Dementia,the fate of brain? Neuropathological point of viewLe destin du cerveau ? Un point de vue neuropathologique sur les démences.

The prevalence of dementia dramatically increases during ageing, and this puts a serious strain on the optimism brought by the continuous increase in life expectancy observed in most industrialised countries. Diseases that produce dementia are numerous, and the cognitive deficit results from lesions of various regions and from different mechanisms. This modulates the possible prediction, prevention and cure of dementia. Emphasis is put on the necessity of, and prerequisite for, efficient research in the field of dementia. Three paradigmatic dementing disorders are reviewed. Subacute spongiform encephalopathies (prion diseases) constitute a biological enigma and a public health concern. In Alzheimer's disease and vascular or mixed dementia, the clinical diagnosis is still imperfect, and this hinders research. Distinguishing and accurately identifying the various types of dementia is essential for understanding their mechanism and for developing efficient therapeutic strategies, preventive and curative. For such objectives, the study of human brain tissue will remain mandatory until non-invasive markers and additional models are available. Ethical reasons banish the use of cerebral biopsy and favour the promotion of autopsy.     

Epidemiology of Alzheimer disease and related disorders

Alzheimer's disease and related disorders (dementia) are a major public health problem due to the number of cases in the general population, the projections for the future, and the consequences of these diseases. We can estimate that about 850 000 cases of dementia were present in France in 2005 and this number will increase to 1,200,000 in 2020 and 2,100,000 in 2040 if the incidence and the duration of the disease did not change. The development of prevention is therefore necessary. Four ways of prevention are credible. The most important is the treatment of vascular risk factors and particularly hypertension. Other ways are nutritional factors, stimulating leisure activities and depression.     

A familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers

Alzheimer's disease is the most common form of dementia that occurs in later years. The diagnosis is confirmed by the pathological findings of βA4-amyloid-containing neuritic plaques and neurofibrillary tangles, the former being present in sufficient quantity commensurate with age. Other forms of dementia are more difficult to diagnose clinically; their pathology is noted for the lack of plaques and tangles. A patient with a family history of dementia presented with the clinical signs of Alzheimer's disease which lasted for 13 years. At autopsy the brain tissue had βA4-amyloid-containing neuritic plaques, but no neurofibrillary tangles (i.e., the tissue was negative for staining with the tau antibody). Genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, indicating that this was not frontotemporal dementia. However, there was linkage with chromosome 3 markers. Thus, this form of Alzheimer's disease with a pathology of plaques only is linked with markers on chromosome 3. Electronic Publication     

A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia?

Because of population ageing, dementias are likely to become a major scourge of the 21st century. Causes of dementia include Alzheimer's disease, cerebrovascular disease, and lesser known entities such as frontotemporal dementia or dementia with Lewy bodies. Neuroinflammation is likely to play an important role in the pathogenesis of dementia by the killing of neurons through inflammatory mechanisms. Such a role of neuroinflammation is well documented for Alzheimer's disease, and it is likely to play a role in other types of dementia as well. Reactive oxygen species (ROS) play a key role in inflammatory tissue destruction. The phagocyte NADPH oxidase NOX2 is the best studied ROS-generating system. In the central nervous system, it is expressed in microglia and--to a lesser extent--in neurons. Indeed, there is emerging experimental evidence for a role of NOX2 in Alzheimer's and cerebrovascular disease. Recently, six novel ROS-generating NADPH oxidases with homology to NOX2 have been discovered. Several of them are also expressed in the central nervous system. In this article, we hypothesize a role of NOX-type NADPH oxidases in inflammatory neuronal loss. We review presently available evidence and suggest that NOX-type NADPH oxidases may become promising pharmacological targets for the treatment and prevention of dementia.     

Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic?

The hypothesis that the symptomatology of Alzheimer's disease is attributable to cholinergic dysfunction is supported by postmortem studies that have demonstrated reduced choline acetyltransferase (ChAT) activity across all areas of cerebral cortex and diminished numbers of perikarya in the basal forebrain nucleus basalis of Meynert. Biopsy studies of ChAT activity, choline uptake, and acetylcholine synthesis also suggest that cholinergic denervation occurs relatively early in the course of the disease, and in confirmation of postmortem data, correlates with the severity of cognitive impairment. An alternative hypothesis to explain the dementia of Alzheimer's disease is the glutamatergic hypothesis. This is based largely on postmortem evidence indicating reduced binding and uptake of D[3H]aspartate, as well as loss of a number of other putative markers, such as phosphate-activated glutaminase activity, glutamate concentration, and the number of pyramidal cell perikarya, with this latter change correlating with the severity of dementia. Short-comings of each hypothesis are discussed and the merits of single neuron hypotheses to explain the dementia of Alzheimer's disease are considered.     

Neuropsychological characteristics and diagnostic approach to Parkinsońs disease dementia and Lewy body dementia

When approaching the neurophysiological characteristics and diagnostic approach to Parkinson's disease dementia (PDD) and Lewy body dementia (LBD), the first idea that comes to mind is that both types of dementia fall within the group of subcortical dementias, with the practical implications that this observation entails. We should therefore leave our knowledge of Alzheimer's dementia and other cortical dementias to one side as, in most cases, these forms of dementia do not correspond clinically or diagnostically to subcortical dementias. Therefore, the clinical and therapeutic approach of PDD and LBD differs from that of cortical dementias in form, if not in essence.     

PENN biomarker core of the Alzheimer's disease Neuroimaging Initiative

There is a pressing need to develop effective prevention and disease-modifying treatments for Alzheimer's disease (AD), a dreaded affliction whose incidence increases almost logarithmically with age starting at about 65 years. A key need in the field of AD research is the validation of imaging and biochemical biomarkers. Biomarker tests that are shown to reliably predict the disease before it is clinically expressed would permit testing of new therapeutics at the earliest time point possible in order to give the best chance for delaying the onset of dementia in these patients. In this review the current state of AD biochemical biomarker research is discussed. A new set of guidelines for the diagnosis of AD in the research setting places emphasis on the inclusion of selected imaging and biochemical biomarkers, in addition to neuropsychological behavioral testing. Importantly, the revised guidelines were developed to identify patients at the earliest stages prior to full-blown dementia as well as patients with the full spectrum of the disease. The Alzheimer's Disease Neuroimaging Initiative is a multicenter consortium study that includes as one of its primary goals the development of standardized neuroimaging and biochemical biomarker methods for AD clinical trials, as well as using these to measure changes over time in mildly cognitively impaired patients who convert to AD as compared to the natural variability of these in control subjects and their further change over time in AD patients. Validation of the biomarker results by correlation analyses with neuropsychological and neurobehavioral test data is one of the primary outcomes of this study. This validation data will hopefully provide biomarker test performance needed for effective measurement of the efficacy of new treatment and prevention therapeutic agents.     

Symptoms of Lewy body dementia and clinical course compared with Alzheimer's disease

Lewy body dementia (LBD) is a neurodegenerative disease with well-defined symptoms and established clinical criteria, characterized by the presence of cortical and subcortical dementia, accompanied by some characteristic features such as Parkinsonism, visual hallucinations and fluctuations in alertness and attention, as well as hypersensitivity to neuroleptics. Compared with Alzheimer's disease, LBD seems to have a more rapid clinical course and greater mortality. The differences with Alzheimer's disease may be more apparent in the initial stages of the disease but tend to disappear with disease progression. Because of the greater presence of neuropsychiatric symptoms and the higher degree of dependency in LBD, there is greater caregiver overload and probably greater resource use.     

Omega-3 fatty acids and dementia

More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid β peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Aβ, including two major kinases that phosphorylate the microtubule-associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline—with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants.     

Neurobiology of exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.     

Risk of dementia and alcohol and wine consumption: a review of recent results

The term dementia refers to a clinical syndrome of acquired intellectual disturbances produced by brain dysfunction. Dementia may result from a wide variety of disorders, including degenerative (e.g. Alzheimer's disease, AD), vascular (e.g. multi-infarct dementia), and traumatic (e.g. head injury). Long-term abuse of alcohol is related to the development of the Wernicke-Korsakoff's syndrome or alcohol dementia. However, light to moderate alcohol intake might also reduce the risk of dementia and AD. In Bordeaux (France), a population-based prospective study found that subjects drinking 3 to 4 standard glasses of wine per day (> 250 and up to 500 ml), categorized as moderate drinkers, the crude odds ratio (OR) was 0.18 for incident dementia (p < 0.01) and 0.25 for Alzheimer's disease (p < 0.03), as compared to the non-drinkers. After adjusting for age, sex, education, occupation, baseline cognitive performances and other possible confounders, the ORs were respectively 0.19 (p < 0.01) and 0.28 (p < 0.05). In the 922 mild drinkers (< 1 to 2 glasses per day) there was a negative association only with AD. after adjustment (OR = 0.55; p < 0.05). The inverse relationship between moderate wine drinking and incident dementia was explained neither by known predictors of dementia nor by medical, psychological or socio-familial factors. These results were confirmed from data of the Rotterdam study. Light-to-moderate drinking (one to three drinks per day) was significantly associated with a lower risk of any dementia (hazard ratio 0.58 [95% CI 0.38-0.90]) and vascular dementia (hazard ratio 0.29 [0.09-0.93]). No evidence that the relation between alcohol and dementia varied by type of alcoholic beverage was found. Stroke constitutes one of the most common causes of serious functional impairment in developed countries. Ischaemic strokes represent about 80% of all strokes. Several studies have been published and the overall conclusion is that heavy drinking is a risk factor for most stroke subtypes. Regular light to moderate drinking seemed to be associated with a decreased risk for ischaemic stroke.     

Alzheimer''s disease: Transgenic models to test new chemicals and pharmaceuticals

Alzheimer's disease is the most common form of senile dementia and is predicted to become even more prevalent as the proportion of elderly in the population increases over the next few decades. As yet, there are no effective treatments for the disorder. A major limitation to identifying new drugs and therapeutic targets for Alzheimer's disease has been the absence of an animal model displaying typical Alzheimer's pathology. Transgenic technology is now providing a powerful new approach for the development of animal models of Alzheimer's disease.     

Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia

Although dementia of the Alzheimer's type (DAT) is the most common form of dementia, the severity of dementia is only weakly correlated with DAT pathology. In contrast, postmortem measurements of cholinergic function and membrane ethanolamine plasmalogen (PlsEtn) content in the cortex and hippocampus correlate with the severity of dementia in DAT. Currently, the largest risk factor for DAT is age. Because the synthesis of PlsEtn occurs via a single nonredundant peroxisomal pathway that has been shown to decrease with age and PlsEtn is decreased in the DAT brain, we investigated potential relationships between serum PlsEtn levels, dementia severity, and DAT pathology. In total, serum PlsEtn levels were measured in five independent population collections comprising >400 clinically demented and >350 nondemented subjects. Circulating PlsEtn levels were observed to be significantly decreased in serum from clinically and pathologically diagnosed DAT subjects at all stages of dementia, and the severity of this decrease correlated with the severity of dementia. Furthermore, a linear regression model predicted that serum PlsEtn levels decrease years before clinical symptoms. The putative roles that PlsEtn biochemistry play in the etiology of cholinergic degeneration, amyloid accumulation, and dementia are discussed.     

Lipid Composition in Different Regions of the Brain in Alzheimer''s Disease/Senile Dementia of Alzheimer''s Type

The lipid compositions of 10 different brain regions from patients affected by Alzheimer's disease/senile dementia of Alzheimer's type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimer's disease, i.e., frontal and temporal cortex and the hippocampus, showed elevated contents of lipid solvent-extractable phosphatidylinositol. Sphingomyelin content was decreased in regions rich in myelin. There was a 20-50% decrease in dolichol amount in all investigated parts of the brain, but no change was seen in the polyisoprenoid pattern. Levels of alpha-unsaturated polyprenes were decreased in Alzheimer brains. Dolichyl-phosphate content increased in most regions, up to 100%. In both control and Alzheimer tissue almost all of the dolichyl-phosphate was covalently bound, apparently through glycosylation. Cholesterol amounts were highly variable but mostly unchanged, whereas ubiquinone concentrations increased by 30-100% in most regions in brains affected by Alzheimer's disease. These results demonstrate that both phospholipids and neutral lipids are modified in brains affected by Alzheimer's disease/senile dementia of Alzheimer's type.     

Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease

There is much evidence suggesting that there is a strong relationship between the deterioration of brain lipid homeostasis, vascular changes and the pathogenesis of Alzheimer's disease (AD). These associations include: (1). recognition that a key cholesterol transporter, apolipoprotein E type 4, acts a major genetic risk factor for both familial and sporadic AD; (2). epidemiological studies linking cardiovascular risk factors, such as hypertension and high plasma cholesterol, to dementia; (3). the discovery that small strokes can precipitate clinical dementia in cognitively normal elderly subjects; (4). the modulation of degradation of the amyloid precursor protein by cholesterol administration in cell culture and in animal models of beta-amyloid overproduction; and (5). the beneficial effect of cholesterol-lowering drugs, such as Probucol and statins, in combating common AD. The recent finding that there is a genetic association between the HMGR gene locus and sporadic AD further suggests that brain cholesterol metabolism is central to AD pathophysiology, and a potential therapeutic target for disease stabilization and primary disease prevention.     

Alzheimer's disease and HIV associated dementia related genes: I. location and function

Alzheimer's disease (AD), the most common cause of dementia, has few clinical similarities to HIV-1-associated dementia (HAD). However, genes were identified related among these dementias. Discovering correlations between gene function, expression, and structure in the human genome continues to aid in understanding the similarities between pathogenesis of these two dementing disorders. The current work attempts to identify relationships between these dementias in spite of their clinical differences, based on genomic structure, function, and expression. In this comparative study, the NCBI Entrez Genome Database is used to detect these relationships. This approach serves as a model for future diagnosis and treatment in the clinical arena as well as suggesting parallel pathways of disease mechanisms. Identifying a correlation among expression, structure, and function of genes involved in pathogenesis of these dementing disorders, may assist to understand better their interaction with each other and the human genome.     

Presynaptic Cholinergic Dysfunction in Patients with Dementia

Abstract: Indices of presynaptic cholinergic nerve endings were assayed in neocortical biopsy samples from patients with presenile dementia. For those patients in whom Alzheimer's disease was histologically confirmed, [¹⁴C]acetylcholine synthesis, choline acetyltransferase activity and choline uptake were all found to be markedly reduced (at least 40%) below mean control values. The changes occurred in samples from both the frontal and temporal lobes and for [¹⁴C]acetylcholine synthesis the decrease was similar under conditions of high and low neuronal activity (as assessed by incubations in 31 mM and 5 mM K⁺ respectively). Samples from other demented patients, in whom the histological features of Alzheimer's disease were not detected, produced values for all three biochemical parameters which were similar to controls. For the total group of patients with presenile dementia there were correlations between values for the three markers of presynaptic cholinergic nerve endings suggestive of a loss of functional activity at these sites in Alzheimer's disease.