Nanobiosensors for Non-Amyloidbeta-Tau Biomarkers as Advanced Reporters of Alzheimer’s Disease

Emerging nanomaterials providing benefits in sensitivity, specificity and cost-effectiveness are being widely investigated for biosensors in the application of Alzheimer’s disease (AD) diagnosis. Core biomarkers amyloid-beta (Aβ) and Tau have been considered as key neuropathological hallmarks of AD. However, they did not sufficiently reflect clinical severity and therapeutic response, proving the difficulty of the Aβ- and Tau-targeting therapies in clinical trials. In recent years, there has still been a shortage of sensors for non-Aβ-Tau pathophysiological biomarkers that serve as advanced reporters for the early diagnosis of AD, predict AD progression, and monitor the treatment response. Nanomaterial-based sensors measuring multiple non-Aβ-Tau biomarkers could improve the capacity of AD progression characterization and supervised treatment, facilitating the comprehensive management of AD. This is the first review to principally represent current nanobiosensors for non-Aβ-Tau biomarker and that strategically deliberates future perspectives on the merit of non-Aβ-Tau biomarkers, in combination with Aβ and Tau, for the accurate diagnosis and prognosis of AD.

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Promise and Challenge: The Lens Model as a Biomarker for Early Diagnosis of Alzheimer's Disease

Disease Markers ◽

10.1155/2014/826503 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

Tian Tian ◽

Boai Zhang ◽

Yanjie Jia ◽

Zhaoming Li

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Diagnosis ◽

Accurate Diagnosis ◽

Lens Model ◽

Non Invasive ◽

Diagnosis And Prognosis ◽

Protein Deposits ◽

Age Related ◽

The Brain

Alzheimer’s disease (AD) is the most common form of dementia pathologically characterized by cerebral amyloid-beta (Aβ) deposition. Early and accurate diagnosis of the disease still remains a big challenge. There is evidence that Aβaggregation starts to occur years before symptoms arise. Noninvasive monitoring of Aβplaques is critical for both the early diagnosis and prognosis of AD. Presently, there is a major effort on looking for a reasonably priced technology capable of diagnosing AD by detecting the presence of Aβ. Studies suggest that AD is systemic rather than brain-limited focus diseases and the aggregation of the disease-causing proteins also takes place in lens except the brain. There is a possible relationship between AD and a specific subtype of age-related cataract (supranuclear cataract). If similar abnormal protein deposits are present in the lens, it would facilitate non-invasive diagnosis and monitoring of disease progression. However, there are controversies on the issues related to performance and validation of Aβdeposition in lens as biomarkers for early detection of AD. Here we review the recent findings concerning Aβdeposition in the lenses of AD patients and evaluate if the ocular lens can provide a biomarker for AD.

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Utility of Developmental Reflexes in the Differential Diagnosis and Prognosis of Incontinence in Alzheimer's Disease

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/089198879701000105 ◽

1997 ◽

Vol 10 (1) ◽

pp. 22-28 ◽

Cited By ~ 10

Author(s):

Emile H. Franssen ◽

Liduïn E.M. Souren ◽

Carol L. Torossian ◽

Barry Reisberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Functional Performance ◽

Clinical Severity ◽

Diagnosis And Prognosis ◽

Healthy Elderly ◽

Study Population ◽

Cortical Dysfunction

Four developmental reflexes, the tactile suck reflex, the palmar and plantar grasp reflexes, and the plantar extensor reflex, were examined in 784 individuals, including healthy elderly, cognitively and functionally mildly impaired individuals, and patients with Alzheimer's disease (AD) in all stages of clinical severity. The study population was classified into six categories of increasingly impaired functional performance, and prevalence of the four individual reflexes and of a summary reflex measure, consisting of a combination of these four reflexes, was determined for each category. Prevalence of all five reflex measures was more than six times higher for those categories that comprised only permanently doubly incontinent patients as compared to those categories that comprised only continent individuals ( P < .001). Frequency of developmental reflexes rose sharply with the onset of progressive incontinence. Since the return of these reflexes in AD is associated with severe cortical dysfunction, it is concluded that these developmental reflexes are useful in differentiating incontinence of cortical origin from incontinence resulting from potentially reversible causes.

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Cardiac Biomarkers in Stroke, Alzheimer’s Disease, and Other Dementia. Are They of Use? A Brief Overview of Data from Recent Investigations

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666201005171003 ◽

2020 ◽

Vol 19 ◽

Author(s):

Shahzad Khan ◽

Mohammad Amjad Kamal

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Neurological Diseases ◽

Short Review ◽

The Other ◽

Cardiac Biomarkers ◽

Cardiac Diseases ◽

Primary Condition ◽

Diagnosis And Prognosis

: Conventionally cardiac biomarkers are recognized as an essential tool to investigate the presence or progression of various cardiovascular diseases. However, in recent years data from several clinical trials have successfully sorted out the utility of cardiac biomarkers in diseases that are not primarily regarded as “cardiac diseases,” especially neurological diseases. Results of freshly published trials have endorsed the use of cardiac biomarkers in various forms of stroke and dementia, including Alzheimer’s disease. Alzheimer’s disease is also one of the other CNS conditions where measuring cardiac biomarkers have found to be useful. Cardiac biomarkers can be helpful in two ways. Firstly, to assess the secondary involvement of the heart during the progression of the primary disease. Secondly, they can be useful in the diagnosis and prognosis of the primary condition itself. In this short review, we have collected encouraging results from recent studies that show the importance of the most widely recognized cardiac biomarkers in two of the most prominent neurological diseases of the current world, i.e., stroke and dementia.

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

Current Alzheimer Research ◽

10.2174/1567205014666171106150309 ◽

2018 ◽

Vol 15 (5) ◽

pp. 429-442 ◽

Cited By ~ 3

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.

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Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Current Molecular Pharmacology ◽

10.2174/1874467213666200422090135 ◽

2020 ◽

Vol 13 (4) ◽

pp. 273-294 ◽

Cited By ~ 2

Author(s):

Elahe Zarini-Gakiye ◽

Javad Amini ◽

Nima Sanadgol ◽

Gholamhassan Vaezi ◽

Kazem Parivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Small Molecules ◽

Clinical Trial Design ◽

Treatment Approaches ◽

Drug Candidates ◽

Novel Treatments ◽

Approved Drugs ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

Clinical Trials ◽

10.1177/17407745211034497 ◽

2021 ◽

pp. 174077452110344

Author(s):

Michelle M Nuño ◽

Joshua D Grill ◽

Daniel L Gillen ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Phosphorylated Tau ◽

Inclusion Criteria ◽

Eligibility Criteria ◽

Total Tau ◽

Prodromal Alzheimer’S Disease ◽

Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

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