Alzheimer Disease: Kenny RA

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.

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.

Kenny RA, Kalaria R, Ballard C. · MRC Development Centre for Clinical Brain Ageing, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. · Ann N Y Acad Sci. · Pubmed #12480751 No free full text.

Abstract: Neurocardiovascular instability (NCVI, neurally mediated disorders causing hypotension with or without bradycardia) represents abnormal neural control of the cardiovascular system and presents as dizziness, syncope, or falls. The mechanisms underpinning NCVI are incompletely understood. The three most common disorders are carotid sinus syndrome (CSS), orthostatic hypotension (OH), and vasovagal syndrome (VVS): CSS, cardioinhibition > 3 s and/or vasodepressor response > or = 50 mmHg drop in systolic pressure during carotid sinus stimulation; OH: fall in systolic blood pressure > 20 mmHg during standing; VVS: cardioinhibition > 3 s and/or vasodepressor response > 50 mmHg during prolonged head-up tilting. In fallers with cognitive impairment or dementia, the prevalence of NCVI is 70%. Multifactorial interventions, including treatment of NCVI, significantly reduce falls and syncope. The predominant components of NCVI in fallers with cognitive impairment and dementia are CSS and OH. In Lewy body and Alzheimer's dementia, the prevalence of NCVI is up to 60%, again predominantly CSS and OH. The prevalence of cardioinhibitory carotid sinus hypersensitivity is particularly high in Lewy body dementia-41% compared with 12% in Alzheimer's disease and 3% in case controls. In addition, patients with Lewy body dementia have greater heart rate slowing (>2 s) and falls in systolic blood pressure (>20 mmHg) than those with Alzheimer's disease or controls during carotid sinus stimulation. The extent of deep white matter hyperintensities on MRI correlates with systolic fall during carotid sinus stimulation (R = 0.58; p < 0.005), suggesting a possible causal association between bradyarrhythmia-induced hypotension and microvascular pathology. NCVI is common in patients with dementia and may be a reversible cause of falls and syncope. Repeated hypotensive episodes may exaggerate cognitive decline in these patients.

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.

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.

Allan LM, Kerr SR, Ballard CG, Allen J, Murray A, McLaren AT, Kenny RA. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #15627761 No free full text.

Abstract: Heart rate variability (HRV) is a sensitive method for the assessment of autonomic function and requires little cooperation from the subject, making it suitable for use in dementia. Preliminary studies have suggested that HRV may be impaired in Alzheimer's disease (AD). HRV has not been studied in vascular dementia (VAD). We investigate autonomic function in AD and VAD, using power spectral analysis of HRV. One hundred and fourteen participants were evaluated (14 AD, 20 VAD and 80 controls). The resting ECG was recorded for 5 min with participants in the supine position. Power spectral analysis used to obtain spectral bands in the very-low-frequency (<0.04 Hz), low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) bands and total spectral power (<0.40 Hz) according to international HRV guidelines. There were no differences in HRV in patients with AD or VAD when compared with controls.

Thomas A, Ballard C, Kenny RA, O'Brien J, Oakley A, Kalaria R. · Institute for Ageing and Health, Newcastle, UK. · Dement Geriatr Cogn Disord. · Pubmed #15572872 No free full text.

Abstract: OBJECTIVE: To examine the relationship of the anatomic distribution of amyloid deposition to focal and global cognitive dysfunction in different subtypes of dementia. METHODS: We quantified AB40 and AB42 in the temporal lobe and entorhinal cortex and examined their relationship to cognitive functions in Alzheimer's disease (AD), vascular dementia (VaD) and dementia with Lewy bodies (DLB). RESULTS: We found a correlation between memory impairment, but not global cognitive impairment, and amyloid load in these areas in AD and VaD but not in DLB. This relationship was stronger for AB42 and in the entorhinal cortex. CONCLUSION: The anatomic location of amyloid deposition is an important factor-specific factor in memory impairment in AD and VaD.

Kenny RA, Shaw FE, O'Brien JT, Scheltens PH, Kalaria R, Ballard C. · MRC Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15201351 links to  free full text

Abstract: 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<0.01)). The strongest predictor of heart rate slowing and CSH was a diagnosis of DLB (Wald 8.0, p<0.005). The fall in SBP during carotid sinus massage was greater with DLB (40 (22) mm Hg) than with Alzheimer's disease (30 (19) mm Hg) or controls (24 (19) mm Hg) (both p<0.02). Deep white matter hyperintensities were present in 29 patients (64%). In DLB, there was a correlation between magnitude of fall in SBP during CSM and severity of deep white matter changes (R = 0.58, p = 0.005). CONCLUSIONS: Heart rate responses to CSM are prolonged in patients with DLB, causing hypotension. Deep white matter changes from microvascular disease correlated with the fall in SBP. Microvascular pathology is a key substrate of cognitive impairment and could be reversible in DLB where there are exaggerated heart rate responses to carotid sinus stimulation.

Ballard C, Stephens S, McLaren A, Wesnes K, Kenny RA, Burton E, O'Brien J, Kalaria R. · Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle NE4 6BE, United Kingdom. · Ann N Y Acad Sci. · Pubmed #12480750 No free full text.

Abstract: This paper examines the frequency of CIND, the profile of early cognitive deficits in stroke patients, the differences in the profile of cognitive impairment in people with CIND and those with vascular dementia, and the MRI associations of CIND in older stroke patients.

Ballard C, O'Brien J, Barber B, Scheltens P, Shaw F, McKeith I, Kenny RA. · Institute for the Health of the Elderly, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Ann N Y Acad Sci. · Pubmed #10818535 No free full text.

Abstract: We investigated whether carotid sinus hypersensitivity (CSH) and orthostatic hypotension (OH) were associated with a greater severity of hyperintensities on MRI scan in 30 patients with neurodegenerative dementia (17 dementia with Lewy bodies, 13 Alzheimer's disease), who had a detailed evaluation of OH and CSH during active standing and head-up tilt. Patients also underwent a 1.0 Tesla MRI scan, from which hyperintensities were rated on a standardized scale. A blood pressure (BP) drop > 30 mm Hg during carotid sinus massage or active standing was significantly associated with the severity of MRI hyperintensities in the deep white matter (OR 10.0, 95%; CI 1.8-55.7) and in the basal ganglia (OR 11.0, 95%; CI 1.2-99.5) but not in periventricular areas (OR 1.4, 95%; CI 0.3-1.8). Patients with the cardio-inhibitory form of CSH with the largest BP drops were the most at risk. Further longitudinal studies need to investigate the direction of causality to determine whether CSH or OH predispose to MRI hyperintensities and accelerate cognitive decline.