Alzheimer Disease: Kalaria RN

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. · London Health Sciences Centre, University Campus, London, Ontario, Canada. · Stroke. · Pubmed #16917086 links to  free full text

Abstract: BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

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.

Ihara M, Kalaria RN. · No affiliation provided · Neuroreport. · Pubmed #17632268 No free full text.

This publication has no abstract.

Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P, Anonymous00415. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #18667359 No free full text.

Abstract: Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions.

Román GC, Kalaria RN. · University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. · Neurobiol Aging. · Pubmed #16300856 No free full text.

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.

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.

Kalaria RN. · Wolfson Centre, Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Neurol Res. · Pubmed #14503021 No free full text.

Abstract: Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid beta whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias.

Kalaria RN. · Institute for Ageing and Health, Newcastle General Hospital, and Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK. · Cerebrovasc Dis. · Pubmed #11901243 No free full text.

Abstract: Current evidence suggests that the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of Alzheimer disease (AD) cases may exhibit significant cerebrovascular pathology, which constitutes distinct small vessel disease (SVD). Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis and fibrosis are often evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. Amyloid beta protein may cause degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. In addition, macro- and microinfarctions, haemorrhages, lacunes and ischaemic white matter changes are also present in AD. The development of SVD in late-onset AD may engage an interaction of perivascular mediators as well as circulation-derived factors that perturb the brain vasculature. Peripheral vascular disease such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease and diabetes could further modify the cerebral circulation such that a sustained hypoperfusion or oligaemia is impacted upon the ageing brain.

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.

Kalaria RN. · Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, NE4 6BE, Newcastle upon Tyne, United Kingdom. · Neurobiol Aging. · Pubmed #10867217 No free full text.

Abstract: The Alzheimer type of dementia and stroke are known to increase at comparable rates with age. Recent advances suggest that vascular risk factors linked to cerebrovascular disease and stroke in the elderly significantly increase the risk of developing Alzheimer's disease (AD). These include atherosclerosis, atrial fibrillation, coronary artery disease, hypertension, and diabetes mellitus. Moreover, review of various autopsy series shows that 60-90% of AD cases exhibit variable cerebrovascular pathology. Although some vascular lesions such as cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions are evident in most cases of AD, a third will exhibit cerebral infarction. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that the co-existence of stroke and AD occurs more than by chance alone. Strokes known to occur in patients with Alzheimer syndrome and most frequently in the oldest old substantially worsen cognitive decline and outcome, implicating some interaction between the disorders. Nevertheless, the nature of a true relationship between the two disorders seems little explored. What predisposes to strokes in underlying cognitive decline or AD? Is it possible that cerebral ischemia is a causal factor for AD? I examined several vascular factors and the vascular pathophysiology implicated in stroke and AD, and propose that cerebral ischemia or oligemia may promote Alzheimer type of changes in the aging brain. Irrespective of the ultimate pathogenetic mechanism, these approaches implicate that management of peripheral vascular disease is important in the treatment or prevention of Alzheimer's disease or mixed dementia.

Kalaria RN. · Institute for Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Ann N Y Acad Sci. · Pubmed #10672233 No free full text.

Abstract: The pathology of Alzheimer's disease (AD) is not limited to amyloid plaques and neurofibrillary tangles. Recent evidence suggests that more than 30% of AD cases exhibit cerebrovascular pathology, which involves the cellular elements that represent the blood-brain barrier. Certain vascular lesions such as microvascular degeneration affecting the cerebral endothelium, cerebral amyloid angiopathy and periventricular white matter lesions are evident in virtually all cases of AD. Furthermore, clinical studies have demonstrated blood-brain barrier dysfunction in AD patients who exhibit peripheral vascular abnormalities such as hypertension, cardiovascular disease and diabetes. Whether these vascular lesions along with perivascular denervation are coincidental or causal in the pathogenetic processes of AD remains to be defined. In this chapter, I review biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described in AD. I also consider genetic influences such as apolipoprotein E in relation to cerebrovascular lesions that may shed light on the pathophysiology of the cerebral vasculature. The compelling vascular pathology associated with AD suggests that transient and focal breach of the blood-brain barrier occurs in late onset AD and may involve an interaction of several factors, which include perivascular mediators as well as peripheral circulation derived factors that perturb the endothelium. These vascular abnormalities are likely to worsen cognitive disability in AD.

Kalaria RN, Ballard C. · Department of Psychiatry, Institute for Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Alzheimer Dis Assoc Disord. · Pubmed #10609690 No free full text.

Abstract: There is overwhelming evidence to suggest that the neuropathology of Alzheimer disease (AD) extends beyond amyloid plaques and neurofibrillary tangles. Review of various consortium data shows that more than 30% of AD cases exhibit cerebrovascular pathology. However, certain vascular lesions such as cerebral amyloid angiopathy, microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD. Whether these vascular lesions are coincidental or causal in the pathogenetic processes of AD remains to be defined. Although systemic vascular influences such as hypertension, coronary artery disease, and other cardiovascular disturbances may be responsible for such pathology in AD, it is equally intriguing that about one third of patients diagnosed with vascular dementia (VaD) will have AD-type pathology at autopsy. Moreover, previous studies have revealed that deficits in cholinergic indices related to the basal forebrain neurones are apparent in multi-infarct dementia. In this short review, we evaluate cerebrovascular pathology of AD in light of peripheral vascular pathophysiology implicated in the etiopathogenesis of the dementia. We also consider pathological findings in relation to genetic influences such as apolipoprotein E that may shed light on the link between AD and VaD. In view of these commonalties, it is reasonable to consider the same treatment strategies for both AD and VaD.

Skoog I, Kalaria RN, Breteler MM. · Institute of Clinical Neuroscience, Section of Psychiatry, Sahlgrenska University Hospital, Göteborg, Sweden. · Alzheimer Dis Assoc Disord. · Pubmed #10609689 No free full text.

Abstract: Vascular risk factors are normally associated with cerebrovascular disease, which may lead to vascular dementia (VaD). Several recent studies suggest that there is increased risk of developing Alzheimer disease when exposed to these same vascular risk factors. In addition to old age, hypertension, peripheral arterial disease, certain types of cardiovascular disorders, diabetes mellitus, and smoking are now considered risk factors for late-onset Alzheimer disease. In this review, we examine several vascular factors and peripheral vascular pathophysiology implicated in Alzheimer disease and suggest certain mechanisms that might promote the association of vascular factors and late-onset Alzheimer disease. We support the implication that prevention or management of peripheral vascular disease may prevent or delay the onset of Alzheimer disease or mixed dementia.

Leys D, Erkinjuntti T, Desmond DW, Schmidt R, Englund E, Pasquier F, Parnetti L, Ghika J, Kalaria RN, Chabriat H, Scheltens P, Bogousslavsky J. · University of Lille, France. · Alzheimer Dis Assoc Disord. · Pubmed #10609680 No free full text.

Abstract: Although vascular dementia (VaD) is the second most frequent cause of dementia after Alzheimer disease (AD), the concept remains controversial in terms of delineation. The objective of this review is to investigate, from available literature, the role of cerebral infarcts in the pathogenesis of VaD and to identify areas of interest that need further evaluation and research. The incidence of new onset dementia is increased after stroke. Stroke subtypes, total volume of cerebral infarction and functional tissue loss, and location of the lesions are probably the major determinants of VaD. Any cause of stroke can lead to VaD. In some circumstances the causal relation between stroke and dementia is clear: (1) in young patients who are unlikely to have associated Alzheimer pathology; (2) when the cognitive functioning was normal before stroke, impaired immediately after, and does not worsen over time; (3) when the lesions are located in strategic areas; and (4) when a well-defined vasculopathy known to cause dementia is proven. However, several issues remain unsolved in VaD: lack of specificity of the diagnostic criteria; influence of white matter changes and associated Alzheimer pathology; influence of preexisting cognitive status; possibility of having VaD without stroke and the clinical relevance of silent infarcts to VaD; and best therapeutic strategy to be used to prevent VaD and to prevent stroke in patients with VaD. These questions form the basis for proposals for future research.

Kalaria RN. · Institute of Health for the Elderly and Department of Psychiatry, University of Newcastle, Newcastle General Hospital, Newcastle upon Tyne, UK. · Int J Neurosci. · Pubmed #10495204 No free full text.

This publication has no abstract.

Kalaria RN. · CBV Path Group, MRC Unit, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Curr Opin Hematol. · Pubmed #9915549 No free full text.

Abstract: Microglia play a major role in the cellular response associated with the pathological lesions of Alzheimer's disease. As brain-resident macrophages, microglia elaborate and operate under several guises that seem reminiscent of circulating and tissue monocytes of the leucocyte repertoire. Although microglia bear the capacity to synthesize amyloid beta, current evidence is most consistent with their phagocytic role. This largely involves the removal of cerebral amyloid and possibly the transformation of amyloid beta into fibrils. The phagocytic functions also encompass the generation of cytokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, events that may exacerbate neuronal damage rather than incite outgrowth or repair mechanisms. Microglia do not appear to function as true antigen-presenting cells. However, there is circumstantial evidence that suggests functional heterogeneity within microglia. Pharmacological agents that suppress microglial activation or reduce microglial-mediated oxidative damage may prove useful strategies to slow the progression of Alzheimer's disease.

Kalaria RN. · Institute for Ageing and Health, Wolfson Research Center (Neuropathology),Newcastle General Hospital, Westgate Road,Newcastle upon Tyne, UK. · Nat Rev Neurol. · Pubmed #19498432 No free full text.

Abstract: Epidemiological studies suggest that the risk of developing cognitive impairment and dementia is increased in individuals with diabetes mellitus, although the evidence from clinicopathological studies on neurodegenerative changes is at odds with these observations. A thorough appraisal of concomitant vascular changes in dementia might resolve this incongruity.

Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, Kalaria RN, O'Brien JT. · Wolfson Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. · Brain. · Pubmed #19022858 No free full text.

Abstract: The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.

Barkhof F, Polvikoski TM, van Straaten EC, Kalaria RN, Sulkava R, Aronen HJ, Niinistö L, Rastas S, Oinas M, Scheltens P, Erkinjuntti T. · Department of Radiology, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #17923614 No free full text.

Abstract: BACKGROUND: Medial temporal lobe atrophy (MTA) is a sensitive radiologic marker for Alzheimer disease (AD) and associated with cognitive impairment. The value of MTA in the oldest old (>85 years old) is largely unknown. METHODS: A total of 132 formalin-fixed brains from the Vantaa 85+ community-based study were subjected to postmortem MRI. Visual ratings of MTA were determined in a blinded fashion and compared with neuropathologic findings and clinical assessment (dementia according to Diagnostic and Statistical Manual of Mental Disorders-III-R). RESULTS: A strong relationship was found between MTA scores and Alzheimer pathology (p < 0.001). The previously proposed cutoff MTA score >2 correctly excluded subjects with no or borderline Alzheimer-type pathology (45/48), but was not very sensitive for AD (modified National Institute on Aging-Reagan Institute criteria). MTA scores >2 were also found in subjects with other primary neurodegenerative hippocampal pathology including hippocampal sclerosis, Lewy-related pathology, and argyrophilic grain disease, either alone or in combination with Alzheimer-type pathology. High MTA scores were associated with clinical dementia-in this subgroup, sensitivity was 63% and specificity 69% for AD. CONCLUSION: Medial temporal lobe atrophy (MTA) on postmortem MRI is sensitive to primary degenerative hippocampal pathology in the very old, but not specific for Alzheimer-type pathology. MTA scores of 2 or less are not frequently associated with dementia.

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.

Kalaria RN. · Institute for Ageing and Health, Newcastle General Hospital, and Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK. · Int Psychogeriatr. · Pubmed #16191216 No free full text.

Abstract: Vascular involvement in Alzheimer disease (AD) is not necessarily coincident. Current evidence suggests the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of recognized AD cases may exhibit cerebrovascular pathology, which also constitutes distinct small vessel disease. Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis, and fibrosis are frequently evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. In addition, amyloid beta protein appears directly involved in the degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. The cerebrovascular pathology in AD also encompasses macro- and micro-infarctions, hemorrhages, lacunas, and ischemic white-matter changes. An interaction of both perivascular mediators and derived factors would perturb the brain vasculature. Peripheral vascular factors such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease, and diabetes mellitus are also apparent in AD. These factors would modify the cerebral circulation such that a sustained hypoperfusion or oligemia is impacted upon the aging processes to induce the characteristic pathology.

Nunomura A, Chiba S, Lippa CF, Cras P, Kalaria RN, Takeda A, Honda K, Smith MA, Perry G. · Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan. · Neurobiol Dis. · Pubmed #15350971 No free full text.

Abstract: An in situ approach was used to identify the oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the frontal cortex of familial Alzheimer's disease (FAD) with a mutation in presenilin-1 (PS-1) or amyloid beta protein precursor (AbetaPP) gene (n = 13, age 47-81 years). Neurons with marked 8OHG immunoreaction in the cytoplasm were widely distributed in the superior/middle frontal gyrus of FAD. Relative intensity measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase in FAD compared with controls (n = 15, age 59-81 years), while there was no difference in relative 8OHG between the PS-1 and the AbetaPP FAD. Interestingly, a presymptomatic case carrying a PS-1 mutation showed a considerable level of relative 8OHG, and the increased levels of neuronal 8OHG in FAD were more prominent in cases with a lower percentage area of Abeta42 burden. These results suggest that oxidative stress is an early event involved in the pathological cascade of FAD.

Lewis HD, Beher D, Smith D, Hewson L, Cookson N, Reynolds DS, Dawson GR, Jiang M, Van der Ploeg LH, Qian S, Rosahl TW, Kalaria RN, Shearman MS. · Department of Molecular and Cellular Neuroscience, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. · Neurobiol Aging. · Pubmed #15312963 No free full text.

Abstract: A homogeneous time-resolved fluorescence immunoassay for detection of beta-amyloid (A beta) peptides has been adapted for quantification of A beta(40) and A beta(42) accumulation in brains of APP695SWE transgenic mice. These over-express human beta APP(swe), beta-amyloid precursor protein (beta-APP) containing the K670N/M671L 'Swedish' familial Alzheimer's disease (FAD) mutation. Both peptides start to accumulate in this line from about 260 to 280 days of age. Co-expression of a human presenilin-1 (PS1) transgene containing the A246E FAD mutation accelerates deposition and also favors-at least initially-accumulation of A beta(42) so that the A beta(2):A beta(40) ratio of peptides from 7- to 12-month-old APP695SWE x PS1A246E animals is significantly elevated above that observed throughout the lifetime of APP695SWE mice. These findings, supported by parallel immunohistochemical staining and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry data, offer important longitudinal characterization of two mouse models of cerebral amyloidosis. Application of the same extraction and quantitation procedures to samples of temporal cortex from AD sufferers indicates however that A beta(40) is only a minor component of beta-amyloid in humans.

Heckmann JM, Low WC, de Villiers C, Rutherfoord S, Vorster A, Rao H, Morris CM, Ramesar RS, Kalaria RN. · Division of Neurology, Groote Schur Hospital and University of Cape Town, South Africa. · Brain. · Pubmed #14570818 links to  free full text

Abstract: Genetically determined Alzheimer's disease (AD) is virtually unknown in Africa. We report clinicopathological findings and a presenilin 1 (PS1) mutation associated with early-onset AD in a large Xhosa family from Southern Africa. Twelve individuals spanning four generations were affected, four of whom underwent clinical and psychometric evaluation. Their phenotype was characterized by memory impairment beginning in the early part of the fifth decade, with progressive dementing illness lasting 6-7 years that did not appear to be modified by the presence of an apolipoprotein E (APOE)-epsilon 4 allele. Initial linkage-based analysis using known DNA markers suggested allele cosegregation with a locus on chromosome 14. Direct sequencing of the PS1 gene disclosed a novel I143M (ATT to ATG at nucleotide 677) mutation that lies in a cluster in the second transmembrane domain of the protein. Examination of the proband's brain at autopsy revealed severe AD pathology characterized by neuronal loss, abundant beta amyloid (A beta) neuritic plaques (A beta 42) and neurofibrillary degeneration extending into the brainstem. The phenotype of the I143M mutation was clearly associated with a high degree of neurofibrillary change compared with early-onset sporadic AD cases. Although sporadic cases of AD do exist in African populations, our study confirms the existence of early-onset familial AD among indigenous Southern Africans.

Kalaria RN. · Institute for Ageing and Health, Wolfson Unit, Newcastle General Hospital, NE4 6BE, Newcastle upon Tyne, UK. · Lancet. · Pubmed #12648963 No free full text.

This publication has no abstract.