Alzheimer Disease: Hachinski V

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.

Merino JG, Hachinski V. · No affiliation provided · Arch Neurol. · Pubmed #10891972 links to  free full text

This publication has no abstract.

Cechetto DF, Hachinski V, Whitehead SN. · Department of Anatomy & Cell Biology, University of Western Ontario, London, ON, Canada. · Expert Rev Neurother. · Pubmed #18457531 No free full text.

Abstract: Vascular cognitive impairment risk factors include stroke, hypertension, diabetes and atherosclerosis. In the elderly, vascular risk factors occur in the presence of high levels of amyloid in the aging brain. Stroke alters the clinical expression of a given load of Alzheimer's disease (AD) pathology. Experimentally, large vessel infarcts or small striatal infarcts are larger in the presence of amyloid. Patients with minor cerebral infarcts and moderate AD lesions will develop the clinical manifestations of dementia. Moreover, there is also an association between other vascular risk factors and the clinical expression of cognitive decline and dementia. The risk of AD is increased in subjects with adult-onset diabetes mellitus, hypertension, atherosclerotic disease and atrial fibrillation. Experimentally, small striatal infarcts in the presence of high levels of amyloid in the brain exhibit a progression in infarct size over time with enhanced degree of cognitive impairment, AD-type pathology and neuroinflammation compared with striatal infarcts or high amyloid levels alone.

Hachinski V, Munoz D. · Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada. · Ann N Y Acad Sci. · Pubmed #10818482 No free full text.

This publication has no abstract.

Rockwood K, Bowler J, Erkinjuntti T, Hachinski V, Wallin A. · Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #10609683 No free full text.

Abstract: The challenge of describing subgroups is particularly important in vascular dementia, which, in contrast to more stereotypic processes affecting cognitive function, is better thought of as several syndromes rather than as a disease. Many current diagnostic descriptions lack a strong empiric basis. Some of the categories now in use suffer from a priori assumptions about causality and pattern associations, which themselves have not been validated. The so-called mixed dementia syndrome may have been underrepresented in our estimation of dementia subtypes, in comparison with so-called pure vascular causes. Within the vascular syndrome, whether seen in isolation or in combination with other causes of dementia, the relative contributions of white matter changes as compared with multiple cortical strokes needs to be clarified. It remains a matter of controversy as to whether prolonged or chronic intermittent cerebral ischemia is a statistically important part of the dementia. The variable relation between clinical presentation and neuroimaging localization has important consequences for understanding the pathophysiology of cognitive impairment arising from vascular causes. Recent data also suggest that we should focus away from both the Alzheimer disease model of dementia and the multi-infarct model of vascular dementia. There are important opportunities available to clinicians from many disciplines to collaborate in precise clinical descriptions of large numbers of patients to advance our understanding of the spectrum of vascular cognitive impairment.

Bowler JV, Steenhuis R, Hachinski V. · Department of Clinical Neurological Sciences and Robarts Research Institute, University of Western Ontario, London, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #10609679 No free full text.

Abstract: The current criteria for vascular dementia use a paradigm that first diagnoses dementia on the basis of Alzheimer-type criteria and then superimposes upon this vascular events and risk factors to convert a diagnosis of Alzheimer disease to one of vascular dementia. There are two fundamental flaws with this approach. First, the neuropsychological features of Alzheimer disease are not the same as those for vascular dementia and so use of the current criteria will fail to diagnose many cases, particularly those in whom memory loss is not prominent. Second, progression of vascular dementia should be modifiable by adjustment of risk factors and, possibly, by the use of neuroprotective agents. Given this, it is absurd to wait until patients are frankly demented. It is far more appropriate to detect patients at risk of developing cognitive loss as soon as possible. This could be in the earliest symptomatic stage (vascular cognitive impairment) or even prior to this (brain-at-risk) stage. New criteria, based on evidence rather than on supposition, that focus on early disease are urgently needed.

Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, Hachinski V, Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A. · Aging Research Center, NVS, Karolinska Institutet, Stockholm, Sweden. · J Cell Mol Med. · Pubmed #18318693 No free full text.

Abstract: The risk of dementia and Alzheimer's disease (AD) probably results from an interaction between genetic and environmental factors. The aim of this study was to investigate the effects and putative interactions between the apoE epsilon4 allele and lifestyle related risk factors for dementia and AD. Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. After an average follow-up of 21 years, 1449 individuals (72.5%) aged 65-79 years were re-examined in 1998. The apoE epsilon4 allele was an independent risk factor for dementia/AD even after adjustments for sociodemographic, lifestyle and vascular factors (odds ratio [OR]=2.83, 95% confidence interval [CI]=1.61-4.97). Physical inactivity, alcohol drinking and smoking increased the risk of dementia/AD particularly among the apoE epsilon4 carriers. Furthermore, low-moderate intake of polyunsaturated, and moderate-high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE epsilon4 carriers. Composite effect of the lifestyle factors was particularly seen among the epsilon4 carriers (OR=11.42, 95% CI=1.94-67.07 in the 4th quartile). Physical inactivity, dietary fat intake, alcohol drinking and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE epsilon4 carriers. The apoE epsilon4 carriers may be more vulnerable to environmental factors, and thus, lifestyle interventions may greatly modify dementia risk particularly among the genetically susceptible individuals.

Cheng G, Whitehead SN, Hachinski V, Cechetto DF. · Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada. · Neurobiol Dis. · Pubmed #16624564 No free full text.

Abstract: It has been well established that neuroinflammation is involved in Alzheimer disease (AD) pathogenesis. Accumulation and aggregation of beta-amyloid (Abeta) peptide in the brains of patients with AD result in activation of glial cells which, in turn, initiates neuroinflammatory responses that involve reactive oxygen intermediates and release of inflammatory cytokines. In this study, bilateral intracerebroventricular (i.c.v.) injections of Abeta (25-35) in the rat resulted in impairment in learning and spatial memory and increased immunoreactive staining of AD-related neuropathological markers (Abeta, APP) and inflammatory mediators (OX-6, COX-2) in CA1 and dentate gyrus regions of the hippocampus. Pyrrolidine dithiocarbamate (PDTC) given intraperitoneally 30 min before Abeta injection and daily for 7 days postsurgery significantly prevented Abeta-induced neuropathological and neuroinflammatory responses, as well as the learning and spatial memory deficits. The potential of PDTC for reducing cognitive and neuropathological deficits may provide preliminary evidence for a new approach of AD treatment.

Bullido MJ, Martínez-García A, Artiga MJ, Aldudo J, Sastre I, Gil P, Coria F, Muñoz DG, Hachinski V, Frank A, Valdivieso F. · Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. · Neurobiol Aging. · Pubmed #16595160 No free full text.

Abstract: Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors. Binding with the transporter associated with antigen processing (TAP) is thought to be the main way in which herpes simplex virus type 1 (HSV-1) evades immune surveillance. Several TAP gene polymorphisms were examined and a TAP2 SNP (rs241448) associated with AD found in two independent case-control samples, especially in carriers of the APOE4 allele. These findings are consistent with the hypothesis that human genetic variants facilitating the access of HSV-1 to the brain might result in susceptibility to AD.

Whitehead S, Cheng G, Hachinski V, Cechetto DF. · Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada. · Stroke. · Pubmed #16040593 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test. RESULTS: Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model. CONCLUSIONS: Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Avda. Orellana s/n, Leganés, 28911 Madrid, Spain. · J Neurol Sci. · Pubmed #15792814 No free full text.

Abstract: OBJECTIVE: To compare the clinical and pathological features of Alzheimer's disease (AD) patients with and without associated cerebral infarcts (CI). METHODS: The consecutive records of 57 prospectively studied demented patients fulfilling the CERAD criteria for the pathological diagnosis of AD were reviewed. Cases with cortical Lewy bodies were excluded. CI were found in 22 cases (39%) (AD+CI group): large infarcts (5), lacunes (13) and/or hippocampal sclerosis (4), and were absent in 35 cases (AD group). Microscopic infarcts, cribiform change, amyloid angiopathy, and white matter rarefaction were not considered in this classification, but were quantified. Cortical atrophy, neurofibrillary tangle and senile plaque (diffuse and neuritic) load were also measured. Pathological evaluation was independent of clinical information. Clinical and pathological data were compared between both groups. RESULTS: AD+CI cases were significantly older, more commonly female, less educated, and more often had blue collar occupations, sleep disturbances, frontal release signs, and EEG spikes than AD cases. Other differences found (acute/subacute onset, behavioral disturbances, and leukoaraiosis on CT scan) disappeared after controlling for age. The frequency of known vascular risk factors and focal motor and sensory signs did not differ between the groups, which showed remarkable clinical similarity overall. The only significant differences on pathological exam were hippocampal microinfarcts and white matter lesions, although there was a trend for lower neurodegenerative lesion load in the AD+CI group. The ischemic lesions were located in temporal lobe in 50% of AD+CI patients; these cases had a significantly lower neocortical neurodegenerative lesion load than those with CI in other sites. CONCLUSIONS: The presence of CI in AD increases significantly with age, but has scarce influence on the clinical features, and cannot be predicted from common vascular risk factors. In spite of a trend, there are no major differences in neurodegenerative lesion load between AD and AD+CI groups, except when CI are located in the temporal lobe (including hippocampus), suggesting that this location may be important in the physiopathology of mixed vascular and AD dementia.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Leganés, Madrid, Spain. · Alzheimer Dis Assoc Disord. · Pubmed #11236823 No free full text.

Abstract: The objectives of this study were to examine the clinical and pathologic features of two subgroups of patients with dementia with Lewy bodies (DLB) differing in Alzheimer disease (AD)-type pathology load and to identify clinical variables useful in the differential diagnosis from AD. The records of 64 consecutive demented patients were reviewed. Pathologic diagnoses were independently established [35 AD cases, 11 cases of pure dementia with Lewy bodies (pDLB), and 18 cases of combined AD plus Lewy bodies (AD+LB)], and several neurodegenerative lesions were quantified. Clinical and pathologic data were compared between groups with univariate and multivariate analyses. Compared with the other groups, pDLB cases had more frequent acute-subacute onset of dementia [45% vs. AD (3%) and AD+LB (16%)], early parkinsonism [45% vs. AD (0%) and AD+LB (0%)], early [27% vs. AD (0%) and AD+LB (0%)] and late [73% vs. AD (11%) and AD+LB (16%)] hallucinations, fluctuating course [46% vs. AD (9%) and AD+LB (22%)], delusions [45% vs. AD (11%) and AD+LB (6%)], spontaneous parkinsonism [63% vs. AD (8%) and AD+LB (16%)], less frequent ideomotor apraxia and loss of insight, earlier urinary incontinence [3.2 +/- 1.4 years after onset vs. AD (6.3 years) and AD+LB (5.8 years)], shorter duration of dementia [7.7 +/- 2.4 years vs. AD (9.6 years) and AD+LB (11 years)], milder atrophy in computed tomography scans, greater brain weight, more transcortical spongiosis, wider cortex and subcortex, and less amyloid angiopathy. All pDLB cases but no AD cases had abnormal CA2 neurites. The clinical features of AD+LB patients were similar to those of AD patients other than more frequent acute-subacute onset and fluctuating evolution. Discriminant analyses selected four clinical variables differentiating pDLB from the other two groups as a whole: acute-subacute onset, early parkinsonism, early hallucinations, and early onset of urinary incontinence. Two or more of these features identified pDLB with a sensitivity of 81.8% and a specificity of 95.9%. Differentiation between the three groups (pDLB, AD+LB, and AD) or between both groups with LB (DLB) from AD could be only attained in 70% of cases. We conclude that early symptomatology is the main clue for the diagnosis of pDLB. We identified by discriminant analysis a set of clinical diagnostic criteria similar to those proposed by the Consortium on Dementia With Lewy Bodies. Accuracy was excellent for the diagnosis of pDLB but only mediocre for separating AD+LB as well as the entire DLB group from AD.

Munoz DG, Ganapathy GR, Eliasziw M, Hachinski V. · Department of Pathology, University of Western Ontario, London, Canada. · Arch Neurol. · Pubmed #10634453 links to  free full text

Abstract: OBJECTIVE: To determine whether patients with autopsy-confirmed Alzheimer disease (AD) have different educational attainment and socioeconomic status than subjects without neurodegenerative disease. DESIGN: Comparison of 2 groups of autopsied patients. Information on education and occupation was obtained by telephone interview of relatives conducted post mortem. PATIENTS: One hundred fifteen patients enrolled in the University of Western Ontario Dementia Study with dementia and fulfilling diagnostic criteria of AD at autopsy were compared with 142 patients 65 years or older without dementia who died in the hospital and in whom autopsy did not show neurodegenerative disease. MAIN OUTCOME MEASURES: Highest education level attained, years of education, occupation, and socioeconomic and income levels. All results were adjusted for sex, age at time of death, and year of birth. RESULTS: There were no statistically significant differences in education, occupation, or socioeconomic and income levels between the groups. CONCLUSIONS: There is no evidence that educational attainment is different in patients with AD than in subjects who die in the hospital from other diseases. These results indicate that education does not protect against advanced AD.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Leganés, Madrid, Spain. · Brain. · Pubmed #10581224 links to  free full text

Abstract: A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.

Hachinski V. · University of Western Ontario, London, Ontario, Canada. · Stroke. · Pubmed #17347469 links to  free full text

Abstract: Advances in stroke are occurring at an unprecedented pace, but often in disciplinary isolation and without optimal mechanisms for systematically translating, integrating and applying the findings. Knowledge accrues in pieces, but is understood in patterns. To optimize knowledge acquisition and application, infrastructures and systems need to be set up along with appealing incentives. The approach needs to be transdisciplinary, going beyond the bounds of any given discipline, reciprocally translational, and transactional, meaning that the interchanges have to yield previously agreed benefits to the parties (The Triple T Approach). A new breed of leaders needs to be developed and nurtured to catalyze the process. Opportunities abound. Stroke and most brain diseases share the same pathophysiological fundamental mechanisms. An integrated, systematic approach to these processes could yield not only greater understanding but new, common therapeutic targets for several diseases. Biphasic clinical trials could combine the best features of pragmatic and explanatory, randomized clinical trials. The greatest opportunity of all may be the largely under-explored and under-exploited borderlands between cerebrovascular and Alzheimer disease. One in three of us will have a stroke, become demented, or both. For each person who has a stroke or Alzheimer disease, two have some cognitive impairment short of dementia, often subclinical cerebrovascular disease on a substrate of Alzheimer changes. The fact that cerebrovascular and Alzheimer disease share the same risk factors, provide a great opportunity for prevention, if implemented at the "brain at risk" stage. Systematically integrating what we know and evaluating what we do could spur progress. Research is not only an activity but an attitude. Making evaluation and incentives to excel part of the funding of all stroke activities would yield far ranging cumulative improvements in all aspects of stroke. No system can replace the individual initiative, creativity and insights that lead to the great discoveries, but progress is not made by breakthroughs alone. No one's work is so exalted that it cannot be improved, nor so humble that it has no value. We can all make a difference.