A clinicopathological approach to the diagnosis of dementia

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 13(8), P. 457 - 476

Published: July 14, 2017

Language: Английский

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Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2017, Volume and Issue: 3(3), P. 440 - 449

Published: Aug. 5, 2017

Abstract Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, contributing to early institutionalization. They among the earliest signs neurocognitive disorders incipient cognitive decline, yet under‐recognized often challenging treat. With this in mind, Association convened a Research Roundtable May 2016, bringing together experts from academia, industry, regulatory agencies discuss latest understanding NPSs review development therapeutics biomarkers AD. This will explore neurobiology AD specific common such as psychosis, agitation, apathy, depression, sleep disturbances. In addition, clinical trial designs considerations be discussed.

Language: Английский

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Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

Biomedical Journal, Journal Year: 2018, Volume and Issue: 41(1), P. 21 - 33

Published: Feb. 1, 2018

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60–80% cases). In 2016, nearly 44 million people were affected by AD or related dementia. characterized progressive neuronal damages leading to subtle latter obvious decline in cognitive functions including symptoms such as memory loss confusion, which ultimately require full-time medical care. Its neuropathology defined extracellular accumulation amyloid-β (Aβ) peptide into amyloid plaques, intraneuronal neurofibrillary tangles (NFT) consisting aggregated hyper- abnormal phosphorylation tau protein. The latter, identified also Tau pathology, observed broad spectrum neurological diseases commonly referred "Tauopathies". Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- astro-glial activation, contribute disease progression. Recent findings from genome wide association studies further support an instrumental role neuroinflammation. While interconnections existing between this innate immune response pathogenesis are widely described complex, elaborated evolving, only few focused on pathology. An adaptive takes place conjointly during course, indicated presence vascular parenchymal T-cell patients' brain. underlying mechanisms infiltration its consequences with regards pathology remain understudied so far. present review, we highlight interplays innate/adaptive responses.

Language: Английский

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Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

Acta Neuropathologica Communications, Journal Year: 2017, Volume and Issue: 5(1)

Published: Jan. 21, 2017

A major feature of Alzheimer's disease (AD) is the loss noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, extent to which LC system degenerates during initial stages AD still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry unbiased stereology in tissue harvested postmortem from subjects who died with a clinical diagnosis no cognitive impairment (NCI), amnestic mild (aMCI, putative prodromal stage), or mild/moderate AD. Stereologic estimates total neuron number revealed 30% transition NCI aMCI, an additional 25% Decreases were significantly associated worsening antemortem global function as well poorer performance on neuropsychological tests episodic semantic working perceptual speed, visuospatial ability. Reduced numbers also increased neuropathology. examine cellular molecular pathogenic processes underlying neurodegeneration single population microarray analysis. These studies significant reductions select functional classes mRNAs regulating mitochondrial respiration, redox homeostasis, neuritic structural plasticity accessed both aMCI compared NCI. Specific gene expression levels within these deterioration neuropathological burden. Taken together, observations suggest pathology prominent contributes dysfunction. Moreover, they lend support rational basis for targeting neuroprotection modifying strategy.

Language: Английский

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Depression in neurodegenerative diseases: Common mechanisms and current treatment options

Neuroscience & Biobehavioral Reviews, Journal Year: 2019, Volume and Issue: 102, P. 56 - 84

Published: April 15, 2019

Language: Английский

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Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

Molecules, Journal Year: 2017, Volume and Issue: 22(7), P. 1192 - 1192

Published: July 15, 2017

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors monoamine oxidases (MAO) and cholinsterases (ChE) that have been used for several pharmacological purposes. review describes key principles approaches reliable determination activities inhibition as well some methods are in current use such studies with these two enzymes. Their applicability potential pitfalls arising from their inappropriate discussed. Since inhibitor potency frequently assessed terms quantity necessary to give 50% (the IC50 value), relationships between this mode also considered, misleading information it may provide. Incorporation more than one functionality into same molecule a multi-target-directed ligands (MTDLs) requires careful assessment ensure specific target effects not significantly altered kinetic behavior remains favourable MTDL does individual components. Such factors will be considered recently developed MTDLs combine MAO ChE inhibitory functions.

Language: Английский

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Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases

Progress in Neurobiology, Journal Year: 2017, Volume and Issue: 163-164, P. 118 - 143

Published: Sept. 10, 2017

Language: Английский

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Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease

Neuropathology and Applied Neurobiology, Journal Year: 2017, Volume and Issue: 43(5), P. 393 - 408

Published: Jan. 24, 2017

Aims Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht‐ NCI ) are the best protein correlate of clinical decline in Alzheimer's disease ( AD ). Qualitative evidence identifies ht‐ accumulating isodendritic core before entorhinal cortex. Here, we used unbiased stereology to quantify burden locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming characterize impact pathology these nuclei with a focus on early stages. Methods We utilized sample 48 well‐characterized subjects enriched for controls counts were estimated 60‐μm‐thick sections immunostained p‐tau throughout LC DRN . Data integrated estimates population subset cases. Results In Braak stage 0, 7.9% 2.6% neurons , respectively, harbour s. Although number + significantly increased by about 1.9× between stages 0 I P = 0.02), failed detect any significant difference II Also, remained stable all Finally, differential susceptibility among nuclear subdivisions was more notable than Conclusions exhibited during precortical The increases along progression both nuclei, but quantitative changes precede changes.

Language: Английский

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The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 631 - 650

Published: Jan. 11, 2021

Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the intracellular accumulation of hyperphosphorylated tau and extracellular deposition amyloid-β plaques, which affect certain brain regions in a progressive manner. The locus coeruleus (LC), small nucleus pons brainstem, widely recognized as one earliest sites neurofibrillary tangle formation AD. Patients with AD exhibit significant neuronal loss LC, resulting marked reduction its size function. vastly innervates several brain, primary source neurotransmitter norepinephrine (NE) central nervous system. Considering that NE major modulator behavior, contributing to neuroprotection suppression neuroinflammation, degeneration LC ultimate dysregulation LC–NE system has detrimental effects brain. In this review, we detail neuroanatomy function essential role neuroprotection, how dysregulated We discuss AD-related neuropathologic changes mechanisms neurons are selectively vulnerable insult. Further, elucidate neurotoxic de-innervation both locally at projection sites, augments pathology, progression severity. summarize preservation could be used treatment other neurodegenerative diseases affected degeneration.

Language: Английский

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The role of serotonin within the microbiota-gut-brain axis in the development of Alzheimer’s disease: A narrative review

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 75, P. 101556 - 101556

Published: Jan. 3, 2022

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for more than 50 million patients worldwide. Current evidence suggests exact mechanism behind this devastating to be multifactorial origin, which seriously complicates quest an effective disease-modifying therapy, as well impedes search strategic preventative measures. Of interest, preclinical studies point serotonergic alterations, either induced via selective serotonin reuptake inhibitors or receptor (ant)agonists, in mitigating AD brain neuropathology next its clinical symptoms, latter being supported by a handful human intervention trials. Additionally, substantial amount trials highlight potential diet, fecal microbiota transplantations, pre- and probiotics modulating brain’s neurotransmitter system, starting from gut. Whether such interventions could truly prevent, reverse slow down progression likewise, should initially tested with mouse models, including sufficient analytical measurements both gut brain. Thereafter, therapeutic effect confirmed rigorously randomized controlled humans, preferentially across continuum, but especially prodromal up mild stages, where high adherence therapies, room noticeable enhancement are feasible still. In end, might aid development comprehensive approach tackle complex disease, since derivatives microbiota-gut-brain axis serve possible biomarkers progression, forming valuable target drug development. narrative review, available concerning orchestrating role within summarized discussed, general considerations future highlighted.

Language: Английский

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