scholarly journals THE ROLE OF CLINICAL TRIALS IN PRECLINICAL ALZHEIMER’S DISEASE DRUG DEVELOPMENT PROGRAMS

2020 ◽  
pp. 1-3
Author(s):  
J. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Functional Impairment ◽  
Amyloid Beta Protein ◽  
Neuropsychological Measures ◽  
Preclinical Phase ◽  
Preclinical Ad ◽  
Positron Emission

Alzheimer’s disease (AD) has a 15-20 year preclinical phase during which the individuals have normal cognition by conventional measures and have state measures of AD pathology including elevated levels of brain amyloid when assessed with positron emission tomography (PET) and abnormally decreased levels cerebrospinal fluid (CSF) amyloid beta-protein (Aß) and increased levels of total tau and hyperphosphorylated tau (p-tau) (1, 2). Recognition of this long-preclinical phase and the presence of biomarker changes affords, the opportunity to plan secondary prevention trials to prevent or delay the onset of cognitive impairment and progression to dementia. The US Food and Drug Administration (FDA) facilitated planning of clinical trials for participants in the preclinical phase of AD by defining two stages of the preclinical period: in stage 1 participants have characteristic pathophysiologic changes of AD but no evidence of clinical impact; in stage 2 participants have characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. Stage 3 participants are no longer in the preclinical phase of AD; they have mild cognitive impairment (MCI)/prodromal AD with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. Stages 4, 5, and 6 describe patients with mild, moderate and severe AD dementia. Biomarker, clinical definitions, and regulatory engagement have set the stage for planning and conduct of trials in preclinical AD.

scholarly journals Identifying Preclinical Alzheimer’s Disease Using Everyday Driving Behavior: Proof of Concept

2020 ◽  
pp. 1-6
Author(s):  
Ganesh M. Babulal ◽  
Ann Johnson ◽  
Anne M. Fagan ◽  
John C. Morris ◽  
Catherine M. Roe
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Driving Behavior ◽  
Amyloid Pet ◽  
Preclinical Alzheimer’S Disease ◽  
Neuropsychological Measures ◽  
Receiver Operating Characteristic Curves ◽  
Preclinical Ad ◽  
Positron Emission

We examined whether driving behavior can predict preclinical Alzheimer’s disease (AD). Data from 131 cognitively normal older adults with cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers were examined with naturalistic driving behavior. Receiver operating characteristic curves were used to predict the highest 10%, 25%, and 50% of values for CSF tau/Aβ42, ptau181/Aβ42, or amyloid PET. Six in vivo driving variables alone yielded area under the curves (AUC) from 0.64–0.82. Addition of age, Apolipoprotein ɛ4, and neuropsychological measures to the models improved the AUC (0.81 to 0.90). Driving can be used as novel neurobehavioral marker to identify presence of preclinical AD.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

scholarly journals Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Arturo G. Isla ◽  
Yuniesky Andrade-Talavera ◽  
Hugo Balleza-Tapia ◽  
Raúl Loera-Valencia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Gamma Rhythm ◽  
Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

scholarly journals Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and –specific lesion patterns

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yaojing Chen ◽  
Mingxi Dang ◽  
Zhanjun Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neuropsychiatric Symptoms ◽  
Onset Time ◽  
Anterior Cingulate ◽  
Neural Basis ◽  
Preclinical Ad ◽  
Disease Stages ◽  
Mild Cognitive Impairment Stage

AbstractNeuropsychiatric symptoms (NPSs) are common in patients with Alzheimer’s disease (AD) and are associated with accelerated cognitive impairment and earlier deaths. This review aims to explore the neural pathogenesis of NPSs in AD and its association with the progression of AD. We first provide a literature overview on the onset times of NPSs. Different NPSs occur in different disease stages of AD, but most symptoms appear in the preclinical AD or mild cognitive impairment stage and develop progressively. Next, we describe symptom-general and -specific patterns of brain lesions. Generally, the anterior cingulate cortex is a commonly damaged region across all symptoms, and the prefrontal cortex, especially the orbitofrontal cortex, is also a critical region associated with most NPSs. In contrast, the anterior cingulate-subcortical circuit is specifically related to apathy in AD, the frontal-limbic circuit is related to depression, and the amygdala circuit is related to anxiety. Finally, we elucidate the associations between the NPSs and AD by combining the onset time with the neural basis of NPSs.

scholarly journals Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Ayati ◽  
Guoyan Yang ◽  
Mohammad Hossein Ayati ◽  
Seyed Ahmad Emami ◽  
Dennis Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Daily Living ◽  
Randomised Clinical Trials ◽  
Disease Assessment ◽  
Significant Difference

Abstract Background Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well-known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti-dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia. Methods An electronic database search of some major English and Chinese databases was conducted until 31st May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev-Man 5.3 software was applied to perform the meta-analyses. Results A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales such as ADAS-cog and CDR-SB. Saffron improved daily living function, but the changes were not statistically significant. No serious adverse events were reported in the included studies. Conclusions Saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.

scholarly journals Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer’s Disease

2015 ◽  
Vol 47 (1) ◽  
pp. 205-214 ◽  
Author(s):  
Hong Liu-Seifert ◽  
Eric Siemers ◽  
Karen Price ◽  
Baoguang Han ◽  
Katherine J. Selzler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Functional Impairment

Non-Ceruloplasmin Copper as a Stratification Biomarker of Alzheimer’s Disease Patients: How to Measure and Use It

2021 ◽  
Vol 18 ◽  
Author(s):  
Rosanna Squitti ◽  
Mariacarla Ventriglia ◽  
Alberto Granzotto ◽  
Stefano L. Sensi ◽  
Mauro Ciro Antonio Rongioletti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Cost Effective ◽  
The Elderly ◽  
The Body ◽  
Eligibility Criterion ◽  
Growing Body ◽  
Proper Balance

: Alzheimer’s disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomark- er of Wilson's disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we pro- pose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploit- ed as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aim- ing at investigating Cu-related interventions against AD/MCI.

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