Predementia Alzheimer Research Articles

Identifying clinically relevant milestone decline in predementia Alzheimer's disease

Identifying clinically relevant milestone decline in predementia Alzheimer's disease

Distinct pattern of hypometabolism and atrophy in preclinical and predementia Alzheimer's disease

The goal of the present study was to determine the earliest patterns of hypometabolism and atrophy in the development of Alzheimer's disease (AD). Stages of AD were defined by positron emission tomography imaging evidence of cortical amyloid pathology in addition to cognitive criteria. Subjects for the study were selected from the Alzheimer's Disease Neuroimaging Initiative database and divided into 4 groups: cognitively normal (CN) amyloid negative (Aβ−) elderly subjects (n = 36), CN amyloid-positive (Aβ+) (n = 21), early mild cognitive impairment Aβ+ (n = 65), and late mild cognitive impairment Aβ+ (n = 23) subjects. Region of interest–based (primary) and voxel-based (secondary) analyses were used to assess gray matter hypometabolism, quantified by [18F]fluorodeoxyglucose-positron emission tomography, and decrease in gray matter volume and cortical thickness was measured by magnetic resonance imaging. Region of interest- and voxel-based analyses showed significant hypometabolism but not atrophy in CN Aβ+ subjects compared with CN Aβ− subjects. The results suggest that hypometabolism exceeds atrophy in preclinical AD, supporting the notion that amyloid load may affect synaptic activity, leading to synaptic loss and subsequent neuronal loss.

Safety and tolerability of avagacestat (BMS-708163) in people with predementia Alzheimer's disease: Association with nonmelanoma skin cancer

Safety and tolerability of avagacestat (BMS-708163) in people with predementia Alzheimer's disease: Association with nonmelanoma skin cancer

A phase II study of the gamma-secretase inhibitor avagacestat (BMS-708163) in predementia Alzheimer's disease

Avagacestat, an oral γ-secretase inhibitor that selectively inhibits amyloid-beta (Aβ) synthesis, was investigated in Phase 2 studies to assess safety in mild-to-moderate Alzheimer's disease (AD) and predementia AD (PDAD). We report interim data from the first prospective, multicenter, randomized, controlled trial in PDAD (CN156–018). CN156–018 assessed the safety, tolerability and biomarker effects of avagacestat in patients with PDAD. Lumbar puncture demonstrating CSF profile consistent with AD pathology was required at entry. Patients were initially randomized to receive placebo or avagacestat (originally targeting a maximum dose of 125 mg/day but amended to 50 mg/day due to intolerability) for a duration of ≥2 years. Interim data are presented herein. 263 patients were randomized, and treatment groups were well-matched on entry criteria. 173 patients were randomized prior to dose amendment. Discontinuations were more frequent with avagacestat than placebo (53% vs. 35%), but were comparable (33% vs. 32%) after dose reduction. Serious adverse events were more frequent with avagacestat than placebo (35% vs. 23%), primarily attributable to avagacestat-associated, increased rates of non-melanoma skin cancers. Treatment-emergent adverse events (TEAEs) more frequent with avagacestat than placebo included diarrhea, nausea, vomiting, rash, fatigue, decreased weight, decreased appetite, and dizziness; these TEAEs were either less frequent or less severe with avagacestat 50 mg/day. Magnetic resonance imaging (MRI) safety readings showed numerically greater rates of amyloid-related imaging abnormalities for avagacestat- versus placebo-treated groups. Laboratory findings suggested non-progressive renal tubular dysfunction of unknown clinical significance with avagacestat. No clinically meaningful differences in cognition were observed between groups. Investigator-reported progression to dementia was similar with avagacestat (24/131) and placebo (27/132) [HR=1.17, 95% CI 0.68–2.03]. Post-baseline CSF amyloid measurements suggested a 10–15% reduction in avagacestat- versus placebo-treated groups. Volumetric MRI at Week 104 showed slightly greater ventricular volume increase and whole-brain volume loss for avagacestat-treated patients, with no differences in hippocampal volume. Safety and tolerability of avagacestat in the PDAD population was similar to that observed in a previous mild-to-moderate AD study (CN156–013). In aggregate, the study was terminated early as there was insufficient target engagement or trends for favorable pharmacodynamic effects to support continued development.

Hippocampal subfield atrophy in preclinical and predementia Alzheimer's disease is different from atrophy observed in non-Alzheimer’s pathology

Hippocampal subfield atrophy in preclinical and predementia Alzheimer's disease is different from atrophy observed in non-Alzheimer’s pathology

Bone Marrow-Derived Mesenchymal Stem Cells Contribute to the Reduction of Amyloid-β Deposits and the Improvement of Synaptic Transmission in a Mouse Model of Pre-Dementia Alzheimer’s Disease

The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on β-amyloid (Aβ) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Aβ deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Aβ deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD.

Bone Marrow-Derived Mesenchymal Stem Cells Contribute to the Reduction of Amyloid-β Deposits and the Improvement of Synaptic Transmission in a Mouse Model of Pre-Dementia Alzheimer’s Disease

Bone Marrow-Derived Mesenchymal Stem Cells Contribute to the Reduction of Amyloid-β Deposits and the Improvement of Synaptic Transmission in a Mouse Model of Pre-Dementia Alzheimer’s Disease

Hope for Catching Alzheimer’s Early

Hope for Catching Alzheimer’s Early

Injury markers predict time to dementia in subjects with MCI and amyloid pathology

Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment

Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42) protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

P3‐398: Impact of access to and acceptance of diagnostic testing and outcomes in predementia Alzheimer's disease

P3‐398: Impact of access to and acceptance of diagnostic testing and outcomes in predementia Alzheimer's disease

P2‐264: Screening for predementia Alzheimer's Disease: Time‐dependent operating characteristics of episodic memory tests from a community‐based sample—Einstein Aging Study cohort

P2‐264: Screening for predementia Alzheimer's Disease: Time‐dependent operating characteristics of episodic memory tests from a community‐based sample—Einstein Aging Study cohort

P2‐422: vMRI and hippocampal volume in patients with suspected predementia Alzheimer's disease

P2‐422: vMRI and hippocampal volume in patients with suspected predementia Alzheimer's disease

Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative

This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.

Impact of early intervention and disease modification in patients with predementia Alzheimer’s disease: a Markov model simulation

Background:Early screenings involving biomarkers and use of potential disease-modifying therapies (DMTs) may have significant humanistic implications for treatment strategies in Alzheimer’s disease.Methods:Markov models simulated transitions of patient cohorts beginning in predementia, a hypothetical early stage of Alzheimer’s disease marked by objective cognitive impairment/memory complaints without functional impairment, and followed for 10 years. Hypothetical cohorts of 10,000 patients included those who were treated with standard of care (donepezil) upon reaching mild–moderate Alzheimer’s disease, a DMT in predementia, and a DMT in mild-moderate Alzheimer’s disease. Transition probabilities were based on data from the Alzheimer’s Disease Neuroimaging Initiative and published clinical data, and estimated for the hypothetical DMT. In each disease stage (predementia, mild, moderate, or severe), time was computed and costs were estimated using literature review and published data, and published data provided mortality rates. The impact of screening was evaluated using positive predictive value (patients identified as predementia truly at risk for transition to dementia).Results:Earlier treatment yielded modest gains in total life-years; however, the distribution was skewed towards milder disease. Assuming a 25% reduction in the annual risk of progression, treating predementia patients with DMT increased life-years in predementia to mild states on average from 3.2 to 4.2, while life-years spent in moderate-to-severe Alzheimer’s disease decreased from 2.6 to 2.2. Average time in the community increased from 4.4 to 5.4 years, while time in long-term care declined from 1.3 to 0.9 years. This impact grows as the advantage of the novel agent increases. Screening accuracy had significant implications for cost-effectiveness.Conclusion:If screening can accurately identify predementia patients at risk for progression, earlier treatment with DMTs has the potential benefit to patients of prolonging time in milder disease, reducing time spent with more severe disease, increasing time in the community, and reducing time in long-term care.

Correlation between baseline measures of amyloid-positron emission tomography (PET) imaging, cerebral spinal fluid (CSF) biomarkers, and clinical scales in predementia Alzheimer's disease

Correlation between baseline measures of amyloid-positron emission tomography (PET) imaging, cerebral spinal fluid (CSF) biomarkers, and clinical scales in predementia Alzheimer's disease

Pre-dementia Memory Impairment is Associated with White Matter Tract Affection

Mild cognitive impairment (MCI), especially amnestic, often represents pre-dementia Alzheimer's disease, characterized by medial temporal lobe atrophy, while white matter (WM) alterations are insufficiently described. We analyze both cortical morphometric and WM diffusivity differences in amnestic versus non-amnestic subtypes and ask if memory and WM tract affection are related independently of cortical atrophy. Forty-nine patients from a university-hospital based memory clinic with a score of 3 on the Global Deterioration Scale aged 43-77 years (45% female) were included. Two neuropsychologists have classified cases as amnestic (aMCI), non-amnestic (naMCI), or less advanced (laMCI), not satisfying criteria for aMCI/naMCI. Diffusion tensor imaging (DTI) WM tract and morphometric data of the temporal-parietal memory network were compared among patient subtypes and related to story, word list, and visual memory. WM radial and mean diffusivity (DR and MD), underlying the entorhinal cortex, were higher in aMCI compared with laMCI. WM DR and MD, underlying the entorhinal, parahippocampal, and middle temporal cortex, explained unique variance in word list and story memory, and this was not due to secondary effects of cortical thinning. DTI may thus potentially aid diagnosis in early disease stages. ).

Lack of Accuracy for the Proposed ‘Dubois Criteria’ in Alzheimer’s Disease: A Validation Study from the Swedish Brain Power Initiative

Background/Aims: Our purpose was to investigate whether the new research criteria for Alzheimer’s disease proposed in 2007 by Dubois et al. are valid in a naturalistic memory clinic sample. Method: Retrospective diagnostic analyses were carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. No patient had gone through all procedures postulated as additional features in the proposed new Dubois criteria. Material: Two independent experienced geriatricians re-examined 150 complete patients’ records. The study physicians were blinded to any of the results of the core and additional features suggested by Dubois et al. to avoid circular diagnostic bias. Results:Among our 96 patients with a clinical diagnosis of subjective cognitive impairment and/or mild cognitive impairment, 2 of the patients with subjective cognitive impairment and 5 patients with mild cognitive impairment would classify as pre-dementia Alzheimer’s disease according to the Dubois criteria. In our 23 Alzheimer patients diagnosed clinically, only 12 of the cases fulfilled the criteria for Alzheimer’s disease suggested by Dubois et al. Interpretation: The proposed new criteria for Alzheimer’s disease are valid in 55% of our patients clinically diagnosed as having full-blown Alzheimer dementia. Additionally, 7.3% ‘true’ Alzheimer cases will be identified in a group of 96 clinically non-demented patients. Our results show that there is a large heterogeneity in a clinical naturalistic sample of patients with an Alzheimer phenotype. Conclusion: There is a need to further validate the currently existing biomarkers in large unselected samples and avoid the pitfall of workup bias and circular diagnostic processes. Additionally, valid age-specific cut-off values for the diagnostic markers in question have to be defined.

Designing clinical trials for early (Pre-Dementia) Alzheimer’s disease: Determining the appropriate population for treatment

Designing clinical trials for early (Pre-Dementia) Alzheimer’s disease: Determining the appropriate population for treatment

Pre-dementia Alzheimer's trials: overview.

A series of negative clinical trials of disease-modifying agents for Alzheimer's disease has increased pessimism regarding the prospects for important therapeutic advances. But limited efficacy may be attributed in part to the advanced degree of neurodegeneration present at the onset of dementia. To optimize the likelihood of success, it is essential to develop the methodology to allow testing of disease-modifying treatments at an early stage of pathology, when modulation of pathophysiologic mechanisms may yield major clinical benefits.