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At least 109 records · Page 6Linked to original sources
PubMed1991

Entorhinal neurofibrillary tangles in Alzheimer disease with Lewy bodies.

Entorhinal cortex is the major source of hippocampal afferents. Its neurons, especially in layer 2, develop neurofibrillary tangles (NFTs) in Alzheimer disease (AD). We quantified entorhinal NFTs in cases of AD, elderly controls, and in brains with both AD pathology and subcortical and neocortical Lewy bodies, (a Lewy body variant, LBV). A nosologic controversy hinges on whether LBVs are a form of AD or a different disease, since they have few neocortical NFTs and their neuritic plaques often lack paired helical filament immunoreactivity. The LBVs had more entorhinal NFTs than controls (P less than 0.001), but fewer than ADs (P less than 0.02), despite comparable numbers of neuritic plaques. AD pathology in LBVs is of moderate severity, or perhaps in an earlier developmental stage.

Aged↗
PubMed1996

Neuropsychological deficits associated with diffuse Lewy body disease.

Diffuse Lewy body disease (DLBD), in its pure form, is a neuropathologic condition in demented patients that is characterized by subcortical and diffusely distributed neocortical Lewy bodies with little or no concomitant Alzheimer's disease (AD) pathology. Clinically, DLBD patients initially present with dementia of insidious onset and subsequently develop mild extrapyramidal motor dysfunction. The present study retrospectively examined the neuropsychological test performance of five patients with DLBD and compared their performance to that of equally demented patients with neuropathologically confirmed "pure" AD. The results showed that the DLBD patients were globally demented with deficits in memory, attention, language, psychomotor performance, and "executive" functions, and a strikingly severe deficit in visuospatial and visuoconstructive abilities. The visuoconstructive and psychomotor impairments of the DLBD patients were significantly worse than those of the AD patients, whereas the memory performance of the AD patients was worse than that of the DLBD patients. These results indicate that DLBD without concomitant AD pathology can produce a global dementia with aspects of both cortical and subcortical dysfunction and suggests that Lewy body pathology contributes importantly to the clinical manifestation of the Lewy body variant of AD.

Aged↗
PubMed1995

Early association of reactive astrocytes with senile plaques in Alzheimer's disease.

The fibrillar beta-amyloid protein (A beta) plaques of Alzheimer's disease (AD) are associated with reactive astrocytes and dystrophic neurites and have been suggested to contribute to neurodegenerative events in the disease. We recently reported parallel in vitro and in situ findings, suggesting that the adoption of a reactive phenotype and the colocalization of astrocytes with plaques in AD may be mediated in large part by aggregated A beta. Thus, A beta-mediated effects on astrocytes may directly affect disease progression by modifying the degenerative plaque environment. Alternatively, plaque-associated reactive astrocytosis may primarily represent a glial response to the neural injury associated with plaques and not significantly contribute to AD pathology. To investigate the validity of these two positions, we examined the differential colocalization of reactive astrocytes and dystrophic neurites with plaques. Hippocampal sections from AD brains--ranging in neuropathology from mild to severe--were triple-labeled with antibodies recognizing A beta protein, reactive astrocytes, and dystrophic neurites. We observed not only plaques containing both or neither cell type, but also plaques containing (1) reactive astrocytes but not dystrophic neurites and (2) dystrophic neurites but not reactive astrocytes. The relative proportion of plaques colocalized with reactive astrocytes in the absence of dystrophic neurites is relatively high in mild AD but significantly decreases over the course of the disease, suggesting that plaque-associated astrocytosis may be an early and perhaps contributory event in AD pathology rather than merely a response to neuronal injury. These data underscore the potentially significant contributions of reactive astrocytosis in modifying the plaque environment in particular and disease progression in general.

Adult↗
PubMedDate not supplied

Cerebral infarctions and the relationship of depression symptoms to level of cognitive functioning in older persons.

OBJECTIVE: Recent studies report an association between depressive symptoms and cognitive impairment in old age. The neurobiologic basis of this association is unknown. The authors examined whether cerebral infarcts (present in 55 persons) accounted for the association of depressive symptoms with cognitive impairment in a group of 153 older Catholic nuns, priests, and brothers (67 with dementia and 86 without dementia). METHODS: Subjects underwent detailed clinical evaluations and brain autopsy at death. RESULTS: Mean values for depressive symptoms during the time of participation were associated with level of cognitive functioning proximate to death in analyses that controlled for age, sex, education, and Alzheimer disease (AD) pathology. The association of depressive symptoms with cognitive functioning was essentially unchanged after controlling for cerebral infarctions, which suggests that depressive symptoms, cerebral infarctions, and AD pathology were independently related to cognitive function. Similar results were found in analyses with episodic memory, semantic memory, working memory, perceptual speed, and visual-spatial ability. The results did not change in analyses examining the volume or location of cerebral infarctions. CONCLUSIONS: These data suggest that cerebral infarctions do not account for the association of depressive symptoms with level of cognitive functioning. The neurobiologic basis for this association remains to be elucidated.

Aged↗
PubMed1995

Changes in protein kinases in brain aging and Alzheimer's disease. Implications for drug therapy.

There is ample evidence for the involvement of aberrant protein phosphorylation reactions in aging and age-associated neurological disorders. Alzheimer's disease (AD) in particular. The exact nature of this involvement, however, is not yet elucidated. In the brain tissue of AD patients, there are numerous examples of altered protein phosphorylation pathways. Individual protein kinases and phosphorylation by these kinases in AD brain tissues have been found to be altered. Protein kinases studied include protein kinase C (PKC), protein tyrosine kinase (PTK), casein kinase II (CKII), Ca++/calmodulin-dependent kinase II and mitogen-activated protein (MAP) kinases, all of which are thought to be necessary for cell survival. Interestingly, different protein kinases are involved in different aspects of AD pathology. It is postulated that the perturbation of amyloid beta/A4-protein precursor (APP) metabolism triggers abnormal protein phosphorylation reactions responsible for dysfunction and eventual death of neurons in the brain. The association of APP mutation with certain familial types of AD strongly suggests that there might be a link between aberrant APP metabolism, protein phosphorylation cascades and the eventual expression of AD pathology (plaques and tangles) and neurodegeneration. In summary, recent studies emphasise the prime importance of protein phosphorylation in aging and AD. This raises the possibility that future pharmacological interventions might be devised to interfere with this kinase cascade for the prevention or treatment of age-associated neurological disorders.

Aging↗
PubMed2005

The role of inflammation in Alzheimer's disease.

Considerable evidence gained over the past decade has supported the conclusion that neuroinflammation is associated with Alzheimer's disease (AD) pathology. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the classic and alternate pathways of the complement system, the pentraxin acute-phase proteins, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferators-activated receptors (PPARs), as well as cytokines and chemokines. Both the microglia and astrocytes have been shown to generate beta-amyloid protein (Abeta), one of the main pathologic features of AD. Abeta itself has been shown to act as a pro-inflammatory agent causing the activation of many of the inflammatory components. Further substantiation for the role of neuroinflammation in AD has come from studies that demonstrate patients who took non-steroidal anti-inflammatory drugs had a lower risk of AD than those who did not. These same results have led to increased interest in pursuing anti-inflammatory therapy for AD but with poor results. On the other hand, increasing amount of data suggest that AChRs and PPARs are involved in AD-induced neuroinflammation and in this regard, future therapy may focus on their specific targeting in the AD brain.

Acute-Phase Proteins↗
PubMed2006

Locus ceruleus degeneration is ubiquitous in Alzheimer's disease: possible implications for diagnosis and treatment.

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer's disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non-focal white matter disease (WMD) in AD. This report is a pathological follow-up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.

Adrenergic Agonists↗
PubMed2026

Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementias.

To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

Humans↗
PubMed2006

Metal exposure and Alzheimer's pathogenesis.

With the growing aging population in Western countries, Alzheimer's disease (AD) has become a major public health concern. No preventive measure and effective treatment for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data strongly suggest that Abeta amyloidosis, which originates from the amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon the age-dependent cerebral Abeta amyloidogenesis are not well recognized. Growing data indicate that cerebral dysregulation of biometals, environmental metal exposure, and oxidative stress contribute to AD pathology. Herein we provided further evidence that both metals (such as Cu) and H(2)O(2) promote formation of neurotoxic Abeta oligomers. Moreover, we first demonstrated that laser capture microdissection coupled with X-ray fluorescence microscopy can be applied to determine elemental profiles (S, Fe, Cu, and Zn) in Abeta amyloid plaques. Clearly the fundamental biochemical mechanisms linking brain biometal metabolism, environmental metal exposure, and AD pathophysiology warrant further investigation. Nevertheless, the study of APP and Abeta metallobiology may identify potential targets for therapeutic intervention and/or provide diagnostic methods for AD.

Alzheimer Disease↗
PubMed1997

The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down's syndrome subjects.

The apolipoprotein E gene (APOE), located on human chromosome 19, has three common alleles (epsilon2, epsilon3, epsilon4) which encode for the three main isoforms indicated as E2, E3 and E4 respectively. Several findings indicate epsilon4 allele as an important risk factor in both sporadic and familial late-onset Alzheimer's disease (AD). Pathological changes similar to AD are seen in almost all patients with Down's syndrome (DS) aged over 35 (senile plaques, neurofibrillary tangles and neuronal loss); a proportion of these may subsequently develop dementia. Aim of this study is to evaluate the possible pathological role of epsilon4 allele as risk factor for developing AD in a DS population. ApoE epsilon4 allele frequency is not significantly different in DS cases and controls. We found a statistically significant inverse correlation between full scale IQ values and age of patients in the subgroup of DS subjects selected for the presence of at least one epsilon4 allele, while no correlation was observed in DS subjects with other ApoE genotypes. A longitudinal analysis of cognitive performances (available in 38 patients) showed a faster rate of decline in intellectual ability in those subjects carrying at least one epsilon4 allele. Our data support the hypothesis that ApoE epsilon4 allele has a contributory role in accelerating the mental deterioration of AD-type in DS patients.

Adolescent↗
PubMed2005

Amyloid imaging: from benchtop to bedside.

Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

Alzheimer Disease↗
PubMed2006

Activated c-Jun is present in neurofibrillary tangles in Alzheimer's disease brains.

Alzheimer's disease (AD) pathology is characterized by the presence of insoluble beta-amyoid deposits and neurofibrillary tangles containing hyperphosphorylated tau. Increased expression of the immediate early gene product c-Jun has also been reported in post-mortem AD brains, and the presence of upstream regulators of c-Jun has been described in tangle formations. Here, we report the presence of c-Jun specifically phosphorylated on ser-63, but not ser-73, in tangle-bearing neurons and in 'late-stage' extracellular tangles in AD brains. Western blot analysis confirmed the presence of c-Jun phosphorylated on ser-63 but not on ser-73 in AD brain tissue. The expression of differentially phosphorylated c-Jun in the AD brain may reflect the contradictory roles of these phosphorylation sites in neurons. Furthermore, the inappropriate sequestration of phosphorylated c-Jun in tangles in AD brains may contribute to AD pathology and neurodegeneration.

Aged↗
PubMed2000

Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid beta-peptide (A beta(42)) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid A beta(42) deposits have to mature in the presence of A beta(40) into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving gamma-secretase cleavages of APP. The mutation had the most drastic effect on A beta(42)/A beta(40) ratio in vitro of approximately 11-fold, simultaneously increasing A beta(42) and decreasing A beta(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta(42) in complete absence of A beta(40). These data indicate that N-truncated A beta(42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length A beta(42 )by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta(42).

Alzheimer Disease↗
PubMed2006

Increased metabolic activity in nucleus basalis of Meynert neurons in elderly individuals with mild cognitive impairment as indicated by the size of the Golgi apparatus.

In this study, we examined the metabolic activity of nucleus basalis of Meynert (NBM) neurons in individuals clinically diagnosed with no cognitive impairment (NCI, n = 8), mild cognitive impairment (MCI, n = 9), and subjects with moderate Alzheimer disease (AD, n = 7). We used Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Subjects with MCI showed increased NBM metabolic activity; they had significantly more neurons with larger GA size as compared with NCI and AD subjects. In contrast, more NBM neurons with extremely small GA sizes, indicating reduced metabolic activity, were seen in AD. When these cases were classified according to their AD pathology (Braak I-II, III-IV, or V-VI), Braak III-IV subjects showed significantly increased GA sizes, comparable with the increase in clinically diagnosed MCI, whereas in Braak V-VI, GA sizes were dramatically reduced. Of all MCI and NCI subjects with similar Braak III-IV pathology, the MCI subjects again had significantly larger GA sizes. The larger NBM neuronal GA size seen in MCI suggests increased metabolic activity, associated with both the clinical progression from NCI to MCI, and with the early stages of AD pathology.

Aged, 80 and over↗
PubMed2005

The amyloid pathology progresses in a neurotransmitter-specific manner.

Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

Acetylcholine↗
PubMed1991

Aberrant localization of MAP5 immunoreactivity in the hippocampal formation in Alzheimer's disease.

Immunocytochemistry was used to examine MAP5 immunoreactivity in the hippocampal formation obtained postmortem from five elderly, normal individuals, six individuals with Alzheimer's disease (AD), and two "transition" cases that did not have a history of dementia but did exhibit significant AD pathology. In all of the cases examined, axonal staining was restricted to the mossy fibers and their terminal field in CA3 stratum lucidum. In control cases, MAP5 immunoreactivity was observed in the neuronal cytoplasm and the proximal portion of the apical dendrites of pyramidal and granule cells. In both AD and transition cases, increased intensity of immunostaining was observed in CA3 pyramidal, subicular, and dentate gyrus granule cell neurons. Within individual neurons, immunoreactivity filled the neuronal perikarya, including the nuclear region, and the apical dendrite. Punctate staining was observed in neuritic plaques, but neurofibrillary tangles and neuropil threads were not immunostained. The increase and altered distribution of MAP5 immunoreactivity in both vulnerable and nonvulnerable neurons in AD may reflect an aberrant sprouting response. The increased expression of early cytoskeletal proteins may be tolerated in some regions such as CA3, but not in others including CA1 where the increased expression appear to precede aberrant phosphorylation, proteolysis, and incorporation of cytoskeletal proteins into AD pathology. Alternatively, the results could reflect sprouting in response to the neuronal loss and degeneration.

Aged↗
PubMed2005

Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction.

Trichothiodystrophy (TTD) patients with a mutation in the XPD gene of nucleotide excision repair (NER) have a short life span and show various features of premature aging, thereby linking DNA damage to the aging process. Xpd(TTD) mutant mice share many features with TTD patients, including a shorter life span, accompanied by a segmental progeroid phenotype. Here we report new pathology features supportive to the premature aging phenotype of Xpd(TTD) mice. Strikingly, accelerated aging pathology is accompanied by signs suggestive of caloric restriction (CR), a condition usually linked to retardation of age-related pathology and life extension. Accelerated aging symptoms in Xpd(TTD) mice are most likely due to accumulation of endogenously generated DNA damage and compromised transcription leading to cell death, whereas CR symptoms may reflect the need of Xpd(TTD) mice to reduce metabolism (ROS production) in an attempt to extend their life span. Our current findings in Xpd(TTD) mice further strengthen the link between DNA damage, repair and aging.

Aging↗