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Walter Kalback,
Chera Esh,
Eduardo M Castaño,
Afroza Rahman,
Tyler Kokjohn,
Dean C Luehrs, Lucia Sue,
Raquel Cisneros,
Francoise Gerber,
Claudia Richardson,
Bernd Bohrmann,
Douglas G Walker,
Thomas G Beach,
Alex E Roher
[show abstract]
[hide abstract]
ABSTRACT: We postulate that severe atherosclerotic occlusion of the circle of Willis and leptomeningeal arteries is an important factor in the pathogenesis of some sporadic Alzheimer's disease (AD) cases. These arterial stenoses are complicated by an overwhelming amyloid accumulation in the walls of leptomeningeal and cortical arteries resulting in a significant decrease in perfusion pressure and consequent ischemia/hypoxia of the brain tissue. We also propose that the distal areas of the white matter (WM) will be the first affected by a lack of oxygen and nutrients. Our hypotheses are supported by the following observations: (1) the number of stenoses is more frequent in AD than in the control population (p = 0.008); (2) the average index of occlusion is greater in AD than in the control group (p < 0.00001); (3) the index of stenosis and the total number of stenoses per case are positively correlated (R = 0.67); (4) the index of stenosis correlates with the neuropathological lesions of AD and with the MMSE psychometric test; (5) the number and degree of atherosclerosis of the anterior, middle and posterior cerebral arteries is more severe in cases of AD than in the control population; (6) atherosclerosis severity is apparently associated with the severity of the vascular amyloidosis; (7) the WM rarefaction correlates with the severity of the atherosclerosis and vascular amyloidosis; (8) the total cell count and microvessel count in the areas of WM rarefaction correlate with the neuropathological lesions of AD and with the MMSE score. Our data strongly suggest that severe hemodynamic disturbances contribute to sporadic AD and support the numerous observations indicating cardiovascular system participation in the pathogenesis of these dementias.
Neurological Research 08/2004; 26(5):525-39. · 1.52 Impact Factor
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Walter Kalback,
Chera Esh,
Eduardo Castao,
Afroza Rahman,
Tyler Kokjohn,
Dean Luehrs, Lucia Sue,
Raquel Cisneros,
Francoise Gerber,
Claudia Richardson,
Bernd Bohrmann,
Douglas Walker,
Thomas Beach,
Alex Roher
[show abstract]
[hide abstract]
ABSTRACT: We postulate that severe atherosclerotic occlusion of the circle of Willis and leptomeningeal arteries is an important factor in the pathogenesis of some sporadic Alzheimer's disease (AD) cases. These arterial stenoses are complicated by an overwhelming amyloid accumulation in the walls of leptomeningeal and cortical arteries resulting in a significant decrease in perfusion pressure and consequent ischemia/hypoxia of the brain tissue. We also propose that the distal areas of the white matter (WM) will be the first affected by a lack of oxygen and nutrients. Our hypotheses are supported by the following observations: (1) the number of stenoses is more frequent in AD than in the control population (p = 0.008); (2) the average index of occlusion is greater in AD than in the control group (p < 0.00001); (3) the index of stenosis and the total number of stenoses per case are positively correlated (R = 0.67); (4) the index of stenosis correlates with the neuropathological lesions of AD and with the MMSE psychometric test; (5) the number and degree of atherosclerosis of the anterior, middle and posterior cerebral arteries is more severe in cases of AD than in the control population; (6) atherosclerosis severity is apparently associated with the severity of the vascular amyloidosis; (7) the WM rarefaction correlates with the severity of the atherosclerosis and vascular amyloidosis; (8) the total cell count and microvessel count in the areas of WM rarefaction correlate with the neuropathological lesions of AD and with the MMSE score. Our data strongly suggest that severe hemodynamic disturbances contribute to sporadic AD and support the numerous observations indicating cardiovascular system participation in the pathogenesis of these dementias.
Neurological Research 06/2004; 26(5):525-539. · 1.52 Impact Factor
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Rena Li,
Kristina Lindholm,
Li-Bang Yang,
Xu Yue,
Martin Citron,
Riqiang Yan,
Thomas Beach, Lucia Sue,
Marwan Sabbagh,
Huaibin Cai,
Philip Wong,
Donald Price,
Yong Shen
[show abstract]
[hide abstract]
ABSTRACT: Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Abeta species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Abeta species detected in rapidly autopsied brains (<3 h) with sporadic AD were Abeta(1-x) and Abeta(1-42), as well as Abeta(x-42). To establish a linkage between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Abeta(1-x) and Abeta(1-42) production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Abeta loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Abeta production and enhanced deposition of amyloid plaques in sporadic AD patients.
Proceedings of the National Academy of Sciences 04/2004; 101(10):3632-7. · 9.68 Impact Factor
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Thomas G Beach, Lucia Sue,
Sarah Scott,
Kathryn Layne,
Amanda Newell,
Douglas Walker,
Matthew Baker,
Naraju Sahara,
Shu-Hui Yen,
Michael Hutton,
Richard Caselli,
Charles Adler,
Donald Connor,
Marwan Sabbagh
[show abstract]
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ABSTRACT: In some elderly individuals with dementia, hippocampal sclerosis (HS) is the only remarkable autopsy finding. The cause of HS in this setting is puzzling, since known causes of HS such as seizures or global hypoxic-ischemic episodes are rarely present. We here describe a series of HS cases that have a widespread neuronal and/or glial tauopathy. Of 14 consecutive cases of HS, 12 had been clinically diagnosed with dementia and/or Alzheimer's disease (AD) while 2 were non-demented; 7 cases had also been clinically diagnosed with parkinsonism. In addition to HS, 6 cases also met pathologic diagnostic criteria for AD. Gallyas silver staining and immunohistochemistry with the AT8 antibody revealed a glial and/or neuronal tauopathy in 12 of 14 cases, with frequent positive neurons and/or glial cells in the neocortex, basal ganglia, thalamus and/or limbic regions; in addition, 8 of the 14 cases had argyrophilic grains. Screening for known tau mutations was negative in all cases. Western blots of sarkosyl-insoluble tau protein showed a mixture of 3- and 4-repeat forms. The results suggest that most cases of HS dementia are sporadic multisystem tauopathies; we suggest the term "hippocampal sclerosis dementia with tauopathy" (HSDT) for these.
Brain Pathology 08/2003; 13(3):263-78. · 3.99 Impact Factor
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Li-Bang Yang,
Kristina Lindholm,
Riqiang Yan,
Martin Citron,
Weiming Xia,
Xiao-Li Yang,
Thomas Beach, Lucia Sue,
Philip Wong,
Donald Price,
Rena Li,
Yong Shen
Nature Medicine 02/2003; 9(1):3-4. · 22.46 Impact Factor
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Alex E Roher,
Nicole Weiss,
Tyler A Kokjohn,
Yu-Min Kuo,
Walter Kalback,
Jacqueline Anthony,
Desiree Watson,
Dean C Luehrs, Lucia Sue,
Douglas Walker,
Mark Emmerling,
Warren Goux,
Thomas Beach
[show abstract]
[hide abstract]
ABSTRACT: Relative to the gray matter, there is a paucity of information regarding white matter biochemical alterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white matter combining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blotting revealed increased quantities of Abeta40 and Abeta42 in AD white matter accompanied by significant decreases in the amounts of myelin basic protein, myelin proteolipid protein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase. In addition, the AD white matter cholesterol levels were significantly decreased while total fatty acid content was increased. In some instances, these white matter biochemical alterations were correlated with patient apolipoprotein E genotype, Braak stage, and gender. Our observations suggest that extensive white matter axonal demyelination underlies Alzheimer's pathology, resulting in loss of capacitance and serious disturbances in nerve conduction, severely damaging brain function. These white matter alterations undoubtedly contribute to AD pathogenesis and may represent the combined effects of neuronal degeneration, microgliosis, oligodendrocyte injury, microcirculatory disease, and interstitial fluid stasis. To accurately assess the success of future therapeutic interventions, it is necessary to have a complete appreciation of the full scope and extent of AD pathology.
Biochemistry 10/2002; 41(37):11080-90. · 3.42 Impact Factor
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Alex E. Roher,
Nicole Weiss,
Tyler A. Kokjohn,
Yu-Min Kuo,
Walter Kalback,
Jacqueline Anthony,
Desiree Watson,
Dean C. Luehrs, Lucia Sue,
Douglas Walker,
Mark Emmerling,
Warren Goux,
Thomas Beach
[show abstract]
[hide abstract]
ABSTRACT: Relative to the gray matter, there is a paucity of information regarding white matter biochemical alterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white matter combining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blotting revealed increased quantities of Aβ40 and Aβ42 in AD white matter accompanied by significant decreases in the amounts of myelin basic protein, myelin proteolipid protein, and 2‘,3‘-cyclic nucleotide 3‘-phosphodiesterase. In addition, the AD white matter cholesterol levels were significantly decreased while total fatty acid content was increased. In some instances, these white matter biochemical alterations were correlated with patient apolipoprotein E genotype, Braak stage, and gender. Our observations suggest that extensive white matter axonal demyelination underlies Alzheimer's pathology, resulting in loss of capacitance and serious disturbances in nerve conduction, severely damaging brain function. These white matter alterations undoubtedly contribute to AD pathogenesis and may represent the combined effects of neuronal degeneration, microgliosis, oligodendrocyte injury, microcirculatory disease, and interstitial fluid stasis. To accurately assess the success of future therapeutic interventions, it is necessary to have a complete appreciation of the full scope and extent of AD pathology.
08/2002;
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[show abstract]
[hide abstract]
ABSTRACT: Argyrophilic grains (AGs) are a pathologic feature found in association with neurodegenerative disease. Some have suggested that these features may occur as a distinctive condition. We reviewed 80 subjects from our tissue bank with pathologically confirmed AGs and identified their clinical features. We compared these subjects' features to the features of subjects with matched clinical diagnoses but without AGs. Subjects with AGs represented 21.7% of the entire autopsy sample from 1999 to 2005 (80 out of 367). Of Alzheimer disease (AD) subjects, 43 out of 233 had AGs (18.4% of AD subjects); 11 out of 42 Parkinson disease with dementia subjects had AGs (26.1% of Parkinson disease with dementia subjects); 2 out of 9 dementia with Lewy bodies subjects had AGs (22.2% of dementia with Lewy bodies subjects); 4 out of 15 mild cognitive impairment subjects had AGs (26.7% of mild cognitive impairment subjects); and 20 out of 68 cognitively normal subjects had AGs (29.4% of cognitively normal). Subjects with AGs tended to be older but only significantly so in AD. Many comorbid non-neurologic health conditions were seen in cases of AGs without any single predilection emerging. AGs occur in approximately 22% of the entire autopsy cohort and are likely associated with advanced age. No distinctive antemortem clinical features were over represented in the AG cases. AGs can occur with or without neurodegenerative conditions and can occur in the absence of significant cognitive decline. AGs are not clearly associated with any single comorbid health condition.
Alzheimer disease and associated disorders 23(3):229-33. · 2.88 Impact Factor
