease. Methods: An observational study in 342 Alzheimer patients followed in a memory clinic for 34.8 months (mean age 73.5 years, mini-mental state examination score (MMSE) 21.3 at entry); 129 were dyslipaemic treated with LLAs (47% with statins), 105 were untreated dyslipaemic, and 108 were normolipaemic. The rate of cognitive decline was calculated as the difference between the first and last MMSE score, divided by the time between the measurements, expressed by year. Patients were divided into slow and fast decliners according to their annual rate of decline (lower or higher than the median annual rate of decline in the total population). Results: Patients treated with LLAs had a slower decline on the MMSE (1.5 point/year, p = 0.0102) than patients with untreated dyslipaemia (2.4 points/year), or normolipaemic patients (2.6 points/year). Patients with a slower decline were more likely to be treated with LLAs. Logistic regression analysis, with low annual cognitive decline as the dependent variable, showed that the independent variable LLA (treated with or not) was positively associated with the probability of lower cognitive decline (odds ratio = 0.45, p = 0.002). Conclusions: LLAs may slow cognitive decline in Alzheimer's disease and have a neuroprotective effect. This should be confirmed by placebo controlled randomised trials in patients with Alzheimer's disease and no dyslipaemia. a hallmark of Alzheimer's disease. In transgenic animal models of Alzheimer's disease, hypercholesterolaemia accelerates the development of Alzheimer amyloid pathology. 91 0 Cholesterol- fed rabbits develop extracellular deposits of b-amyloid, and when they are placed subsequently on a control diet, a significant reduction in identifiable b-amyloid immunoreac- tivity is observed. 11 A strong association of late life high density lipoprotein (HDL) cholesterol levels with the number of neuritic plaques and neurofibrillary tangles in a population based necropsy series also support the view that cholesterol plays a role in the formation of Alzheimer's disease pathology.

Objectives: To investigate whether metacognitive impairments in self-awareness and self-monitoring occur in patients with frontotemporal dementia (FTD), particularly among those with prominent social and dysexecutive impairments. Methods: Patients diagnosed with FTD were divided by clinical subtype (social–dysexecutive (n = 12) aphasic (n = 15), and constituent subgroups of progressive non-fluent aphasia and semantic dementia) and compared with subjects with probable Alzheimer's disease (AD, n = 11) and age-matched healthy controls (n = 11). All subjects completed comprehensive behavioural ratings scales, which were compared with caregiver ratings. Subjects also rated their test performances in verbal associative fluency, word list learning, and memory task with comparisons made between actual and judged performance levels. Results: The FTD sample as a whole showed significantly less behavioural self-awareness and self-knowledge than the AD and healthy control samples. FTD patients with prominent social and dysexecutive impairments demonstrated the most extensive loss of self-awareness and self-knowledge, significantly overrating themselves in multiple social, emotional, and cognitive domains, and failing to acknowledge that any behavioural change had occurred in most areas. The remaining clinical samples showed select and minimal discrepancies. All clinical groups were significantly unaware of their apathy levels. Most FTD patients judged episodic cognitive test performance adequately, with partial difficulties observed in the socially impaired and progressive non-fluent aphasia subgroups. Conclusions: FTD patients, particularly those with prominent social and dysexecutive impairments, exhibit profound metacognitive anosognosia that may represent a loss of self-awareness, self-monitoring, and self-knowledge, likely related to significant prefrontal pathophysiology. Other FTD clinical groups and AD patients showed less pervasive and more select metacognitive deficiencies.

Background: The short term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced levodopa responsive Parkinson's disease (PD) are well documented, but long term benefits are still uncertain. Objectives: This study provides a 5 year follow up of PD patients treated with stimulation of the STN. Methods: Thirty seven consecutive patients with PD treated with bilateral STN stimulation were assessed prospectively 6, 24, and 60 months after neurosurgery. Parkinsonian motor disability was evaluated with and without levodopa treatment, with and without bilateral STN stimulation. Neuropsychological and mood assessments included the Mattis Dementia Rating Scale, the frontal score, and the Montgomery-Asberg Depression Rating Scale (MADRS). Results: No severe peri- or immediate postoperative side effects were observed. Six patients died and one was lost to follow up. Five years after neurosurgery: (i) activity of daily living (Unified Parkinson Disease Rating Scale (UPDRS) II) was improved by stimulation of the STN by 40% ("off" drug) and 60% ("on" drug); (ii) parkinsonian motor disability (UPDRS III) was improved by 54% ("off" drug) and 73% ("on" drug); (iii) the severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%. The MADRS was unchanged, but cognitive performance declined significantly. Persisting adverse effects included eyelid opening apraxia, weight gain, addiction to levodopa treatment, hypomania and disinhibition, depression, dysarthria, dyskinesias, and apathy. Conclusions: Despite moderate motor and cognitive decline, probably due to disease progression, the marked improvement in motor function observed postoperatively was sustained 5 years after neurosurgery.

Background: Mild cognitive impairment (MCI) has been considered a transitional state between normal aging and dementia, characterised by memory impairment but normal general cognitive functioning. Recently other cognitive deficits have been reported. This has led to a modification of MCI criteria. Objective: To examine which neuropsychological tests most clearly distinguish MCI subjects from normal controls. Methods: 112 consecutive MCI subjects and 35 controls were included in the study. The diagnosis of MCI was based on an objective history of cognitive decline and a neuropsychiatric examination, comprising instruments STEP, I-Flex, MMSE, and CDR. Participants were examined with 21 neuropsychological tests in the cognitive domains speed/attention, memory and learning, visuospatial function, language, and executive function. Results: Controls were significantly older. No differences were found in education or general intellectual capacity. Controls performed significantly better than MCI on tests within all five cognitive domains. The clearest differences were seen on language tests, followed by executive function, and learning and memory. Only two subjects (1.8%) were purely amnestic; 17% showed no impairment compared with controls, with a cut off of 1.5 SD below age mean. These subjects were better educated and performed significantly better on measures of general cognitive capacity. Conclusions: The results illustrate the heterogeneity of MCI, with a significant degree of impairment in all five cognitive domains. When examined with a comprehensive neuropsychological battery, very few subjects had an isolated memory impairment.

Background: Olfactory abnormalities are reported in Alzheimer’s disease and Parkinson’s disease. Anosmia appears to be common in dementia with Lewy bodies but not in pure Alzheimer’s disease. Objective: To determine whether anosmia improves discrimination between the Lewy body variant (LBV) of Alzheimer’s disease and “pure” Alzheimer’s disease. Methods: 106 cases of necropsy confirmed pure Alzheimer’s disease (n = 89) or LBV (n = 17) were reviewed. All had received butanol odour threshold testing. Anosmia was defined as a score ⩽1.0 on a 0–9 point scale. Logistic regression analysis was used to model potential predictors (for example, parkinsonism, smoking, hallucinations) of neuropathological diagnosis and anosmia. Results: LBV cases had an increased prevalence of anosmia (65%) compared with Alzheimer’s disease (23%; odds ratio (OR) = 6.3, p = 0.00045), or normal elderly people (6.7%). Within the dementia cases, the negative predictive value (92%) and specificity (78%) of anosmia were both good; sensitivity for detecting LBV was 65%, but the positive predictive value (PPV) was only 35%. Logistic regression models showed anosmia (OR = 5.4, p = 0.005) and visual hallucinations (OR = 7.3, p = 0.007) were strong independent predictors of Lewy body pathology. When anosmia was added as a core feature to consensus diagnostic criteria for probable Lewy body dementia, five additional cases of LBV were detected (29% increased sensitivity), but with four additional false positives (1% increased discrimination, 4% decreased specificity, 33% decreased PPV). Conclusions: Anosmia is very common in LBV. Adding anosmia as a core feature improved sensitivity for detecting LBV, but did not improve discrimination between Alzheimer’s disease and LBV owing to a concomitant increase in false positives.

Background: Drugs effective in Alzheimer-type dementia have been tested in subjects with mild cognitive impairment (MCI) because these are supposed to have Alzheimer's disease in the predementia stage. Objectives: To investigate whether MCI criteria used in these drug trials can accurately diagnose subjects with predementia Alzheimer's disease. Methods: MCI criteria of the Gal-Int 11 study, InDDEx study, ADCS memory impairment study, ampakine CX 516 study, piracetam study, and Merck rofecoxib study were applied retrospectively in a cohort of 150 non-demented subjects from a memory clinic. Forty two had progressed to Alzheimer type dementia during a five year follow up period and were considered to have predementia Alzheimer's disease at baseline. Outcome measures were the odds ratio, sensitivity, specificity, and positive and negative predictive value. Results: The odds ratio of the MCI criteria for predementia Alzheimer's disease varied between 0.84 and 11. Sensitivity varied between 0.46 and 0.83 and positive predictive value between 0.43 and 0.76. None of the criteria combined a high sensitivity with a high positive predictive value. Exclusion criteria for depression led to an increase in positive predictive value and specificity at the cost of sensitivity. In subjects older than 65 years the positive predictive value was higher than in younger subjects. Conclusions: The diagnostic accuracy of MCI criteria used in trials for predementia Alzheimer's disease is low to moderate. Their use may lead to inclusion of many patients who do not have predementia Alzheimer's disease or to exclusion of many who do. Subjects with moderately severe depression should not be excluded from trials in order not to reduce the sensitivity.

Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. Methods: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

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.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).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.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, p0.0001) and 23% in PDD (n = 30, p0.0001) 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.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.

Background: Whereas apathy is increasingly recognised as a frequent abnormal behaviour in dementia, its overlap with depression remains poorly understood. Aims: To assess the psychometric characteristics of a structured interview for apathy, and to examine the overlap between apathy and depression in dementia. Methods: A total of 150 patients with Alzheimer’s disease (AD) underwent a comprehensive psychiatric and cognitive assessment. Results: Twelve per cent of the sample met criteria for both apathy and depression, 7% met criteria for apathy only, and 31% met criteria for depression only. Apathy (but not depression) was significantly associated with more severe cognitive deficits. Apathy and anxiety scores accounted for 65% of the variance of depression scores in dementia, and the diagnosis of apathy had a minor impact on the rating of severity of depression. Conclusions: The Structured Interview for Apathy demonstrated adequate psychometric characteristics. Using a novel structured interview for apathy in AD we demonstrated that whereas the construct of depression primarily consists of symptom clusters of apathy and anxiety, apathy is a behavioural dimension independent of depression.

Objective: To assess visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Alzheimer's disease. Methods: 33 drivers with probable Alzheimer's disease of mild severity and 137 neurologically normal older adults underwent a battery of visual and cognitive tests and were asked to report detection of specific landmarks and traffic signs along a segment of an experimental drive. Results: The drivers with mild Alzheimer's disease identified significantly fewer landmarks and traffic signs and made more at-fault safety errors during the task than control subjects. Roadside target identification performance and safety errors were predicted by scores on standardised tests of visual and cognitive function. Conclusions: Drivers with Alzheimer's disease are impaired in a task of visual search and recognition of roadside targets; the demands of these targets on visual perception, attention, executive functions, and memory probably increase the cognitive load, worsening driving safety.

Background: Loss of insight is a core diagnostic criterion for frontotemporal dementia (FTD), whereas failure to recognise cognitive deficits and unawareness of disease (anosognosia) are well established findings in Alzheimer’s disease (AD). However, self awareness of personality has not been quantified in these patient groups. Methods: Twenty two patients (12 with frontal variant FTD; 10 with early AD) and 11 older adult normal controls completed self report questionnaires (the Interpersonal Adjectives Scales) describing their current personality. First degree relative informants completed two questionnaires, one describing the subject’s current personality, the other retrospectively describing the subject’s personality before disease onset. Differences between subject and informant reports of current personality were used to measure the accuracy of self awareness. Results: Discriminant function analysis showed significant differences in self awareness among the three groups, with those in the FTD group showing the greatest magnitude of error in the largest number of personality dimensions (dominance, submissiveness, cold heartedness, introversion, and ingenuousness). Despite personality changes over time, patients with AD showed accurate self awareness in all personality dimensions except submissiveness and extraversion. Normal controls showed a pattern of underestimating positive qualities, whereas patients with FTD exaggerated positive qualities and minimised negative qualities. For the personality facets showing impaired insight, the self reports of patients with FTD and AD most closely matched their premorbid personalities, suggesting a failure to update their self image after disease onset. Conclusions: This study operationalises research criteria for loss of insight in FTD.

Objective: To investigate the heterogeneity of idiopathic Parkinson's disease (PD) in a data driven manner among a cohort of patients in the early clinical stages of the disease meeting established diagnostic criteria. Methods: Data on demographic, motor, mood, and cognitive measures were collected from 120 consecutive patients in the early stages of PD (Hoehn and Yahr I–III) attending a specialist PD research clinic. Statistical cluster analysis of the data allowed the existence of the patient subgroups generated to be explored. Results: The analysis revealed four main subgroups: (a) patients with a younger disease onset; (b) a tremor dominant subgroup of patients; (c) a non-tremor dominant subgroup with significant levels of cognitive impairment and mild depression; and (d) a subgroup with rapid disease progression but no cognitive impairment. Conclusions: This study complements and extends previous research by using a data driven approach to define the clinical heterogeneity of early PD. The approach adopted in this study for the identification of subgroups of patients within Parkinson's disease has important implications for generating testable hypotheses on defining the heterogeneity of this common condition and its aetiopathological basis and thus its treatment.

Objectives: To explore the neural substrates corresponding to the perseverative errors in the Wisconsin Card Sorting Test (WCST). Methods: The study examined the correlations between the WCST performances and the SPECT measurements of regional cerebral blood flow (rCBF) in subjects with neurodegenerative dementia. Negative non-linear correlations between the rCBF and the two different types of the perseverative errors ("stuck-in-set" and "recurrent" perseverative errors) were calculated on a voxel basis and volume-of-interest basis in the mixed groups of 72 elderly and dementia patients. Results: The stuck-in-set perseverative error was associated with the reduced rCBF in the rostrodorsal prefrontal cortex, whereas the recurrent perseverative error was related to the left parietal activity but not to the prefrontal activity. Conclusions: These findings augment evidence that the rostrodorsal prefrontal cortex crucially mediates attentional set shifting, and suggest that the stuck-in-set perseverative errors would be a true pathognomonic sign of frontal dysfunction. Moreover, this study shows that the recurrent perseverative errors may not be associated closely with the prefrontal function, suggesting that this error and the stuck-in-set error should be differentially estimated in the WCST.

Background: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent. Objective: To study the pattern of brain atrophy in MCI. Methods: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p

Objective: To review the nature of the presentation of neurosyphilis, the value of diagnostic tests, and the classification of the disease. Methods: A retrospective review was carried out of the records of patients who had been identified as possible cases of neurosyphilis by a positive FTA-abs test in the CSF. The review extended over 10 years at a single hospital which served a population of mixed ancestry in a defined catchment area in the Western Cape province of South Africa. Patients were placed in predefined diagnostic categories, and clinical, radiological, and laboratory features were assessed. Results: 161 patients met diagnostic criteria for neurosyphilis: 82 presented with combinations of delirium and dementia and other neuropsychiatric conditions, and the remainder had typical presentations such as stroke (24), spinal cord disease (15), and seizures (14). The average age of presentation ranged from 35.9 to 42.6 years in the different categories of neurosyphilis. Of those followed up, 77% had residual deficits from their initial illness. Cerebrospinal fluid (CSF) VDRL was positive in 73% of cases. Conclusions: The diagnosis of neurosyphilis can be made with reasonable certainty if there is an appropriate neuropsychiatric syndrome associated with a positive CSF VDRL. If the VDRL is negative, a positive FTA-abs in an appropriate clinical setting, associated with raised CSF cell count, protein, or IgG index, is a useful method of identifying neurosyphilis. Tabes dorsalis has become uncommon, but this is likely to be the only manifestation of neurosyphilis that has been altered during the antibiotic era.

Item does not contain fulltext BACKGROUND: Vascular risk factors could play a role in the aetiology of Alzheimer's disease, but this has not been investigated in relation to neuroimaging findings OBJECTIVE: To evaluate the distribution of blood pressure and an indicator of atherosclerosis (pulse pressure) in patients with Alzheimer's disease with and without small vessel disease. METHODS: 152 Alzheimer patients underwent 1.0T MRI scanning. Blood pressure was measured with a sphygmomanometer. Small vessel disease was assessed by the presence of lacunar infarcts and white matter lesions. The distribution of blood pressure and pulse pressure, with or without small vessel disease, was assessed by linear regression analysis. RESULTS: Patients with small vessel disease had a higher blood pressure, a wider pulse pressure, and an increased prevalence of hypertension. These findings were strongly age dependent: for patients under 65, mean systolic blood pressure was higher in the subpopulation with small vessel disease than in those without (mean (SD): 149.9 (19.3) v 135.7 (20.5) mm Hg; p = 0.02). Hypertension was more common in patients with white matter lesions than in those without (75.6% v 45.1%; p = 0.03) and the pulse pressure was higher (61.9 (14.4) v 51.7 (11.5) mm Hg; p = 0.01). There was no relation between blood pressure and the degree of (sub)cortical and hippocampal atrophy in patients without small vessel disease. CONCLUSIONS: There was heterogeneity in Alzheimer's disease patients with respect to blood pressure and pulse pressure. Alzheimer's disease encompasses a heterogeneous group of disorders which share a common cognitive profile but with distinct radiological features with respect to white matter lesions.

Objective: To determine whether a cognitive test package can predict the onset of dementia up to 11 years later, and the extent to which this prediction is independent of that provided by APOE genotype. Methods: Prospective cohort study based on 54 general practices in the UK; 657 survivors of the 1088 participants in the MRC treatment trial of hypertension in older adults were followed for up to 11 years; 370 participants (57% of survivors) were traced, screened for dementia, and genotyped for APOE in 1994. Baseline assessments included trail making test A, paired associated learning test, Raven’s progressive matrices, and national adult reading test. At follow up, both mini-mental state examination and CAMCOG were used. Outcome measures were DSM-IIIR dementia and NINCDS-ADRDA possible and probable Alzheimer’s disease. Results: All the cognitive tests completed in 1983 predicted onset of dementia and Alzheimer’s disease up to 11 years later, as did APOE genotype. Cognitive test performance was not associated with APOE genotype. Addition of cognitive tests increased the area under the ROC curve for the prediction of Alzheimer’s disease provided by age, family history, and APOE genotype (0.81 v 0.69, p = 0.048); addition of APOE genotype did not increase the area under the ROC curve for the prediction provided by age, family history, and cognitive tests (0.81 v 0.77, p = 0.28). Conclusions: Simple tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia. The predictive information provided is independent of, but not enhanced by, the addition of APOE genotype.

Background: Carotid sinus syndrome (CSS) is a common cause of syncope in older persons. There appears to be a high prevalence of carotid sinus hypersensitivity (CSH) in patients with dementia with Lewy bodies (DLB) but not in Alzheimer's disease. Objective: To compare the prevalence of CSH in DLB and Alzheimer's disease, and to determine whether there is an association between CSH induced hypotension and brain white matter hyperintensities on magnetic resonance imaging (MRI). Methods: Prevalence of CSH was compared in 38 patients with DLB (mean (SD) age, 76 (7) years), 52 with Alzheimer's disease (80 (6) years), and 31 case controls (73 (5) years) during right sided supine carotid sinus massage (CSM). CSH was defined as cardioinhibitory (CICSH; >3 s asystole) or vasodepressor (VDCSH; >30 mm Hg fall in systolic blood pressure (SBP)). T2 weighted brain MRI was done in 45 patients (23 DLB, 22 Alzheimer). Hyperintensities were rated by the Scheltens scale. Results: Overall heart rate response to CSM was slower (RR interval = 3370 ms (640 to 9400)) and the proportion of patients with CICSH greater (32%) in DLB than in Alzheimer's disease (1570 (720 to 7800); 11.1%) or controls (1600 (720 to 3300); 3.2%) (p

Background and objective: Methodological variability in the assessment of white matter hyperintensities (WMH) in dementia may explain inconsistent reports of its prevalence and impact on cognition. We used a method of brain MRI segmentation for quantifying both tissue and WMH volumes in Alzheimer's disease (AD) and examined the association between WMH and structural and cognitive variables. Methods: A consecutive series of 81 patients meeting NINCDS-ADRDA criteria for probable AD was studied. Nineteen healthy volunteers of comparable age served as the control group. Patients had a complete neurological and neuropsychological evaluation, and a three dimensional MRI was obtained. Images were segmented into grey matter, white matter, and cerebrospinal fluid. WMH were edited on segmented images, and lobar assignments were based on Talairach coordinates. Results: Mild and moderate to severe AD patients had significantly more WMH than controls (p

The risk effect of APOE epsilon 4 allele for Alzheimer's disease is acknowledged, whereas the putative protective effect of epsilon 2 allele remains in debate.To investigate whether those inconsistent findings may be attributable to differences in age and sex composition of the study populations.A community dementia free cohort (n = 985) agedor =75 years was followed up to detect Alzheimer's disease cases (DSM-III-R criteria). Data were analysed using Cox models with adjustment for major potential confounders.Over a median 5.6 year follow up, Alzheimer's disease was diagnosed in 206 subjects. Compared with APOE epsilon 3/epsilon 3 genotype, the relative risk (RR) of Alzheimer's disease was 1.4 (95% confidence interval (CI), 1.0 to 2.0; p = 0.03) for heterozygous epsilon 4 allele and 3.1 (95% CI, 1.6 to 5.9) for homozygous epsilon 4 allele. The association between epsilon 4 allele and Alzheimer's disease risk was stronger in men than in women (RR related to the interaction term epsilon 4 allele by sex, 0.4; 95% CI, 0.2 to 0.9). The epsilon 4 allele accounted for one third of Alzheimer's disease cases among men, but only one tenth among women. The epsilon 2 allele was related to a reduced Alzheimer's disease risk mainly in people aged85 years (RR, 0.4; 95% CI, 0.2 to 0.8). The RR of Alzheimer's disease related to the interaction term of epsilon 2 allele by age was 2.4 (95% CI, 1.0 to 6.0; p = 0.06).The APOE genotype specific effects on Alzheimer's disease vary by age and sex, in which the epsilon 4 allele has a stronger risk effect in men, and the epsilon 2 allele confers a protective effect only in younger-old people.

Objectives: Although stroke associated with small vessel disease (SSVD) can induce both motor and cognitive impairment, the latter has received less attention. We aimed to evaluate the frequency of the varying severity levels of cognitive impairment, the determinants of severe cognitive impairment, and the association of cognitive impairment with functional outcome after SSVD. Methods: Consecutive patients admitted to hospital because of SSVD were assessed at 3 months after stroke. We performed a semi-structured clinical interview to screen for cognitive symptoms. Severity of cognitive symptoms was graded according to the Clinical Dementia Rating Scale (CDR). Performance on psychometric tests (Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale (cognition subscale), Mattis Dementia Rating Scale (initiation/perseverence subscale; MDRS I/P)) of patients of different CDR gradings was compared with that of 42 healthy controls. Basic demographic data, vascular risk factors, stroke severity (National Institute of Health Stroke Scale; NIHSS), pre-stroke cognitive decline (Informant Questionnaire on Cognitive Decline in the Elderly; IQCODE), functional outcome (Barthel index; BI), Instrumental Activities Of Daily Living; IADL), and neuroimaging features (site of recent small infarcts, number of silent small infarcts, white matter changes) were also compared among the groups. Regression analyses were performed to find predictors of severe cognitive impairment and poor functional outcome. Results: Among the 75 included patients, 39 (52%) complained of cognitive symptoms. The number of patients in each CDR grading was as follows: 39 (52%) had a CDR of 0, 26 (34.7%) had a CDR of 0.5, 10 (13.3%) had a CDR of ⩾1. Pre-stroke IQCODE and previous stroke predicted CDR⩾1. The NIHSS was associated with more impaired BI. The NIHSS and MDRS I/P contributed most to impaired IADL. Conclusions: Half of the patients with SSVD complained of varying severity of cognitive problems 3 months after stroke. Pre-stroke cognitive decline and previous stroke predict severe cognitive impairment post stroke. Stroke severity and executive dysfunction contribute most to a poor functional outcome.