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Paul S Aisen

Publications and source records attributed to Paul S Aisen.

At least 19 recordsLinked to original sources
PubMed2026

Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment.

IMPORTANCE: Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed. OBJECTIVE: To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025. EXPOSURE: Baseline plasma p-tau217. MAIN OUTCOMES AND MEASURES: The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores ≥0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance). RESULTS: Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including β-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group. CONCLUSIONS AND RELEVANCE: In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.

Aged↗
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2006

BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice.

Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abeta-lowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible.

Amyloid Precursor Protein Secretases↗
PubMed2005

Oral administration of pyridostigmine bromide and huperzine A protects human whole blood cholinesterases from ex vivo exposure to soman.

Cholinesterases (ChEs) are classified as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) according to their substrate specificity and sensitivity to selected inhibitors. The activities of AChE in red blood cells (RBC-AChE) and BChE in serum can be used as potential biomarkers of suppressed and/or heightened activity in the central and peripheral nervous systems. Exposure to organophosphate (OP) chemical warfare agents (CWAs), pesticides, anesthetics, and a variety of drugs such as cocaine, as well as some neurodegenerative and liver disease states, selectively reduces AChE or BChE activity. In humans, the toxicity of pesticides is well documented. Therefore, blood cholinesterase activity can be exploited as a tool for confirming exposure to these agents and possible treatments. Current assays for measurement of RBC-AChE and serum BChE require several labor-intensive processing steps, suffer from wide statistical variation, and there is no inter-laboratory conversion between methods. These methods, which determine only the serum BChE or RBC-AChE but not both, include the Ellman, radiometric, and deltapH (modified Michel) methods. In contrast, the Walter Reed Army Institute of Research Whole Blood (WRAIR WB, US Patent #6,746,850) cholinesterase assay rapidly determines the activity of both AChE and BChE in unprocessed (uncentrifuged) whole blood, uses a minimally invasive blood sampling technique (e.g., blood from a finger prick), and is semi-automated for high-throughput using the Biomek 2000 robotic system. To date, the WRAIR whole blood assay was used to measure AChE and BChE activities in human blood from volunteers in FDA clinical trials. In the first FDA study, 24 human subjects were given either 30 mg PB orally (n = 19) or placebo (n = 5). Blood samples were obtained pre-dosing and 2.5, 5, 8, and 24 h post-dosing. The samples were analyzed for AChE and BChE activity using the WRAIR WB robotic system, and for PB concentration by HPLC. We found that maximal inhibition of AChE (26.2%) and concentration of PB (17.1 ng/mL) occurred at 2.5 h post-PB dosing. AChE activity returned to almost 100% of pre-dose values by 6 h. A dose-dependent linear correlation was found between the amount of PB measured in the blood and the inhibition of AChE. Following soman (GD) exposure, recovered AChE activity was similar to levels that were reversibly protected by the PB administration. Therefore, the WRAIR ChE WB data clearly supports the conclusion that PB is an effective pre-treatment drug for nerve agent exposure (GD). In the second FDA human study for the treatment of Alzheimer's disease, the WRAIR ChE WB assay was used to determine the RBC-AChE and serum BChE profile of healthy elderly volunteers receiving Huperzine A. Huperzine A is a plant-derived reversible and selective AChE inhibitor compared to BChE, and is a more potent inhibitor of AChE than PB. Huperzine A is available as a nutraceutical, a natural supplement reported to improve memory, and has a variety of neuroprotective effects. Individuals received an increasing dose regimen of huperzine A (final dose 200 microg after 4 weeks), which produced more than 50% inhibition of RBC-AChE. Huperzine A was well tolerated by these patients at doses that sequestered more RBC-AChE than PB, and thus warrants further study as a prophylaxis for OP poisoning in addition to Alzheimer's therapy. Due to the documented use of OPs by terrorists and in warfare around the globe, Federal, State, and local authorities need a reliable, fast, inexpensive, and standard method for confirming such an assault in order to initiate appropriate containment, decontamination, and treatment measures. This assay is ideal for prescreening military personnel for atypical ChE activities that would preclude their deployment to areas of potential CWA exposure. The WRAIR WB ChE assay will fulfill the requirement for rapid and reliable monitoring of such exposure in military and civilian populations.

Administration, Oral↗
PubMed2005

NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP).

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

The development of anti-amyloid therapy for Alzheimer's disease : from secretase modulators to polymerisation inhibitors.

The leading hypothesis of the pathophysiology of Alzheimer's disease holds that the pivotal event is cleavage of the amyloid precursor protein to release intact the 42-amino-acid amyloid-beta peptide (Abeta); this hypothesis best explains the known genetic causes of Alzheimer's disease. If this theory is correct, optimal strategies for altering the disease process should be directed toward modifying the generation, clearance and/or toxicity of Abeta. Abeta is highly aggregable, spontaneously assuming a beta-sheet conformation and polymerising into oligomers, protofibrils, fibrils and plaques. The relative contribution of the various forms of Abeta to neuronal dysfunction in Alzheimer's disease remains uncertain; however, recent evidence implicates diffusible oligomeric species. This article reviews the range of strategies that have been investigated to target Abeta to slow the progression of Alzheimer's disease, from secretase modulators to anti-polymerisation agents. One amyloid-binding drug, tramiprosate (3-amino-1-propanesulfonic acid; Alzhemed), which is effective in reducing polymerisation in vitro and plaque deposition in animals, has now reached phase III clinical trials. Thus, it is plausible that an effective anti-amyloid strategy will become available for the treatment of Alzheimer's disease within the next few years.

Alzheimer Disease↗
PubMed2005

Pharmacologic treatment options in Alzheimer's disease: optimizing disease management.

Cholinesterase inhibitors and memantine have been shown to improve symptoms associated with AD. Mechanisms of action and the pathophysiologic targets are distinct for the 2 classes, but clinical outcomes demonstrate both medications improve patient symptomatology. In addition, memantine and a ChEI appear to produce an additive effect resulting in a well-tolerated, effective treatment strategy.

Acetylcholine↗
PubMed2004

Benchmarking a test of temporal orientation with data from american and taiwanese persons with Alzheimer's disease and american normal elderly.

Orientation questions are readily incorporated into longitudinal population surveys, but their value as a screening tool for cognitive impairment is uncertain. We evaluated the screening value of four orientation-to-time items (TTO) from the Mini-Mental State Examination (MMSE) by determining their association with full-scale MMSE scores. Data collected under protocols with strict eligibility criteria in the US (64 normal elderly, 242 persons with probable Alzheimer's disease) and Taiwan (241 persons with probable Alzheimer's disease) were analyzed. The TTO and full-scale MMSE scores were significantly correlated (p < 0.05) in persons with a Clinical Dementia Rating (CDR) score of 0 or 1; this was not significant in persons with a CDR of >1 (p > 0.05). Both TTO and MMSE were significantly associated with education in persons with 0-7 years of education; some MMSE items, but none of the TTO items, were associated with education in persons with more than 7 years of education. TTO may be a useful component of cognitive screening efforts.

Aged↗
PubMed2004

Development of Abeta terminal end-specific antibodies and sensitive ELISA for Abeta variant.

Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Senile plaques are a pathological hallmark of AD, and amyloid beta (Abeta) peptides are a major component of these plaques. Abeta peptides are derived from proteolytic cleavage of the Abeta protein precursor (APP) by beta- and gamma-secretases to generate two principal species, Abeta1-40 and Abeta1-42. We have developed antibodies against the N- and C-termini of these peptides, and an ELISA for accurate and sensitive quantitative assessment. Sandwich ELISA composed of N-terminus (Abeta1) end-specific antibody, clone 82E1, and C-termini end-specific antibodies, and clones 1A10 and 1C3 for Abeta40 and Abeta42, respectively, detects full-length Abeta1-40 and 1-42 with a sensitivity in the sub single digit fmol/ml (equivalent to single digit pg/ml) range with no cross-reactivity to APP. A combination of C-termini antibodies and an antibody against the middle region of Abeta detects mouse Abeta in non-transgenic mouse brains.

Aged↗
PubMed2004

Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Aged↗
PubMed2004

Inflammatory processes and Alzheimer's disease.

The inflammatory hypothesis of Alzheimer's disease, which states that anti-inflammatory drugs could have beneficial effects on the pathophysiology of Alzheimer's disease, has been extensively investigated in clinical, epidemiological and basic research studies over the last 20 years. However, despite much hope, the hypothesis remains unproven. Although the results from the first small clinical trial with an anti-inflammatory agent in Alzheimer's disease appeared promising, subsequent trials with a variety of anti-inflammatory agents have failed to show beneficial effects. There are many potential reasons for this including drug selection, drug dose, timing and duration of treatment. This article reviews evidence in support of the inflammatory hypothesis in Alzheimer's disease, as well as the progress of clinical trials using specific anti-inflammatory treatment regimens. It is concluded that such treatments should not be recommended, although additional investigation is warranted.

Alzheimer Disease↗
PubMed2003

Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.

CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Activities of Daily Living↗
PubMed2002

Anti-inflammatory agents in Alzheimer's disease.

Epidemiologic studies have raised expectations that existing anti-inflammatory drugs may be useful in slowing the progression of Alzheimer's disease (AD). However, the first large-scale studies of anti-inflammatory drug treatment regimens have been negative. These disappointing results, along with new evidence from cell culture and animal model systems, suggest that the inflammatory hypothesis must be refined. Generalizations about inflammation and anti-inflammatory drugs have not been useful in developing treatment strategies for AD. But new studies suggest that specific anti-inflammatory drugs may have beneficial effects mediated by unexpected mechanisms. Continued exploration of the neuroprotective potential of specific antirheumatic therapies, as well as consideration of treatment duration and subject selection, will improve the outlook for successful development of one or more of these drugs in the prevention or treatment of AD.

Alzheimer Disease↗
PubMed2002

Evaluation of selective COX-2 inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a worldwide problem that affects 5 million people in the United States alone. Until the approval of tacrine in the mid-1990s, there was no effective therapy for the cognitive symptoms of AD. Although cholinergic therapy provides modest but significant symptomatic relief, the development of effective disease-modifying therapy is essential. It has been demonstrated that a number of inflammatory processes are active in the brain of patients with AD, and therefore it is believed that an anti-inflammatory regimen may offer some degree of neuroprotection. Several studies have indicated that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with delayed onset and/or slowed cognitive decline in AD. Although not currently approved for this condition, recent findings have demonstrated that cyclooxygenase (COX)-2 is of primary importance in the inflammatory response and may have a role in neurodegeneration. Therefore, selective COX-2 inhibitors (coxibs) may have an advantage over traditional NSAIDs as potential therapeutic agents in AD. The Alzheimer's Disease Cooperative Study (ADCS) is conducting an ongoing multicenter, double-blind, placebo-controlled trial to determine whether rofecoxib, a coxib, or naproxen, a nonselective NSAID, will slow the rate of cognitive and clinical decline in AD. This study, along with other clinical studies currently under way, will determine the utility of selective and nonselective COX inhibitors for the prevention and treatment of AD.

Aged↗
PubMed2002

The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease.

Genetic evidence suggests that generation of amyloid beta peptide is the pivotal step in the pathophysiology of Alzheimer's disease (AD). The mechanism by which this peptide induces neurodegeneration may involve inflammatory processes. Pharmacological suppression of inflammation may therefore ameliorate the neuropathology. Basic research studies provide substantial evidence that inflammatory processes present in the brains of patients with AD are destructive, and that anti-inflammatory drugs can provide protection. Furthermore, epidemiological studies suggest that anti-inflammatory drugs reduce the risk of AD. However, there is not yet any strong evidence from completed randomised controlled trials that anti-inflammatory treatment is beneficial. Large trials of glucocorticoid therapy, hydroxychloroquine, and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AD have so far been disappointing. Several studies, including a large primary prevention trial with NSAIDs, are still in progress. Major issues of selection of patients, drug regimen, and duration of treatment remain unresolved.

Alzheimer Disease↗