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PubMed2000

Morphological substrates of mental dysfunction in Lewy body disease: an update.

Mental dysfunction including cognitive, behavioural changes, mood disorders, and psychosis are increasingly recognized in patients with Parkinson's disease (PD) and related disorders. Their morphological correlates are complex due to multiple system degeneration. CNS changes contributing to cognitive changes in PD include 1. Dysfunction of subcorticocortical networks with neuron losses in a) the dopaminergic nigrostriatal loop, causing striato-(pre)frontal deafferentation and mesocortico-limbic system (medial substantia nigra, ventral tegmentum); b) noradrenergic (locus coeruleus), and serotonergic systems (dorsal raphe nuclei), c) cholinergic forebrain system (nucleus basalis of Meynert, etc), and d) specific nuclei of amygdala and limbic system (thalamic nuclei, hippocampus); 2. Limbic and/or cortical Lewy body and Alzheimer type pathologies with loss of neurons and synapses, 3. Combination of subcortical, cortical, and other pathologies. In general, degeneration of subcortical and striato-frontal networks causes cognitive, executive, behavioural, and mood disorders but less severe dementia than cortical changes which, when present in sufficient numbers, are important factors for overt dementia. In PD, cortical tau pathology with similar or differential patterns than in Alzheimer disease (AD) shows significant linear correlation with cognitive decline. In dementia with Lewy bodies (DLB), the second most frequent cause of dementia in the elderly, cortical Lewy bodies (LB) may or may not be associated with amyloid plaques and neuritic AD lesions. They predominantly affect the limbic system with less frequent isocortical Braak stages, whereas the cholinergic forebrain system is more severely affected than in AD. Both neuritic degeneration in limbic system in PD and DLB and the density of cortical synapse markers correlate with neuritic AD pathology and less with cortical LB counts. Apolipoprotein E epsilon4 allele frequency may represent a common genetic background for both AD and LB pathologies but there are different proportions of plaques between DLB (less Abeta1-40) and AD (more frequent Abeta1-40). Familial parkinsonism with dementia, linked to chromosome 17 (frontotemporal dementia with Parkinsonism (FTDP-17), and other tauopathies pathologically resembling PD plus AD, are often related to mutations of the tau gene, whereas familial PD with alpha-synuclein and Parkin mutations usually show no cognitive impairment. Mood disorders, in particular depression, and psychotic complications in both PD and DLB are related to complex involvement of noradrenergic and serotonergic systems, not confirmed in AD with depression, and both the prefrontal and limbic dopaminergic systems. The specific contributions of cortical and subcortical pathologies to mental dysfunction in PD and related disorders, their relationship to AD, and their genetic and aetiological backgrounds await further elucidation.

Aged↗

PubMed1996

Gap-43 message levels in anterior cerebellum in Alzheimer's disease.

We have previously reported that decreased growth-associated protein (GAP-43) message in frontal association cortex (area 9) of Alzheimer's disease (AD) patients is associated with increased density of neurons containing neurofibrillary tangles (NFTs) [9]. This finding leads to the hypothesis that decreased GAP-43 message in AD may be related to NFTs, rather than to some other aspect of AD pathology. Therefore, we predicted that in areas of brain unaffected by NFTs in AD the GAP-43 message levels should be similar to those of controls. The cerebellum is known to have a number of pathologies of AD, including diffuse plaques (DPs), microglial activation and reactive astrocytes. NFTs, however, are not typically found in the cerebellum. mRNA was extracted from anterior cerebellum of AD and control cases, Northern- and slot-blotted and hybridized against a GAP-43 probe. Poly(dT) and glucose-3-phosphate dehydrogenase probes were used for normalization. The average relative GAP-43 message level was 0.582 in the AD cases and 0.448 in control cases. This 23% difference failed to reach statistical significance. Regression analysis within the AD group demonstrated that GAP-43 message level in cerebellar cortex was not significantly correlated with diffuse plaque density in cerebellar cortex. GAP-43 message levels in cerebellar cortex were also not correlated with summed density of neuritic plaques or summed density of NFTs in cortical regions-here used as an index of severity of disease. The data reported here also emphasize that the (NFT-dependent) reduction in GAP-43 mRNA levels previously reported in frontal association cortex in Alzheimer's disease [9] appears to be region specific and not a general brain phenomenon. The preservation of normal GAP-43 message levels in the cerebellum in AD is consistent with the hypothesis that events related to NFT formation have a major impact on the expression of GAP-43 in Alzheimer's disease.

Alzheimer Disease↗

PubMed2001

Receptor-G-protein signalling in Alzheimer's disease.

Based on radioligand binding studies, it has long been assumed that the neurochemical pathology of Alzheimer's disease (AD) does not involve widespread changes in post-synaptic neurotransmitter function. However, more recent studies suggest that receptor function in AD may be compromised due to disrupted post-receptor signal transduction, in particular that mediated by the G-protein regulated phosphoinositide hydrolysis and adenylate cyclase (AC) pathways. The phosphoinositide hydrolysis pathway has been shown to be altered at a number of levels in AD post-mortem brains, including impaired agonist and G-protein regulation of phospholipase C, decreased protein kinase C (PKC) levels and activity, and a reduced number of receptor sites for the second messenger, Ins(1,4,5)P3. Of these, loss of Ins(1,4,5)P3 receptors and PKC in the entorhinal cortex and hippocampus correlates with AD-related neurofibrillary changes, as staged according to Braak's protocol. Disregulation of the phosphoinositide hydrolysis pathway may therefore have consequences for the progression of AD pathology. In contrast to the extensive pattern of disruption seen with the phosphoinositide hydrolysis pathway, changes to AC signalling in AD appear more circumscribed. Disruptions include a lesion at the level of Gs-protein stimulation of AC and, at least in the hippocampus, reduced enzyme activities in response to forskolin stimulation. Of these, the latter change has been shown to precede neurofibrillary changes. Apart from a loss of calcium/calmodulin sensitive AC isoforms, other components of this signalling pathway, including G-protein levels, Gi-protein mediated inhibition and protein kinase A levels and activity, remain relatively preserved in the disorder.

Adenylyl Cyclases↗

PubMed2000

Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease.

BACKGROUND: The cause of dementia in subcortical ischemic vascular disease (SIVD) is controversial. OBJECTIVES: To determine whether cognitive impairment in SIVD 1) correlates with measures of ischemic brain injury or brain atrophy, and/or 2) is due to concomitant AD. METHODS: Volumetric MRI of the brain was performed in 1) elderly subjects with lacunes (L) and a spectrum of cognitive impairment-normal cognition (NC+L, n = 32), mild cognitive impairment (CI+L, n = 26), and dementia (D+L, n = 29); 2) a comparison group with probable AD (n = 28); and 3) a control group with normal cognition and no lacunes (NC). The authors examined the relationship between the severity of cognitive impairment and 1) volume, number, and location of lacunes; 2) volume of white matter signal hyperintensities (WMSH); and 3) measures of brain atrophy (i. e., hippocampal, cortical gray matter, and CSF volumes). RESULTS: Among the three lacune groups, severity of cognitive impairment correlated with atrophy of the hippocampus and cortical gray matter, but not with any lacune measure. Although hippocampal atrophy was the best predictor of severity of cognitive impairment, there was evidence for a second, partially independent, atrophic process associated with ventricular dilation, cortical gray matter atrophy, and increase in WMSH. Eight autopsied SIVD cases showed variable severity of ischemic and neurofibrillary degeneration in the hippocampus, but no significant AD pathology in neocortex. The probable AD group gave evidence of only one atrophic process, reflected in the severity of hippocampal atrophy. Comparison of regional neocortical gray matter volumes showed sparing of the primary motor and visual cortices in the probable AD group, but relatively uniform atrophy in the D+L group. CONCLUSIONS: Dementia in SIVD, as in AD, correlates best with hippocampal and cortical atrophy, rather than any measure of lacunes. In SIVD, unlike AD, there is evidence for partial independence between these two atrophic processes. Hippocampal atrophy may result from a mixture of ischemic and degenerative pathologies. The cause of diffuse cortical atrophy is not known, but may be partially indexed by the severity of WMSH.

Aged↗

PubMed1999

Neuronal cell death in Down's syndrome.

Down's syndrome (DS), occurring in 0.8 out of 1,000 live births, is a genetic disorder in which an extra portion of chromosome 21 leads to several abnormalities. With respect to the nervous system, it causes mental retardation. It is conceived that abnormal neuronal cell death in development is involved, but there is no direct evidence yet. In addition to developmental brain abnormalities, almost all DS brains over 40 years old manifest a similar pathology to Alzheimer's disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although there was a debate to segregate dementia from underlying mental retardation, at least some portion of DS patients exhibit deteriorated mental status with aging. The mechanism underlying these abnormalities at the molecular level remains to be elucidated. Recently there have been several reports suggesting abnormalities reflecting increased risk to apoptosis in DS brains. Increased expression of several apoptosis-related genes (p53, fas, ratio of bax to bcl-2, GAPDH) in DS brains has been reported. Cultured neurons from both patients and model animals are reportedly more vulnerable to apoptosis. Overproduction of reactive oxygen species and its causative roles for increased apoptosis in DS tissues are suggested. One possible hypothesis is an increased susceptibility to apoptosis due to p53 overactivation in DS brains. A beta 42, a critical peptide for AD pathology from amyloid precursor protein (APP), can be detected in DS brains. A beta 42 is deposited in SP from an early stage, suggesting common molecular mechanisms in DS and AD. Animal models for DS are important in the search of molecular mechanisms. Several types of models are now available. Future DS studies are expected to integrate information from animal models and human tissues.

Adult↗

PubMed2003

Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach.

Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer's disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis. Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress.Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction occurs together with the induction of other HSPs during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimer's disease, in fact, involves a chronic inflammatory response associated with both brain injury and beta-amyloid associated pathology. All of the above evidence suggests that stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as an antidegenerative mechanism potentially important in AD pathogenesis. These findings have offered new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes, such as the HO gene, conceivably may delay the aging process and decrease the occurrence of age-related neurodegenerative diseases.

Aging↗

PubMed2003

Nutritional antioxidants and the heme oxygenase pathway of stress tolerance: novel targets for neuroprotection in Alzheimer's disease.

Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer's disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis. Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat-shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction, which occurs together with the induction of other HSPs during various physiopathological conditions, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, represents a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Recently, increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimer's disease, in fact, involves a chronic inflammatory response associated with both brain injury and beta-amyloid associated pathology. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as antidegenerative mechanism operating in AD pathogenesis. We also discuss the role that exogenous antioxidant supplementation, conceivably, could play in AD in combating oxidative damage and compensating for the decreased level of endogenous antioxidants. Conceivably, dietary supplementation with vitamin E or with polyphenolic agents, such as curcumin and its derivatives, can forestall the development of AD, consistent with a major "metabolic" component to this disorder. Such an outcome would provide optimism that the signs and symptoms of this devastating brain disorder of aging may be largely delayed and/or modulated.

Alzheimer Disease↗

PubMed2002

Alzheimer disease and cerebrovascular pathology: an update.

Recent epidemiological and clinico-pathologic data suggest overlaps between Alzheimer disease (AD) and cerebrovascular lesions that may magnify the effect of mild AD pathology and promote progression of cognitive decline or even may precede neuronal damage and dementia. Vascular pathology in the aging brain and in AD includes: 1. cerebral amyloid angiopathy (CAA) with an incidence of 82-98% often associated with ApoE epsilon 2 and causing a) cerebral mass hemorrhages (around 70%, mainly in the frontal and parietal lobes), b) multiple or recurrent microhemorrhages (15%), and c) ischemic (micro-)infarcts or lacunes (around 20%). The frequency of these lesions increases with the severity of CAA and shows no correlation with that of senile amyloid plaques. CAA, significantly more frequent in patients with cerebral hemorrhages or infarcts than in aged controls, is an important risk factor for cerebrovascular lesions in AD. 2. Microvascular changes with decreased density and structural abnormalities causing regional metabolic and blood-brain barrier dysfunctions with ensuing neuronal damage. In large autopsy series of demented aged subjects, around 80% show Alzheimer type pathology, 20-40% with additional, often minor vascular lesions, 7-10% "pure" vascular dementia, and 3-5% "mixed" dementia (combination of AD and vascular encephalopathy). AD cases with additional minor cerebrovascular lesions have significantly more frequent histories of hypertension or infarcts than "pure" AD patients. Vascular lesions in AD include cortical microinfarcts, subcortical lacunes, white matter lesions / leukoencephalopathy, small hemorrhages and corticosubcortical infarcts, while in mixed type dementia multiple larger or hemispheral infarcts are more frequent. Small infarcts in AD patients have no essential impact on global cognitive decline which mainly depends on the severity of Alzheimer pathology, but in early stage of AD they may influence and promote the development of dementia. Recent studies showed lower density of plaques and tangles in brains with cerebrovascular lesions, and similar severity of dementia was related to fewer AD lesions in brains with than in those without small vascular lesions. Further studies will help to elucidate the risk factors and impact of cerebrovascular lesions on the development and progression of dementia in AD.

Alzheimer Disease↗

PubMed1997

Inhibiting the formation of classical C3-convertase on the Alzheimer's beta-amyloid peptide.

Amyloid plaques are the pathological hallmark of Alzheimer Disease (AD) brains, being found primarily in the hippocampus and neocortex, where AD pathology is most evident. Complement activation is associated with amyloid plaques which are made from fibrils of aggregated amyloid peptides, 39-42 amino acids long. In vitro studies show that aggregated amyloid peptides activate complement via the classical pathway, implying that amyloid plaques themselves cause complement activation in AD brains. In order to test this hypothesis, we sought to determine if a major peptide component of amyloid plaques, A beta 1-42, supports the formation of the classical pathway C3 convertase. Using normal human serum depleted of C3, we are able to detect C3 convertase activity on aggregated A beta 1-42 in vitro. The convertase activity is associated with the binding of C1q and activation of C4 on the aggregated peptide. Inhibitors of C1 esterase and the cation chelator EGTA both block the formation of the convertase activity. Congo red, a histochemical stain for amyloid deposits and an inhibitor of amyloid aggregation, reduces C3 convertase activity on aggregated A beta 1-42, indicated by decreased C3a production. Our results provide further evidence that aggregated A beta 1-42 alone is sufficient to serve as a nidus for complement activation, and thus may be involved directly in initiating the inflammation seen in AD brains.

Alzheimer Disease↗

PubMed2006

Inflammatory changes parallel the early stages of Alzheimer disease.

Alzheimer disease (AD) is the most prominent cause of dementia in the elderly. To determine changes in the AD brain that may mediate the transition into dementia, the gene expression of approximately 10,000 full-length genes was compared in mild/moderate dementia cases to non-demented controls that exhibited high AD pathology. Including this latter group distinguishes this work from previous studies in that it allows analysis of early cognitive loss. Compared to non-demented high-pathology controls, the hippocampus of AD cases with mild/moderate dementia had increased gene expression of the inflammatory molecule major histocompatibility complex (MHC) II, as assessed with microarray analysis. MHC II protein levels were also increased and inversely correlated with cognitive ability. Interestingly, the mild/moderate AD dementia cases also exhibited decreased number of T cells in the hippocampus and the cortex compared to controls. In conclusion, transition into AD dementia correlates with increased MHC II(+) microglia-mediated immunity and is paradoxically paralleled by a decrease in T cell number, suggesting immune dysfunction.

Aged↗

PubMed2006

Age-dependent decline of neprilysin in Alzheimer's disease and normal brain: inverse correlation with A beta levels.

Brain deposition of amyloid-beta (A beta) is a pathological hallmark of Alzheimer disease (AD) but A beta is also detected in non-demented elderly individuals. Neprilysin has been shown to be an important enzyme to degrade A beta in brain. We investigated whether decreased neprilysin levels contributes to the accumulation of A beta in AD and in normal aging. No difference in neprilysin protein and mRNA levels were found between AD subjects and age-matched controls. Protein levels of neprilysin were reduced with age in the temporal and frontal cortex of AD and normal brain. A significant positive correlation between insoluble A beta 40 and A beta 42 with age was found in cortex of normal brain whereas in AD brain the correlation between age and A beta was weaker. Our findings of an inverse correlation between neprilysin and insoluble A beta levels in both groups suggest that neprilysin is involved in the clearance of A beta. The observed age-dependent decline in neprilysin may be related to the increased A beta levels during normal aging. The similar rate of decline in neprilysin with age may not be the major cause of the high levels of A beta associated with AD but is likely to be a trigger of AD pathology.

Aged↗

PubMed2002

Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100.

To examine the regulation of amyloid secretion in more detail, Abeta sandwich ELISAs with high sensitivity and specificity were developed. Using this technique, we measured Abeta secreted from COS7 cells transiently transfected with APP C100 in the presence of LiCl, a potent glycogen synthase kinase (GSK)-3beta inhibitor. We found that both Abetax-40 and Abetax-42 secretion were reduced by LiCl treatment in a dose-dependent manner. Diminished amyloid secretion was associated with GSK-3beta activity. These results suggest that GSK-3beta might function as a possible mediator for regulating both amyloid deposition and tau pathology in Alzheimer's disease (AD), and that lithium should be re-evaluated as a candidate reagent for preventing AD pathology.

Alzheimer Disease↗

PubMed2002

Water-soluble chitosan inhibits the production of pro-inflammatory cytokine in human astrocytoma cells activated by amyloid beta peptide and interleukin-1beta.

A chronic inflammatory response associated with beta-amyloid (Abeta) and interleukin-1beta (IL-1beta) is responsible for the pathology of Alzheimer's disease (AD). Astrocytes are predominant neuroglial cells of the central nervous system and are actively involved in cytokine-mediated events in AD. To investigate the biological effect of water-soluble chitosan (WSC), we examined cytotoxicity, production of pro-inflammatory cytokines and inducible nitric-oxide synthase (iNOS) on human astrocytoma cell line CCF-STTG1 stimulated with IL-1beta and Abeta fragment 25-35 (Abeta[25-35]). In 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide colorimetric assay, WSC by itself had no effect on cell viability on human astrocytoma cells. The effects of WSC on tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were evaluated with enzyme-linked immunosorbent assay and Western blotting. The production of TNF-alpha and IL-6 was induced by IL-1beta and Abeta[25-35] and synergistically amplified by the co-stimulation of IL-1beta and Abeta[25-35]. The secretion and expression of pro-inflammatory cytokines, TNF-alpha and IL-6, was significantly inhibited by pretreatment with WSC in human astrocytoma cells. The expression of iNOS was induced by IL-1beta and Abeta[25-35] and was partially inhibited by treatment with WSC. We demonstrate the regulatory effects of WSC in human astrocytes for the first time and suggest the anti-inflammatory effect of WSC may reduce and delay AD pathologic events.

Alzheimer Disease↗

PubMed1997

Dementia with Lewy bodies: clustering of Lewy bodies in human patients.

Clustering of Lewy bodies (LB) was studied in four regions of the medial temporal lobe in 12 cases of dementia with LB (DLB). LB exhibited clustering in 67/70 (96%) brain areas analysed. In 34/70 (49%) analyses, LB were present in a single large cluster > or = 6400 microns in diameter, in 33/70 (47%) LB occurred in smaller clusters 200-3200 microns in diameter which exhibited a regular periodicity relative to the tissue boundary and in 3/70 (4%), LB were randomly distributed. A regular pattern of LB clusters was observed equally frequently in the cortex and hippocampus, in upper and lower cortical laminae and in 'pure' cases of DLB with negligible Alzheimer's disease (AD) pathology compared with cases of AD with DLB. In cortical regions, there was no significant correlation between LB cluster size in the upper and lower cortical laminae. The regular periodicity of LB clusters suggests that LB develop in relation to the cells of origin of specific cortico-cortical and cortico-hippocampal projections.

Aged↗

PubMed2000

Selective increase in cellular A beta 42 is related to apoptosis but not necrosis.

Amyloid beta protein ending at 42 (A beta 42) plays an important role in the pathology of Alzheimer's disease (AD). Here we show an increase in cellular A beta 42 in damaged neurons, with both ELISA and immunocytochemistry. The cellular A beta 42 increase was caused by 3-day treatments with H2O2, etoposide or melphalan, all of which induce genotoxic apoptosis, but not by treatment with sodium azide, which causes necrosis. Secreted A beta was similarly decreased with all these treatments. The cellular A beta 42 increase appeared even with minimal damage (ELISA) and A beta 42-positive cells were TUNEL negative (double staining), indicating that any early apoptosis mechanism may induce the cellular A beta 42 increase. Thus, neuronal apoptosis and cellular A beta 42 increase may be linked in a way that contributes importantly to AD pathology.

Amyloid beta-Peptides↗

PubMed2006

The morphological basis of mental dysfunction in Parkinson's disease.

Mental dysfunction including dementia in Parkinson's disease (PD), the incidence of which averages 20-40%, is suggested to have six-fold lifetime risk compared to age-matched controls. It is caused by a variety of functional and pathological lesions ranging from damage to subcortical-cortical networks to cortical and limbic Lewy body and neuritic Alzheimer pathologies, the relationship and impact of which are still under discussion. Based on two consecutive autopsy series of PD, with prevalence of cognitive impairment of 33% to 35.7%, its essential morphological changes and their impact on the natural history (survival) are discussed. Whereas cortical Lewy body stages 5 and 6 without additional pathologies only rarely were associated with dementia, around 20% of demented PD cases were classified as dementia with Lewy bodies (DLB) with variable degrees of Alzheimer (AD) pathology, and around one third showed severe neuritic AD lesions which occurred in PD patients with later disease onset and significantly shorter survival. Frequent close relations in the severity between alpha-synuclein and tau-pathologies suggest synergistic reaction and common underlying pathogenesis of both lesions. Clinico-pathological studies in PD showed a significantly negative relation between cognitive impairment and neuritic AD lesions somewhat different from that in AD, suggesting that neuritic AD pathology, either alone or in combination with cortical and limbic Lewy bodies, are major causes of mental and cognitive dysfunction in PD.

Aged↗

PubMedDate not supplied

Laminar distribution of beta-amyloid deposits in dementia with Lewy bodies and in Alzheimer's disease.

This study tested whether the laminar distribution of the beta-amyloid (Abeta) deposits in dementia with Lewy bodies (DLB) cases with significant Alzheimer's disease (AD) pathology (DLB/AD) was similar to "pure" AD. In DLB/AD, the maximum density of the diffuse and primitive deposits occurred either in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. A bimodal distribution of the classic Abeta deposits was also observed. Compared with AD, DLB/AD cases had fewer primitive deposits relative to the diffuse and classic deposits; the primitive deposits exhibited a bimodal distribution more frequently, and the diffuse deposits occurred more often in the upper laminae. These results suggest that Abeta pathology in DLB/AD may not simply represent the presence of associated AD.

Aged↗

PubMed2004

Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer's disease.

It has been widely accepted that vascular hypoperfusion induces oxidative stress and the outcome of this misbalance is brain energy failure. This abnormality leads to neuronal death which manifests as cognitive impairment and the development of brain pathology as in Alzheimer's disease (AD). It has been demonstrated that the AD brain is characterized by impairments in energy metabolism. We theorize that hypoperfusion induced mitochondrial failure plays a key role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and in selective population of neurons with high metabolic activity in the AD brain. All of these abnormalities have been found to occur before classic AD pathology inducing neuronal degeneration and amyloid deposition during the progression of AD. Therefore, expanding investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors such as chronic hypoxia/reperfusion may open a new avenue for effective treatments of AD. Future studies examining the importance of mitochondrial pathobiology in brain cellular compartments provide insight not only into the better understanding of the neurodegenerative and/or cerebrovascular disease but also provide targets for treating these conditions.

Journal Article↗