Therapy for Alzheimer’s disease: Missing Targets and Functional Markers?

2021 ◽  
pp. 101318
Author(s):  
Milan Stoiljkovic ◽  
Tamas L. Horvath ◽  
Mihály Hajós
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Markers

scholarly journals Synaptic Molecular and Neurophysiological Markers Are Independent Predictors of Progression in Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Una Smailovic ◽  
Ingemar Kåreholt ◽  
Thomas Koenig ◽  
Nicholas J. Ashton ◽  
Bengt Winblad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Global Field ◽  
Prognostic Indicators ◽  
Early Event ◽  
Functional Markers ◽  
Beta Band ◽  
Global Field Power ◽  
Synaptic Markers ◽  
Eeg Recordings

Background: Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer’s disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum. Objective: The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients. Methods: Patients diagnosed with MCI (n = 99) underwent CSF conventional AD biomarkers and neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n = 41) and progressive MCI (n = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands. Results: CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone. Conclusion: qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia.

scholarly journals Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9734
Author(s):  
Carmen Romero-Molina ◽  
Victoria Navarro ◽  
Sebastian Jimenez ◽  
Clara Muñoz-Castro ◽  
Maria V. Sanchez-Mico ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Density Functional ◽  
Critical Role ◽  
Brain Regions ◽  
Functional Markers ◽  
Time Varying ◽  
Promising Tool ◽  
Pathological Conditions ◽  
Chronic Model

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

scholarly journals Alzheimer’s Disease and Artificial Intelligence: Long-term Personalized Rehabilitation and Medical and Social Support

2019 ◽  
Vol 5 (11) ◽  
pp. 136-175 ◽  
Author(s):  
S. Bulgakova ◽  
P. Romanchuk ◽  
N. Romanchuk ◽  
V. Pyatin ◽  
D. Romanov ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Homo Sapiens ◽  
Phenotypic Variability ◽  
Functional Markers ◽  
Pathological Aging ◽  
Clinical Biomarkers ◽  
Combining Data ◽  
The Brain

Modern technologies and tools for the rehabilitation of patients with Alzheimer’s disease have many potential applications for the treatment of dementia from diagnosis and evaluation to medical care, medical, social and economic support: from healthy aging, to accelerated and pathological aging of Homo sapiens. Doctor and neuroscientist: a modern solution to problems of rehabilitation ‘cognitive brain’ of Homo sapiens using on the one hand, tools and technologies of artificial intelligence, and with another — a multidisciplinary collaboration with clinical neurophysiologist ‘universal’ specialist in the field of neurology, psychiatry, psychotherapy, psychoanalysis and geriatrics. Systems biology, Biophysics, physiology, neurophysiology and highlight the multidimensional and combinatorial profiles of genetic, biological, pathophysiological and clinical biomarkers that reflects the heterogeneity of neurodegeneration, by means of modern efficient analysis tools to register and create comprehensive maps of the brain and recording of dynamic models in different systems: from molecules to neurons to brain regions. Bioinformatics, neuroimaging and neurophysiology of systems are aimed at calculating neural network models of the relationship between structure and dynamic function in brain networks. Structural and functional markers of the brain establish a link between clinical phenotypes and molecular pathophysiological mechanisms. Phenotypic variability is now considered one of the biggest problems in gerontology and geriatrics. MRI imaging to detect subtle changes in brain tissue and structure, fMRI imaging to measure changes in brain activity, and EEG to measure electrical activity have given clinicians many new insights into what happens in the brain in healthy and pathological aging. The paradigm of system neurophysiology is aimed at studying the fundamental principles of functioning of integrated neural systems through the integration and analysis of neural information recorded in a multimodal way (for example, fMRI and EEG), through computational modeling and combining data mining methods. The ultimate goal of systemic neurophysiology is to find out how signals are represented in neocortical networks and what role many different neural components play. Modern artificial intelligence technologies are capable of many things, including predicting Alzheimer's disease with the help of combined and hybrid neuroimaging, sequencing of a new generation, etc., in order to start timely and effective rehabilitation brain Homo sapiens.

P1-223: Functional Markers for Cerebral Norepinephrine Deficiency in Alzheimer’s Disease

2016 ◽  
Vol 12 ◽  
pp. P492-P493
Author(s):  
Verena Kiven ◽  
Lars Loetgering ◽  
Luca Kleineidam ◽  
Daniel Brenner ◽  
Michael Wagner ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Markers

scholarly journals Aberrant iPSC-derived human astrocytes in Alzheimer's disease

2017 ◽  
Vol 8 (3) ◽  
pp. e2696-e2696 ◽  
Author(s):  
V C Jones ◽  
R Atkinson-Dell ◽  
A Verkhratsky ◽  
L Mohamet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Excitatory Amino Acid ◽  
Late Onset ◽  
Induced Pluripotent Stem Cell ◽  
Functional Markers ◽  
Excitatory Amino Acid Transporter ◽  
Human Astrocytes

Abstract The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.

scholarly journals Intracranial stenosis in cognitive impairment and dementia

2016 ◽  
Vol 37 (6) ◽  
pp. 2262-2269 ◽  
Author(s):  
Saima Hilal ◽  
Xin Xu ◽  
M Kamran Ikram ◽  
Henri Vrooman ◽  
Narayanaswamy Venketasubramanian ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Vascular Dementia ◽  
Treatment Strategies ◽  
Vascular Cognitive Impairment ◽  
Intracranial Stenosis ◽  
Functional Markers ◽  
Pathophysiological Mechanism ◽  
Cognitive Impairment No Dementia

Intracranial stenosis is a common vascular lesion observed in Asian and other non-Caucasian stroke populations. However, its role in cognitive impairment and dementia has been under-studied. We, therefore, examined the association of intracranial stenosis with cognitive impairment, dementia and their subtypes in a memory clinic case-control study, where all subjects underwent detailed neuropsychological assessment and 3 T neuroimaging including three-dimensional time-of-flight magnetic resonance angiography. Intracranial stenosis was defined as ≥50% narrowing in any of the intracranial arteries. A total of 424 subjects were recruited of whom 97 were classified as no cognitive impairment, 107 as cognitive impairment no dementia, 70 vascular cognitive impairment no dementia, 121 Alzheimer’s Disease, and 30 vascular dementia. Intracranial stenosis was associated with dementia (age/gender/education – adjusted odds ratios (OR): 4.73, 95% confidence interval (CI): 1.93–11.60) and vascular cognitive impairment no dementia (OR: 3.98, 95% CI: 1.59–9.93). These associations were independent of cardiovascular risk factors and MRI markers. However, the association with Alzheimer’s Disease and vascular dementia became attenuated in the presence of white matter hyperintensities. Intracranial stenosis is associated with vascular cognitive impairment no dementia independent of MRI markers. In Alzheimer’s Disease and vascular dementia, this association is mediated by cerebrovascular disease. Future studies focusing on perfusion and functional markers are needed to determine the pathophysiological mechanism(s) linking intracranial stenosis and cognition so as to identify treatment strategies.

Cognitive control constrains memory attributions

2019 ◽  
Vol 42 ◽  
Author(s):  
Colleen M. Kelley ◽  
Larry L. Jacoby
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

Formation of paired helical filaments in Alzheimer's disease

1984 ◽  
Vol 42 ◽  
pp. 302-303
Author(s):  
J. Metuzals ◽  
D. F. Clapin ◽  
V. Montpetit
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Lobe ◽  
Giant Axon ◽  
Paired Helical Filaments ◽  
Normal Brain ◽  
Protein Assemblies ◽  
Electron Microscopic ◽  
Helical Symmetry ◽  
Structural Levels

Information on the conformation of paired helical filaments (PHF) and the neurofilamentous (NF) network is essential for an understanding of the mechanisms involved in the formation of the primary lesions of Alzheimer's disease (AD): tangles and plaques. The structural and chemical relationships between the NF and the PHF have to be clarified in order to discover the etiological factors of this disease. We are investigating by stereo electron microscopic and biochemical techniques frontal lobe biopsies from patients with AD and squid giant axon preparations. The helical nature of the lesion in AD is related to pathological alterations of basic properties of the nervous system due to the helical symmetry that exists at all hierarchic structural levels in the normal brain. Because of this helical symmetry of NF protein assemblies and PHF, the employment of structure reconstruction techniques to determine the conformation, particularly the handedness of these structures, is most promising. Figs. 1-3 are frontal lobe biopsies.

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