Search

Background: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors. [ABSTRACT FROM AUTHOR]

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex. [ABSTRACT FROM AUTHOR]

Clinically diagnosed Alzheimer's disease (AD) is pathologically heterogeneous. In this multicenter cohort of 215 clinically diagnosed AD patients and 249 controls, E-selectin and vascular cell adhesion molecule 1 (VACM-1) were measured along with amyloid-β peptide 1-42 (Aβ42) and tau. We discovered that E-selectin, a biomarker of endothelial function/vascular injury, was inversely correlated with cerebrospinal fluid (CSF) tau/Aβ42 ratio and significantly elevated in clinical AD patients without the typical AD CSF biomarker signature (i.e., low tau/Aβ42 ratio) compared to those with the signature. These findings suggest that E-selectin may be an objective biomarker related to vascular mechanisms contributing to dementia. [ABSTRACT FROM AUTHOR]

Progressive cognitive impairment and its clinical culmination in dementia loom as a major public health problem in the coming generation of older adults, and this fact compels investigation to develop interventions that prevent, delay, or cure. The tools of anatomic pathology have provided key insights into the complex convergence of multiple diseases that commonly contribute to the dementia syndrome and its prodrome in the community setting, and they have suggested some exposures that may modulate disease burden. The tools of clinical pathology, in combination with neuroimaging, have revolutionized the approach to clinical investigation of Alzheimer's disease and are now doing the same with Lewy body disease and vascular brain injury. The tools of anatomic and clinical pathology will continue to contribute to our understanding of these diseases as we advance toward effective interventions for the diseases that commonly cause cognitive impairment and dementia in older adults. [ABSTRACT FROM AUTHOR]

Dementia from Alzheimer's disease (AD) represents a significant and growing public health burden and presents a clear therapeutic imperative. Key to success in this undertaking will be biomarkers for the objective assessment of disease progression and response to therapeutics. Oxidative damage is one facet of AD pathogenesis for which there are experimentally validated quantitative in vivo biomarkers, the F_{2}-isoprostanes (IsoPs). While plasma- or urine-based assays are desirable, consistent and reproducible cross-sectional data for increased F_{2}-IsoPs in AD and mild cognitive impairment have been obtained only for CSF. In addition, measurement of CSF F_{2}-IsoPs can increase the accuracy of laboratory-based classification of geriatric dementias, and have been used to assess objectively the response to anti-oxidant interventions in AD. [ABSTRACT FROM AUTHOR]

The clinical diagnosis of major neurodegenerative disorders, e.g. Alzheimer's disease, Parkinson's disease, and dementia with Lewy body, remains unsatisfactory based on current clinical criteria and limited laboratory investigations. The possibility of identifying multiple novel biomarkers for neurodegenerative diseases, those related to disease pathogeneses in particular, has been greatly enhanced with recent advances in genomics, proteomics, and metabolomics. In this chapter, we will be reviewing a few issues related to proteomic identification of proteins in human cerebrospinal fluid (CSF) as well as unique protein markers that could be used for clinical diagnosis of various neurodegenerative diseases or monitoring their progression. Great attention has been directed to practical considerations and limitations of several major aspects of proteomic analysis of human CSF. [ABSTRACT FROM AUTHOR]

Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17. [ABSTRACT FROM AUTHOR]

Biomarkers to assist in the diagnosis and medical management of Alzheimer disease (AD) are a pressing need. We have employed a proteomic approach, microcapillary liquid chromatography mass spectrometry of proteins labeled with isotope-coded affinity tags (ICAT), to quantify relative changes in the proteome of human cerebrospinal fluid (CSF) obtained from the lumbar cistern. Using CSF from well-characterized AD patients and age-matched controls at 2 different institutions, we quantified protein concentration ratios of 42% of the 390 CSF proteins that we have identified and found differences ≥ 20% in over half of them. We confirmed our findings by western blot and validated this approach by quantifying relative levels of amyloid precursor protein and cathepsin B in 17 AD patients and 16 control individuals. Quantitative proteomics of CSF from AD patients compared to age-matched controls, as well as from other neurodegenerative diseases, will allow us to generate a roster of proteins that may serve as specific biomarker panels for AD and other geriatric dementias. [ABSTRACT FROM AUTHOR]

Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-β (Aβ)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of Aβ/CTF expression and not altered by α-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of Aβ/CTFs and suppressed by α-tocopherol. α-tocopherol cytoprotection was accompanied by decreased Aβ/CTF aggregation. G also promoted β/CTF aggregation but by mechanisms unaffected byα-tocopherol treatment. Our findings showed that Aβ/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by α-tocopherol. Moreover, our results suggest that while intracellular aggregation of Aβ/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated Aβ/CTFs does not invariably lead to cytotoxicity. [ABSTRACT FROM AUTHOR]

Presents a foreword to the "Journal of Alzheimer's Disease."

Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-beta (A beta)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of A beta/CTF expression and not altered by alpha-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of A beta/CTFs and suppressed by alpha-tocopherol. alpha-tocopherol cytoprotection was accompanied by decreased A beta/CTF aggregation. G also promoted beta/CTF aggregation but by mechanisms unaffected by alpha-tocopherol treatment. Our findings showed that A beta/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by alpha-tocopherol. Moreover, our results suggest that while intracellular aggregation of A beta/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated A beta/CTFs does not invariably lead to cytotoxicity.