Alzheimer Disease: McKeith IG

Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B, Anonymous00263. · Memory Disorders Research Group, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark. · Eur J Neurol. · Pubmed #17222085 No free full text.

Abstract: The aim of this international guideline on dementia was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta-analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

McKeith IG, Burn DJ, Ballard CG, Collerton D, Jaros E, Morris CM, McLaren A, Perry EK, Perry R, Piggott MA, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK. · Semin Clin Neuropsychiatry. · Pubmed #12567332 No free full text.

Abstract: The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Barber R, Panikkar A, McKeith IG. · Centre for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Int J Geriatr Psychiatry. · Pubmed #11748785 No free full text.

Abstract: OBJECTIVE: To summarize the clinical, pathological, imaging and treatment aspects of dementia with Lewy bodies (DLB). METHOD: Review of literature (MEDLINE). RESULTS: DLB is the second most common form of degenerative dementia, accounting for up to 20% of cases in the elderly. It is characterized by fluctuating cognitive impairment, spontaneous parkinsonism and recurrent visual hallucinations. Consensus clinical criteria have been published and have been shown to have high specificity, but they may still lack sensitivity. Pathologically, DLB may be classified as a Lewy body (LB) disorder and/or as an alpha-synucleinopathy. It is probable that a spectrum of LB disorders exists with the clinical features reflecting the distribution and severity of pathology. Although both DLB and Alzheimer's disease (AD) show a reduction in pre-synaptic cholinergic transmission from the basal forebrain, in DLB there are also deficits in cholinergic transmission from brain stem nuclei. Post-synaptic cortical muscarinic receptors are more functionally intact in DLB suggesting potential responsiveness to cholinergic enhancement. Neuroimaging findings indicate a relative preservation of medial temporal lobe structures in DLB but similar distribution of white matter changes on MRI compared with AD. Defects in nigrostriatal dopamine pathways in DLB have been demonstrated with functional neuroimaging using ligands highlighting pre- and post-synaptic dopaminergic systems. Preliminary studies also indicate subtle differences in perfusion patterns on SPECT with a greater degree of occipital hypoperfusion in DLB compared with AD. Accurate diagnosis of DLB is clinically important as the management of psychosis and behavioural disturbances is complicated by sensitivity to neuroleptic medication. There is accumulating evidence to suggest that DLB may be particularly amenable to cholinergic enhancers. The clinical management of DLB is considered using a four step approach: making a diagnosis; identification of problem symptoms; appropriate non-pharmacological interventions; and pharmacological interventions. CONCLUSIONS: Consensus criteria for probable DLB have high specificity-a positive clinical diagnosis is likely to be correct. Treatment choices must consider effects upon motor, cognitive and psychiatric symptoms. Non-pharmacological management is an essential first step, as is reduction or withdrawal of drugs with potential adverse effects. Neuroleptic sensitivity reactions appear less likely to occur with the newer atypical antipsychotics. Cholinesterase inhibitors have been shown in open-label studies and one placebo RCT to be well tolerated and effective in treating cognitive and psychiatric symptoms in DLB. They may become first-line treatments.

Kalaria RN, Ballard CG, Ince PG, Kenny RA, McKeith IG, Morris CM, O'Brien JT, Perry EK, Perry RH, Edwardson JA. · MRC-Newcastle University Centre Development in Clinical Brian Ageing, Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Novartis Found Symp. · Pubmed #11280033 No free full text.

Abstract: Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Colloby SJ, O'Brien JT, Fenwick JD, Firbank MJ, Burn DJ, McKeith IG, Williams ED. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle- upon-Tyne NE4 6BE, UK. · Neuroimage. · Pubmed #15528096 No free full text.

Abstract: Dopaminergic loss can be visualised using (123)I-FP-CIT single photon emission computed tomography (SPECT) in several disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Most previous SPECT studies have adopted region of interest (ROI) methods for analysis, which are subjective and operator-dependent. The purpose of this study was to investigate differences in striatal binding of (123)I-FP-CIT SPECT using the automated technique of statistical parametric mapping (SPM99) in subjects with DLB, Alzheimer's disease (AD), PD and healthy age-matched controls. This involved spatial normalisation of each subject's image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean occipital count per voxel. Group differences were assessed using a two-sample t test. Applying a height threshold of P <or= 0.05 corrected, the SPM[t] maps showed a significant bilateral reduced uptake in caudate, anterior and posterior putamen in DLB and PD subjects compared to AD subjects and controls. Significant reduction in binding was also observed bilaterally in the caudate nucleus in AD compared to controls. Striatal binding was indistinguishable between patients with DLB and PD. To investigate the usefulness of SPM as a decision aid in the evaluation of visually rated normal and abnormal patterns of uptake, receiver operator characteristic (ROC) curve analysis was performed using data from single-subject SPMs. The areas under the ROC curves were greater than 0.92, demonstrating comparable discriminatory power with visual rating. The automated voxel-based approach is a viable alternative to the subjective and often time-consuming method of ROI and, in addition, may have the potential to differentiate between normal and abnormal patterns of uptake in a manner similar to visual inspection.

Cousins DA, Burton EJ, Burn D, Gholkar A, McKeith IG, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neurology. · Pubmed #14610119 No free full text.

Abstract: OBJECTIVE: To compare the volume of the putamen on MRI in subjects with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and age-matched normal control subjects, along with the relationship between putamen volume and severity of both extrapyramidal signs and cognitive impairment. METHODS: MRI-based volumetric measurements at 1.5 T of total intracranial volume, total brain volume, and putamen volume were acquired in elderly patients with AD (n = 27; 77.6 years) and DLB (n = 14; 76.2 years) and normal control subjects (n = 37; 75.4 years). Patients and control subjects also underwent a standardized neuropsychiatric examination including the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Cambridge Cognitive Examination (CAMCOG) with Mini-Mental State Examination (MMSE). RESULTS: Patients with DLB had smaller raw putamen volumes than control subjects (right 12.5% reduction, p = 0.007; left 13.7% reduction, p = 0.003). When putamen volume was normalized to total intracranial volume, patients with DLB had significantly smaller volume ratios than both controls and patients with AD. Patients with AD did not differ from control subjects on any measure of putamen volume. Putamen volume did not correlate with age or with scores on UPDRS III, CAMCOG, or MMSE in any of the groups. CONCLUSIONS: Atrophy of the putamen is a feature of DLB. This may be important in understanding the etiology of parkinsonian features seen in DLB, though in this study, no direct correlation was found between degree of volume loss and severity of parkinsonism.

Firbank MJ, Colloby SJ, Burn DJ, McKeith IG, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Neuroimage. · Pubmed #14568499 No free full text.

Abstract: Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.

Karas GB, Burton EJ, Rombouts SA, van Schijndel RA, O'Brien JT, Scheltens P, McKeith IG, Williams D, Ballard C, Barkhof F. · Department of Diagnostic Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #12725765 No free full text.

Abstract: Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimer's disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

Burton EJ, Karas G, Paling SM, Barber R, Williams ED, Ballard CG, McKeith IG, Scheltens P, Barkhof F, O'Brien JT. · Institute for Ageing and Health, University of Newcastle upon Tyne, United Kingdom. · Neuroimage. · Pubmed #12377138 No free full text.

Abstract: Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

Walker MP, Ayre GA, Perry EK, Wesnes K, McKeith IG, Tovee M, Edwardson JA, Ballard CG. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #11044778 No free full text.

Abstract: Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. · Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle, UK. · Neurology. · Pubmed #10762503 No free full text.

Abstract: BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.

Ballard CG, Ayre G, O'Brien J, Sahgal A, McKeith IG, Ince PG, Perry RH. · MRC Neurochemical Pathology Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #10026383 No free full text.

Abstract: Consecutive patients from a dementia case register received a standardised evaluation which incorporated a neuropsychological assessment with the Cambridge Assessment for disorders in the elderly (CAMCOG). Operationalised clinical diagnoses were made (consensus criteria for dementia with Lewy bodies, DLB; NINCDS- ADRDA for Alzheimer's disease, AD, NINCDS AIRENS for vascular dementia, VaD). Two-hundred and twenty-eight patients were studied (DLB 54, AD102, VaD 72). DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis. DLB patients also had significantly better recent memory than those with VaD. Optimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.

Colloby SJ, Firbank MJ, Pakrasi S, Lloyd JJ, Driver I, McKeith IG, Williams ED, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. · Int Psychogeriatr. · Pubmed #18752700 No free full text.

Abstract: BACKGROUND: The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging. METHODS: Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis. RESULTS: Inter-rater agreement for categorizing uptake was "moderate" (mean kappa = 0.53) for 99mTc-exametazime and "excellent" (mean kappa = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03. CONCLUSION: Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.

Matthews FE, Stephan BC, McKeith IG, Bond J, Brayne C, Anonymous00158. · Medical Resarch Council Biostatistics Unit, Institute of Public Health, Cambridge, United Kindom. · J Am Geriatr Soc. · Pubmed #18662209 No free full text.

Abstract: OBJECTIVES: To determine the 2-year outcome from 16 different current classifications of mild cognitive impairment (MCI) in a population-based sample. DESIGN: Prospective cohort study: baseline and 2-year follow-up phases. SETTING: Large-scale multicenter study, United Kingdom. PARTICIPANTS:: Thirteen thousand four individuals aged 65 and older from the Medical Research Council Cognitive Function and Ageing Study. From this, a subsample of 2,640 individuals was selected and completed a more-detailed cognitive assessment. Individuals who underwent further assessment were asked to complete annual or 2-year follow-ups. MEASUREMENTS: Information on sociodemographic status, general health, cognitive impairment and functional ability were collected using a structured interview. Individuals were classified according to 16 different definitions of MCI. These were applied retrospectively. RESULTS: The dominant outcome across definitions was an impairment that was not classifiable or reversion to normality. Progression to dementia was variable and generally poor. Overall progression was highest in classifications in which impairment extended to memory and nonmemory domains. Predictability was age dependent in some but not all classifications. CONCLUSION: Current classifications of MCI have variable outcomes in population-based samples. Progression to dementia is relatively rare and is dependent on age and definition. Selection criteria developed for the clinic are based on a "high risk" approach that leads to exclusion of a large percentage of the impaired population who are neither normal nor demented and for whom no intervention options are currently available. A refined definition of this construct is urgently needed if MCI is to be used to predict dementia in population-based studies.

Mukaetova-Ladinska EB, Milne J, Andras A, Abdel-All Z, Cerejeira J, Greally E, Robson J, Jaros E, Perry R, McKeith IG, Brayne C, Xuereb J, Cleghorn A, Doherty J, McIntosh G, Milton I. · Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #18577885 No free full text.

Abstract: BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

Piggott MA, Ballard CG, Rowan E, Holmes C, McKeith IG, Jaros E, Perry RH, Perry EK. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, United Kingdom. · Synapse. · Pubmed #17663455 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is a progressive dementia frequently accompanied by psychotic symptoms. Similar symptoms can occur in Alzheimer's disease (AD) to a lesser extent. The use of neuroleptic medication to treat psychosis in both diseases is of modest efficacy and can induce severe adverse reactions in DLB. Dopamine D2 receptors in the cerebral cortex are the putative target for the antipsychotic action of these drugs, but the status of these receptors in DLB is unknown. Autoradiography was used to examine the density D2 receptors in postmortem temporal cortex tissue from prospectively assessed patients with neuropathologically confirmed DLB and AD. D2 receptors were substantially (over 40%) and significantly (P < 0.001) reduced in temporal cortex in DLB, and in DLB with concomitant Alzheimer pathology, but was not significantly changed in AD. This reduction correlated with greater cognitive decline (P < 0.01), but was not significantly related to visual or auditory hallucinations or delusions. D2 receptor density was inversely correlated with cortical Lewy body pathology in the neocortex (P < 0.001). The specific loss of D2 receptors associated with Lewy body pathology, in conjunction with our previous finding of low D2 receptors in striatum in DLB, provides a possible explanation for neuroleptic intolerance. That the reduction of D2 receptors correlated with cognitive decline suggests that neuroleptics, as dopamine D2 receptor antagonists, may have a deleterious effect on cognition in DLB.

Pakrasi S, Colloby SJ, Firbank MJ, Perry EK, Wyper DJ, Owens J, McKeith IG, Williams ED, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · J Neurol. · Pubmed #17361343 No free full text.

Abstract: BACKGROUND : One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. OBJECTIVE : To investigate differences in the distribution of M1/M4 receptors using (R, R) (123)I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare (123)I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. METHODS : Forty two subjects (18 AD and 24 healthy elderly controls) underwent (123)IQNB and perfusion (99m)Tc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. RESULTS : Significant reductions in (123)I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p < or = 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. CONCLUSION : Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.

Taylor JP, Colloby SJ, McKeith IG, Burn DJ, Williams D, Patterson J, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17299017 No free full text.

Abstract: 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.

Allan LM, Ballard CG, Allen J, Murray A, Davidson AW, McKeith IG, Kenny RA. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17178816 No free full text.

Abstract: 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.

Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, Marlowe L, Lees A, Leung D, McKeith IG, Perry RH, Morris CM, Trojanowski JQ, Clark C, Karlawish J, Arnold S, Forman MS, Van Deerlin V, de Silva R, Hardy J. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892-3707, USA. · Neurobiol Dis. · Pubmed #17174556 No free full text.

Abstract: Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer's disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.

O'Brien JT, Colloby SJ, Pakrasi S, Perry EK, Pimlott SL, Wyper DJ, McKeith IG, Williams ED. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17135460 No free full text.

Abstract: 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.

Boddy F, Rowan EN, Lett D, O'Brien JT, McKeith IG, Burn DJ. · Institute for Ageing and Health, University of Newcastle, UK. · Int J Geriatr Psychiatry. · Pubmed #17096456 No free full text.

Abstract: OBJECTIVE: We compared subjective sleep quality and excessive daytime somnolence (EDS) in controls, Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We investigated whether sleep dysfunction and EDS associate with motor phenotype in PD, PDD and DLB. METHOD: Assessments included the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: EDS was more frequent in PD, DLB and PDD patients than in AD. PDD, PD and DLB patients also had worse sleep quality when compared with AD and controls. Baseline postural instability-gait difficulty (PIGD) motor phenotype in PDD was associated with a higher ESS score and frequency of EDS, but this association was lost at two years. PSQI scores did not differ between PIGD dominant and non-dominant PD, PDD and DLB patients. CONCLUSION: EDS and poor sleep quality are greater in PD, PDD and DLB, compared with AD. The dissociation of EDS and motor phenotype suggests their pathophysiology is anatomically and/or temporally distinct.

Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · Am J Geriatr Psychiatry. · Pubmed #17001024 No free full text.

Abstract: OBJECTIVE: The objective of this study was to investigate cross-sectional and longitudinal white matter hyperintensity (WMH) changes in older subjects with clinically diagnosed dementia. METHODS: Fluid-attenuated inversion recovery images were acquired one year apart in subjects with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Alzheimer disease (AD), and also healthy elderly comparison subjects. WMH volume was quantified using an automated technique. RESULTS: Baseline WMH (as a percent of brain volume) was significantly greater compared with healthy subjects (N=33, geometric mean WMH: 0.4%) in subjects with AD (N=23 [1.3%], analysis of variance post hoc p <0.001) but not PDD (N=13 [0.6%]) or DLB (N=14 [0.4%]). Increase in WMH volume (as a percent of brain volume) was not significantly different (Kruskal-Wallis p=0.4) between groups (AD median change: 0.08%; DLB: 0.025%; PDD: 0.07%, healthy: 0.02%). Severity of baseline WMH, rather than diagnosis or severity of dementia, was a significant predictor of lesion progression. Rate of change of WMH had no association with change in global cognitive performance. CONCLUSIONS: Significant WMH progression occurs in degenerative dementias with rates influenced by severity of lesions at baseline rather than dementia type or cognitive decline.

McKeith IG, Rowan E, Askew K, Naidu A, Allan L, Barnett N, Lett D, Mosimann UP, Burn D, O'Brien JT. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle-Upon-Tyne, UK. · Am J Geriatr Psychiatry. · Pubmed #16816011 No free full text.

Abstract: OBJECTIVE: The objective of this study was to compare functional impairments in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and their relationship with motor and neuropsychiatric symptoms. METHODS: The authors conducted a cross-sectional study of 84 patients with DLB or AD in a secondary care setting. Patients were diagnosed according to published criteria for DLB and AD. The Bristol Activities of Daily Living Scale (BADLS) was used to assess functional impairments. Participants were also assessed using the Unified Parkinson's Disease Rating Scale (motor section), the Neuropsychiatric Inventory, and the Mini-Mental Status Examination. RESULTS: Patients with DLB were more functionally impaired and had more motor and neuropsychiatric difficulties than patients with AD with similar cognitive scores. In both AD and DLB, there were correlations between total BADLS scores and motor and neuropsychiatric deficits. There was more impairment in the mobility and self-care components of the BADLS in DLB than in AD, and in DLB, these were highly correlated with UPDRS score. In AD, orientation and instrumental BADLS components were most affected. CONCLUSION: The nature of functional disability differs between AD and DLB with additional impairments in mobility and self-care in DLB being mainly attributable to extrapyramidal motor symptoms. Consideration of these is important in assessment and management. Activities of daily living scales for use in this population should attribute the extent to which functional disabilities are related to cognitive, psychiatric, or motor dysfunction.