Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Brain, Journal Year: 2019, Volume and Issue: 142(9), P. 2558 - 2571

Published: June 11, 2019

Abstract Pathological alterations to the locus coeruleus, major source of noradrenaline in brain, are histologically evident early stages neurodegenerative diseases. Novel MRI approaches now provide an opportunity quantify structural features coeruleus vivo during disease progression. In combination with neuropathological biomarkers, imaging could help understand contribution neurodegeneration clinical and pathological manifestations Alzheimer’s disease, atypical dementias Parkinson’s disease. Moreover, as functional sensitivity noradrenergic system is likely change progression, measures integrity new pathophysiological insights into cognitive behavioural symptoms. Locus also holds promise stratify patients trials according dysfunction. this article, we present a consensus on how non-invasive assessment can be used for research We outline next steps vivo, post-mortem studies that lay groundwork evaluate potential biomarker

Language: Английский

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The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline

Brain, Journal Year: 2017, Volume and Issue: 141(1), P. 37 - 47

Published: July 11, 2017

The cerebellum has long been regarded as essential only for the coordination of voluntary motor activity and learning. Anatomical, clinical neuroimaging studies have led to a paradigm shift in understanding cerebellar role nervous system function, demonstrating that appears integral also modulation cognition emotion. search understand contribution cognitive processing increased interest exploring neurodegenerative neuropsychiatric disorders. Principal among these is Alzheimer's disease. Here we review an already sizeable existing literature on neuropathological, structural functional We consider observations light deficits characterize disease so doing introduce new perspective its pathophysiology manifestations. propose integrative hypothesis there draw dysmetria thought theory suggest this component manifests neurobehavioural deficits. provide suggestions future investigate and, ultimately, establish comprehensive, causal clinicopathological model.

Language: Английский

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Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease

Trends in Neurosciences, Journal Year: 2018, Volume and Issue: 41(4), P. 211 - 223

Published: Feb. 20, 2018

Language: Английский

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Neuropathology of Alzheimer's Disease

Neurotherapeutics, Journal Year: 2021, Volume and Issue: 19(1), P. 173 - 185

Published: Nov. 2, 2021

Language: Английский

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Rostral locus coeruleus integrity is associated with better memory performance in older adults

Nature Human Behaviour, Journal Year: 2019, Volume and Issue: 3(11), P. 1203 - 1214

Published: Sept. 9, 2019

Language: Английский

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Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease

Brain, Journal Year: 2017, Volume and Issue: 140(11), P. 3023 - 3038

Published: Aug. 22, 2017

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus noradrenergic dysfunction may be critical early step Alzheimer's disease progression. Yet, an accurate preclinical model of these phenotypes includes pretangle accrual coeruleus, loss innervation deficits coeruleus/norepinephrine modulated behaviours, does not exist, hampering identification underlying mechanisms development coeruleus-based therapies. Here, transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) presenilin-1 (PS1ΔE9) was characterized histological behavioural signs reminiscent mild cognitive impairment/early disease. In TgF344-AD rats, hyperphosphorylated detected prior to medial entorhinal cortex or hippocampus, pathology negatively correlated with cortex. Likewise, rats displayed progressive hippocampal norepinephrine levels fibres dentate gyrus, no frank cell body loss. Cultured mouse neurons hyperphosphorylation-prone human had shorter neurites than control neurons, but similar viability, suggesting causal link between altered fibre morphology. impaired reversal learning Morris water maze compared their wild-type littermates, which rescued by chemogenetic activation via designer receptors exclusively activated drugs (DREADDs). Our results indicate uniquely meet several key criteria suitable progression, suggest substantial window opportunity coeruleus/ norepinephrine-based therapeutics exists.

Language: Английский

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Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2018, Volume and Issue: 66(1), P. 115 - 126

Published: Sept. 7, 2018

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer’s disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate odds of developing across increasing burdens neurofibrillary tangle amyloid-β pathology. Participants who passed away 2004 2014 underwent comprehensive neuropathologic evaluation at Biobank Aging Studies from Faculty Medicine University São Paulo. Postmortem interviews with reliable informants were used to collect information regarding cognitive status. Of 1,092 cases collected, those any non-Alzheimer excluded, bringing cohort 455 cases. Braak staging was evaluate burden, CERAD neuropathology score burden. The 12-item inventory CDR-SOB dementia In I/II, significantly increased detected agitation, anxiety, appetite changes, depression, sleep disturbances, compared controls. Increased agitation continue into III/IV. V/VI is associated higher delusions. No found correlate are early pathology, suggesting that subcortical accumulation minimal cortical sufficient impact quality life a manifestation AD biological processes.

Language: Английский

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In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(612)

Published: Sept. 22, 2021

In vivo and autopsy evidence supports locus coeruleus MRI measures as proxy of initial TAU deposition amyloid-related memory decline.

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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Cerebral Iron Deposition in Neurodegeneration

Biomolecules, Journal Year: 2022, Volume and Issue: 12(5), P. 714 - 714

Published: May 17, 2022

Disruption of cerebral iron regulation appears to have a role in aging and the pathogenesis various neurodegenerative disorders. Possible unfavorable impacts accumulation include reactive oxygen species generation, induction ferroptosis, acceleration inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow examination macroscopic patterns brain deposits vivo, while modern analytical methods ex vivo enable determination metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes whole brain, cellular, subcellular diseases genetic sporadic origin. We provide an update on mechanisms, biomarkers, effects these disorders, focusing recent publications. In Parkinson’s disease, Friedreich’s several disorders neurodegeneration with group, there is focal siderosis, typically regions most pronounced neuropathological second group including multiple sclerosis, Alzheimer’s amyotrophic lateral sclerosis shows globus pallidus, caudate, putamen, cortical regions. Yet, other such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest diffuse deep gray matter pattern comparable even more extensive than that observed during normal aging. On microscopic level, are mostly dystrophic microglia variably accompanied by iron-laden macrophages astrocytes, implicating changes blood–brain barrier disturbance accumulation. Options potential benefits reducing strategies discussed. Future research investigating whether predispositions play Fe necessary. If confirmed, prevention further uptake individuals at risk may be key for preventing

Language: Английский

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