Alzheimer Disease: Ballard CG

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.

O'Brien JT, Ballard CG. · No affiliation provided · BMJ. · Pubmed #11463665 links to  free full text

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Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S. · Department of Biomedical Sciences, Wolfson Centre for Age-related Diseases, Hodgkin Building, Guy's Campus, King's College, London, SE1 1UL, UK. · Curr Alzheimer Res. · Pubmed #15974896 No free full text.

Abstract: The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.

Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. · Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK. · J Neurol Sci. · Pubmed #15537525 No free full text.

Abstract: Cerebrovascular disease is highly heterogeneous but can culminate in vascular cognitive impairment or vascular dementia (VaD). As much as the clinical diagnosis warrants scrutiny, the neuropathological substrates of VaD also need to be better defined. Atherosclerosis and small vessel disease are the main causes of brain infarction. Lacunar infarcts or multiple microinfarcts in the basal ganglia, thalamus, brainstem and white matter are associated with more than half of VaD cases consistent with subcortical ischaemic VaD. White matter changes including regions of incomplete infarction are usually widespread in VaD, but their contribution to impairment is not explicit. Other pathologies including hippocampal injury and Alzheimer type of lesions may also modify the course of dementia. Similar to other common dementias consensus criteria for VaD need unambiguous definition to impact on preventative and treatment strategies and are critical for selective recruitment to clinical trials.

Ballard CG. · Wolfson Research Centre, Institute for Ageing and Health, Newcastle General Hospital, Newcastle-upon-Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #14676465 No free full text.

Abstract: Significant advances have been made in neuropathologic identification procedures for dementia with Lewy bodies (DLB), but difficulties remain in clinical diagnosis. Consensus criteria state that the core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations and spontaneous motor features of parkinsonism. At least two of these features must be present for the diagnosis of probable DLB. Assessments of the validity of the consensus criteria against autopsy generally indicate high specificity but varying sensitivity. More detailed assessments of core diagnostic features or better operationalization, particularly of fluctuating cognition, may help improve the diagnostic guidelines. Greater utilization of some features described as supporting the diagnosis (such as auditory hallucinations) and the potential inclusion of additional symptoms (such as REM sleep behavioral disorder) also may be useful. In addition, the potential role of more detailed neuropsychology and neuroimaging in the diagnostic process needs to be evaluated, although it is important that changes to the diagnostic criteria are based on empirical evidence. Other key issues pertain to the classification of DLB patients with concurrent Alzheimer's disease and the differentiation of DLB and Parkinson's disease dementia based on less than a 1-year history of parkinsonism preceding the dementia.

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.

Ballard CG. · Newcastle General Hospital, Newcastle-upon-Tyne, UK. · Eur Neurol. · Pubmed #11803198 No free full text.

Abstract: Cholinesterase inhibitors have produced the best evidence of clinical efficacy for treating patients with Alzheimer's disease (AD). Many of these drugs selectively inhibit acetylcholinesterase (AChE), but agents that also target butyrylcholinesterase (BuChE) may provide added benefits. As AD progresses, ACh regulation may become increasingly dependent on BuChE and dual inhibitors may provide more sustained efficacy than AChE-selective agents. Dual inhibition may also help to slow the formation of amyloidogenic compounds, providing an important disease-modifying mechanism. Rivastigmine is a dual inhibitor that has demonstrated benefits across the spectrum of AD severity and across the cognitive, functional and behavioural domains of AD. It is a priority for future clinical trials to determine whether agents with dual inhibition properties have greater clinical efficacy.

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.

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.

Porter RJ, Lunn BS, Walker LL, Gray JM, Ballard CG, O'Brien JT. · Academic Department of Psychiatry, University of Newcastle upon Tyne, England. · Am J Psychiatry. · Pubmed #10739429 links to  free full text

Abstract: OBJECTIVE: The study assessed the effects on global cognitive function and mood of a reduction of brain serotonin by means of acute tryptophan depletion in 16 patients with dementia of the Alzheimer type and in 16 cognitively intact comparison subjects. METHOD: In a double-blind, crossover design, subjects received a tryptophan-free amino acid drink to induce acute tryptophan depletion and, on a separate occasion, a placebo drink containing a balanced mixture of amino acids. On each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the Modified Mini-Mental State was administered at baseline and 4 hours later. RESULTS: Patients with dementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo. The comparison group showed no difference in mean score on the Modified Mini-Mental State after acute tryptophan depletion and after receiving placebo. No significant changes in mood were found in either group. CONCLUSIONS: Acute tryptophan depletion significantly impaired cognitive function in patients with dementia of the Alzheimer type. Compromised serotonergic function, in combination with cholinergic deficit, may make an important contribution to cognitive decline in dementia of the Alzheimer type.

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.

Ballard CG, Gauthier S, Cummings JL, Brodaty H, Grossberg GT, Robert P, Lyketsos CG. · King's College London, London, UK. · Nat Rev Neurol. · Pubmed #19488082 No free full text.

Abstract: Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms-atypical antipsychotics-have a modest but significant beneficial effect in the short-term treatment (over 6-12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics-preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.

Jones EL, Hanney M, Francis PT, Ballard CG. · Wolfson Centre for Age-related Disease, Wolfson CARD, Guy's Campus, King's College London, London SE1 1UL, United Kingdom. <> · Neurosci Lett. · Pubmed #19111900 No free full text.

Abstract: People with Down syndrome develop Alzheimer's disease with an early age of onset. Plasma amyloid beta (Abeta) levels were measured in individuals with Down syndrome who were over the age of 40. No associations between age and Abeta1-40 and Abeta1-42 concentrations were found and nor were Abeta1-40 and Abeta1-42 levels found to vary between those with Alzheimer's-type dementia and those without dementia. The APOE genotype was not found to have an impact upon Abeta1-40 or Abeta1-42 concentrations. These data suggest that other factors play important roles in determining the onset and progression of dementia in the Down syndrome population.

Jones EL, Margallo-Lana M, Prasher VP, Ballard CG. · Wolfson Centre for Age-Related Disease, Guy's Campus, King's College London, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #18765933 No free full text.

Abstract: BACKGROUND/AIMS: Most people with Down syndrome (DS) develop Alzheimer's disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype's effect on the age of onset of AD in DS. METHODS: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE and a polymorphism in APP, attt(5-8). RESULTS: Haplotype frequencies vary between those developing AD before 45 and those developing dementia after this age (p = 0.03). H1/H2 individuals are more likely to develop dementia before 45 than H1/H1 individuals (OR = 3, 95% CI = 1.01-8.91). CONCLUSION: Even in a condition driven by excess amyloid pathology, factors affecting tau are also important and should be considered as potential treatment targets.

Wilcock GK, Ballard CG, Cooper JA, Loft H. · From the Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, UK. · J Clin Psychiatry. · Pubmed #18294023 No free full text.

Abstract: OBJECTIVE: Long-standing evidence indicates that Alzheimer's disease patients with behavioral symptoms have a worse prognosis and a more rapid disease progression. The current retrospective analysis evaluated the efficacy and safety of memantine in a subpopulation of patients with Alzheimer's disease exhibiting behavioral symptoms of agitation/aggression or psychosis at baseline. METHOD: A pooled analysis was conducted in people with agitation/aggression or psychosis from 3 large 6-month, randomized studies in moderately severe to severe Alzheimer's disease. The effect of memantine and placebo on these specific symptoms was evaluated using the Neuropsychiatric Inventory (NPI) subitem cluster of agitation and psychosis. Outcomes on global, cognitive, and functional measures were also analyzed. RESULTS: Sixty percent of the total patient group had baseline symptoms of agitation/aggression, delusions, or hallucinations on the NPI. At both 12 and 24/28 weeks, there was a significant treatment advantage for memantine over placebo for the proportion of patients showing improvement on the defined neuropsychiatric symptom cluster (55.6% vs. 44.4% at week 12, p = .008; 58.0% vs. 44.8% at week 24/28, p = .002) and specifically for the treatment of agitation/aggression (55.3% vs. 43.1% at week 12, p = .011; 61.0% vs. 45.0% at week 24/28, p < .001). Placebo-treated patients in this population demonstrated an accelerated disease progression for global (Clinician's Interview-Based Impression of Change Plus Caregiver Input), cognitive (Severe Impairment Battery), and functional (Alzheimer Disease Cooperative Study Activities of Daily Living Inventory 19-item scale) outcomes, but memantine conferred statistically significant benefit for all measures. Tolerability in this population remained good, and fewer memantine-treated patients than placebo-treated patients withdrew due to adverse events. CONCLUSIONS: This post hoc analysis provides important evidence from placebo-controlled trials that memantine may be a safe and effective treatment in Alzheimer's disease patients with agitation/aggression or psychosis, who are otherwise prone to rapid progression. Memantine treatment provided benefits in cognitive, functional, and global outcomes in these patients and for their agitation/aggression.

Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O'Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, Anonymous00016. · Medical Research Council Neurogeneration Research Centre, Institute of Psychiatry, King's College London, London, United Kingdom. · N Engl J Med. · Pubmed #17914039 links to  free full text

Abstract: BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

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.

Andersson M, Hansson O, Minthon L, Ballard CG, Londos E. · Neuropsychiatric Clinic, Malmö University Hospital, Malmö, Sweden. · Int J Geriatr Psychiatry. · Pubmed #17621385 No free full text.

Abstract: OBJECTIVES: To determine whether orthostatic hypotension (OH) is more common in patients with dementia than in older people without cognitive impairment and to identify key differences in the profile of the orthostatic response and the pulse drive during orthostatic challenge between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: The orthostatic response was evaluated in 235 patients with AD, 52 patients with DLB and 62 elderly controls. The blood pressure and pulse rate were measured in supine position, immediately after standing up and after 1, 3, 5 and 10 min of standing. OH was defined as a reduction of systolic blood pressure (SBP) of at least 20 mm Hg or a reduction of diastolic blood pressure (DBP) of at least 10 mm Hg. RESULTS: OH occurred in 69% of the DLB patients and in 42% of the AD patients, but only in 13% of the controls (p<0.001 controls vs AD and controls vs DLB, p=0.001 AD vs DLB) The DLB patients had a greater drop in SBP than the other study groups during orthostatic challenge and had a more prolonged period of orthostasis. The pulse drive on orthostatic challenge was similar in between groups. However, in the DLB group it was not adequate to restore the blood pressure to supine values. CONCLUSIONS: Patients with DLB react different to orthostatic challenge than patients with AD or controls, with important clinical implications for key disease symptoms and treatment.

Sharp SI, Ballard CG, Chen CP, Francis PT. · King's College London, Wolfson Centre for Age-Related Diseases, UK. · Am J Geriatr Psychiatry. · Pubmed #17463193 No free full text.

Abstract: OBJECTIVE: Aggressive behavior in dementia is a major clinical management problem. METHOD: Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to alpha1-AdR was determined. RESULTS: Aggressive behavior was significantly correlated with alpha1-adrenoceptor number in patients with AD (R(s)=0.454, N=24). Furthermore, patients receiving ongoing neuroleptics had significantly higher Bmax for [3H] prazosin (21 +/- 2, N=9) than those who were not (16 +/- 1, N=15). CONCLUSIONS: Upregulation of alpha1-AdR is associated with aggressive behavior and chronic treatment with neuroleptic medication.

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.

Lewis H, Beher D, Cookson N, Oakley A, Piggott M, Morris CM, Jaros E, Perry R, Ince P, Kenny RA, Ballard CG, Shearman MS, Kalaria RN. · Department of Molecular & Cellular Neuroscience, Merck, Sharp & Dohme Research Laboratories, Terlings Park, Essex. · Neuropathol Appl Neurobiol. · Pubmed #16599940 No free full text.

Abstract: Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.

Allan LM, Ballard CG, Burn DJ, Kenny RA. · Institute for Aging and Health, University of Newcastle upon Tyne, United Kingdom. · J Am Geriatr Soc. · Pubmed #16181166 No free full text.

Abstract: OBJECTIVES: To compare the prevalence, severity, and type of gait and balance disorders in Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease with dementia (PDD), dementia with Lewy bodies (DLB), Parkinson's disease without dementia (PD), and age-matched controls. DESIGN: Cross-sectional. SETTING: Secondary care clinics in geriatric psychiatry, neurology, and geriatrics. PARTICIPANTS: Two hundred forty-five participants aged 65 and older (AD, n=40; VaD, n=39; PDD, n=46; DLB, n=32; PD, n=46; and controls, n=42). MEASUREMENTS: Prevalence and severity of gait and balance disorders were assessed using the Tinetti gait and balance scale. The types of gait disorders in each diagnostic group were classified using the Nutt et al. classification. RESULTS: Gait and balance disorders were more common with PDD (93%), VaD (79%), and DLB (75%) than with PD (43%) and AD (25%) and in controls (7%). The risk of gait and balance disorder was higher in the non-Alzheimer's dementia groups (VaD, PDD, and DLB) than in the AD group (odds ratio=15 (95% confidence interval=6-37). If a gait disorder was present in mild dementia (Cambridge Examination for Mental Disorders of the Elderly cognitive subsection score >65), this was diagnostic of non-Alzheimer's dementia, with sensitivity of 78% and specificity of 100%. Non-Alzheimer's dementia groups had worse Tinetti gait and balance scores than the AD group (all P<.001). The types of gait disorders discriminated between non-Alzheimer's dementias. CONCLUSION: The findings support the idea that gait and balance assessment may augment the diagnostic evaluation of dementia.

Ballard CG, Perry RH, McKeith IG, Perry EK. · Wolfson Centre for Age Related Diseases, King's College London, UK. · Int J Geriatr Psychiatry. · Pubmed #16116579 No free full text.

Abstract: BACKGROUND: Neuroleptics are only modestly effective in dementia and associated with a range of adverse effects including cognitive decline. Effects of the drugs on molecular pathology in brain tissue from people with dementia have not been investigated. OBJECTIVES: To compare the severity of Alzheimer type pathology in matched groups of people with dementia with Lewy bodies (DLB), treated and not treated with neuroleptics. METHODS: The relationship between neuroleptics and Alzheimer-type pathology was determined in 40 (17 neuroleptic treated, 23 neuroleptic free, matched for age, disease duration and psychosis) clinically prospectively studied, autopsy diagnosed DLB patients. RESULTS: In regression analyses, taking neuroleptics was significantly associated with increased neurofibrillary tangles but not amyloid plaques in cortical areas examined. The patient characteristics and the frequencies of key psychiatric symptoms were similar in the patients taking and not taking neuroleptics. CONCLUSION: Although patients were not randomized and the results which are observed need to be interpreted cautiously, if substantiated, this is an important finding with major implications for the pharmacological management of DLB patients and highlights the need to determine the impact of neuroleptics upon tangle pathology in AD.