Journal of Alzheimer's Disease - Volume 3, issue 3

Authors: Small, David H.

Article Type: Research Article

DOI: 10.3233/JAD-2001-3301

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 257-259, 2001

Authors: Storey, Elsdon | Kinsella, Glynda J. | Slavin, Melissa J.

Article Type: Research Article

Abstract: Neuropsychological assessment potentially subserves several functions in subjects in whom Alzheimer's disease (AD) is suspected. Such assessment can detect the presence of brain disease once significant neuronal disruption has occurred. Analysis of the pattern and evolution of cognitive deficits allows inferences to be drawn regarding the likely underlying pathology. Neuropsychological assessment enables delineation of the particular cognitive strengths and weaknesses of individual patients, facilitating the construction of individual management programs. Lastly, cognitive testing provides a cost-effective means of monitoring disease progression and the effects of treatment. This review describes the typical pattern and evolution of cognitive deficits in AD, outlines …a number of variant presentations, discusses the differential diagnosis from other dementias, and addresses the issue of progression to clinically probable AD in the cognitively impaired, non-demented elderly. It is anticipated that biomarkers for AD will complement neuropsychological assessment by enabling disease detection before unequivocal cognitive deterioration has ensued, and by improving the accuracy of clinical diagnosis of dementia type. The development of reliable biomarkers will also enable improvements in the sensitivity and accuracy of neuropsychological assessment in AD to be made, more quickly and efficiently than is currently possible using longitudinal studies. Show more

DOI: 10.3233/JAD-2001-3302

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 261-285, 2001

Authors: Growdon, John H.

Article Type: Research Article

Abstract: Incorporating biomarkers into clinical drug trials for Alzheimer's disease (AD) could 1) increase the homogeneity of patients through improved diagnosis, 2) establish surrogate outcome measures for drug efficacy, 3) test pharmacogenetic bases of drug response, and 4) verify proposed mechanisms of drug action. Among biological correlates of AD, those with the greatest potential to improve diagnostic accuracy are genetic abnormalities that cause AD or increase the risk of AD; characteristic changes in amyloid derivatives and tau and blood in CSF; and neuroimaging detection of brain atrophy and reduction in brain metabolism and blood flow. Although there are no AD biological …markers that qualify as true surrogate endpoints in clinical drug trials, indices of brain atrophy show promise as a technique to track progression of dementia and as a measure of treatment efficacy. Anti-amyloid strategies for treatment are the leading candidates for the next generation of Alzheimer therapies. Predicted changes in amyloid derivative levels in CSF can help verify drug activity and illuminate the mechanism of action. Show more

DOI: 10.3233/JAD-2001-3303

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 287-292, 2001

Authors: Rogaeva, Ekaterina | Tandon, Anurag | St. George-Hyslop, Peter H.

Article Type: Research Article

Abstract: Abbreviations: AD, Alzheimer's disease; AβPP, amyloid β protein precursor; BACE, β-site AβPP cleaving enzyme; PS1, presenilin-1; PS2, presenilin-2; APOE, apolipoprotein E; LRP, low density lipoprotein receptor-related protein; SNPs, single-nucleotide polymorphisms; A2M, α-2-macroglobulin. Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly population. Its clinical symptoms are manifest with increasing prominence during mid- to late stages of adulthood. In the absence of precise biological indicators that precede or accompany the cognitive decline, diagnostic confirmation of AD requires postmortem detection of histopathological characteristics such as amyloid plaques, neurofibrillary tangles, and extensive cortical atrophy. While …the etiology of AD remains incompletely understood, it was recognized early on that the observed familial aggregation of AD implied the presence of one or more inherited susceptibility markers that could be useful in diagnosis and treatment. To date, genetic analyses of these pedigrees have resolved four independent genetic loci linked with inherited susceptibility to AD. Show more

DOI: 10.3233/JAD-2001-3304

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 293-304, 2001

Authors: McLean, Catriona A. | Beyreuther, Konrad | Masters, Colin L.

Article Type: Research Article

Abstract: The biogenesis and degradation/clearance of Aβ amyloid lies at the centre of the pathogenesis of Alzheimer's disease. Quantification of the various metabolic pools of Aβ in the brains and in the periphery may aid in diagnosis, prognosis and the elucidation of the natural history of this disorder. Estimation of the Aβ levels using immunoassays (ELISA and the western blots) are complementary techniques which are now being applied in humans and experimental models. The various forms of Aβ in differing cellular compartments are now being assayed, and a picture of the natural history of Alzheimer's disease is beginning to emerge.

DOI: 10.3233/JAD-2001-3305

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 305-312, 2001

Authors: Shoji, Mikio | Kanai, Mitsuyasu

Article Type: Research Article

Abstract: Amyloid β protein 40 (Aβ40) and 42 (Aβ42), major components of senile plaque amyloids, are physiological peptides present in the brain, cerebrospinal fluid (CSF) and plasma. The levels of CSF Aβ40 and β42(43) show a U-shaped natural course in normal aging. The increase of Aβ42(43) over 60 years of age is inhibited in Alzheimer's disease (AD). This specific alteration of CSF Aβ42(43) correlates with Aβ deposits in the AD brain providing a biological basis for a biomarker of AD. In the GTT2 study, assays of the CSF Aβ ratio [(Aβ40/ Aβ42(43)] showed a diagnostic sensitivity (59%) specificity (88%) The levels …of the Aβ ratio increased from early to late stages of AD. Combination assays of CSF tau and Aβ ratio provided further efficient diagnostic sensitivity (81%) reliability of the assay may prompt worldwide usage of these CSF biomarkers for Alzheimer's patients. Show more

DOI: 10.3233/JAD-2001-3306

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 313-321, 2001

Authors: Sáez-Valero, Javier | Small, David H.

Article Type: Research Article

Abstract: The identification of a biochemical marker in cerebrospinal fluid (CSF) that can discriminate between Alzheimer's disease (AD) and other dementia-causing diseases would be a major advance. Our previous studies have shown that the glycosylation of acetylcholinesterase (AChE) is altered in the post mortem brain and cerebrospinal fluid of AD patients. We have also found that the glycosylation of AChE is altered in lumbar CSF collected ante mortem. The change in glycosylation of AChE is very specific for AD and is not seen in many other neurological diseases including other dementias. The sensitivity of detection of AD using AChE glycosylation (60–80%) …satisfactory diagnostic marker. However, more recently we have found that the glycosylation of the related enzyme butyrylcholinesterase (BuChE) is also altered in AD CSF. By combining the analysis of AChE glycosylation with that of BuChE glycosylation, improved sensitivity of detection is obtained. We propose that AChE and BuChE glycosylation may be of diagnostic value, especially when used in combination with other CSF markers such as Aβ or tau. Show more

DOI: 10.3233/JAD-2001-3307

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 323-328, 2001

Authors: Gibson, Gary E. | Zhang, Hui

Article Type: Research Article

Abstract: Overwhelming evidence demonstrates that oxidative stress occurs in brains from patients with Alzheimer's Disease (AD). Whether the oxidative stress is secondary to neurodegeneration, or if it underlies the pathology is not clear. The persistence of AD-related abnormalities in oxidative processes in non-neuronal tissues, including cultured cells, infers that an imbalance in production and removal of reactive oxygen species is an inherent property of cells from AD patients. These results suggest that changes in oxidative processes in AD cells could precede and/or cause AD-related neuropathology. Abnormalities in oxidative processes may also cause changes in signal transduction systems such as calcium that …occur in cells from AD patients. The ability to manipulate oxidative processes in peripheral tissues, especially cultured cells, from AD patients should facilitate a mechanistic understanding of the changes in oxidative processes in AD brain. The use of peripheral tissues has the potential to identify both state and trait dependent diagnostic markers, which could be used as endpoints for selecting treatments or monitoring therapeutic effectiveness. Show more

DOI: 10.3233/JAD-2001-3308

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 329-338, 2001

Authors: Jefferies, Wilfred A. | Dickstein, Dara L. | Ujiie, Maki

Article Type: Research Article

Abstract: The search is ongoing for a reliable serum biomarker for AD. The level of iron is elevated in the brain of Alzheimer's disease (AD) patients. Our studies have demonstrated that the level of the iron transport protein, p97, is increased in the serum of AD patients but not in various control groups. These results have recently been confirmed by another laboratory who extended our findings by demonstrating that p97 is not elevated in other neurodegenerative diseases. This qualifies p97 as a potentially powerful biomarker for AD. Although the relationship between increased level of iron and p97 in the AD brain …is not well understood, our research supports the hypothesis that p97 over-expressed by senile plaque associated reactive microglia is exocytosed and appears in blood. The relationship between elevated levels of serum p97 and AD, together with the possible future clinical application of p97 are considered in this report. Show more

DOI: 10.3233/JAD-2001-3309

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 339-344, 2001

Authors: de la Monte, Suzanne M. | Wands, Jack R.

Article Type: Research Article

Abstract: Dementia in Alzheimer's disease (AD) is ultimately due to cell loss mediated by several mechanisms including, apoptosis, impaired mitochondrial function, and possibly necrosis. A second major neuroanatomic correlate of dementia is aberrant cortical neuritic sprouting with abundant proliferation of dystrophic neurites. Early in vivo detection of AD will require non-invasive assays of highly sensitive and relatively specific biomarkers that reflect these fundamental abnormalities in cellular function. The AD-associated neuronal thread protein (AD7c-NTP) gene encodes a ~ kD membrane-spanning phosphoprotein that causes apoptosis and neuritic sprouting in transfected neuronal cells. The AD7c-NTP gene is over-expressed in AD beginning early in the …course of disease. In the brain, increased AD7c-NTP immunoreactivity is associated with phospho-tau-immunoreactive cytoskeletal lesions, but not with amyloid-β accumulations. The levels of AD7c-NTP in postmortem brain tissue correlate with the levels measured in paired ventricular fluid samples, suggesting that the protein is secreted or released by dying cells into cerebrospinal fluid (CSF). In this regard, elevated levels of AD7c-NTP can be detected in both CSF and urine of patients with early or moderately severe AD, and the CSF and urinary levels of AD7c-NTP correlate with the severity of dementia. The newest configuration of the AD7c-NTP assay, termed ``7c Gold'', has greater than 90% aggregate results from a number of studies suggest that AD7c-NTP is an excellent biomarker that could be helpful in the routine clinical evaluation of elderly patients at risk for AD. Show more

Keywords: Neuronal thread protein-AD7c-NTP-ELISA-7C Gold

DOI: 10.3233/JAD-2001-3310

Citation: Journal of Alzheimer's Disease, vol. 3, no. 3, pp. 345-353, 2001