Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight

Nature reviews. Neuroscience, Год журнала: 2023, Номер 24(10), С. 620 - 639

Опубликована: Авг. 24, 2023

Язык: Английский

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Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation

Neuron, Год журнала: 2023, Номер 112(4), С. 676 - 686.e4

Опубликована: Дек. 13, 2023

In early Alzheimer's disease (AD) β-amyloid (Aβ) deposits throughout association cortex and tau appears in the entorhinal (EC). Why these initially appear disparate locations is not understood. Using task-based fMRI multimodal PET imaging, we assess impact of local AD pathology on network-to-network interactions. We show that pathologies flip interactions between default mode network (DMN) medial temporal lobe (MTL) from inhibitory to excitatory. The DMN hyperexcited with increasing levels Aβ, which drives hyperexcitability within MTL this directed hyperexcitation by predicts rate accumulation EC. Our results support a model whereby Aβ induces disruptions excitatory-inhibitory balance DMN, driving MTL, leading accumulation. propose Aβ-induced candidate causal route remote EC-tau

Язык: Английский

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A synergetic turn in cognitive neuroscience of brain diseases

Trends in Cognitive Sciences, Год журнала: 2024, Номер 28(4), С. 319 - 338

Опубликована: Янв. 21, 2024

Язык: Английский

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Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Сен. 18, 2024

Язык: Английский

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Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

eLife, Год журнала: 2023, Номер 12

Опубликована: Янв. 6, 2023

Background: Estimates of ‘brain-predicted age’ quantify apparent brain age compared to normative trajectories neuroimaging features. The gap (BAG) between predicted and chronological is elevated in symptomatic Alzheimer disease (AD) but has not been well explored presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, more recently other modalities, including functional connectivity (FC) multimodal explored. Methods: We trained three models predict from FC, (S), or MRI (S+FC) 390 amyloid-negative cognitively normal (CN/A−) participants (18–89 years old). In independent samples 144 CN/A−, 154 CN/A+, impaired (CI; CDR > 0) participants, we tested relationships AD biomarkers amyloid tau, as a global cognitive composite. Results: All the control training set, model outperforming unimodal models. estimates were significantly CI controls. FC-BAG was reduced CN/A+ CN/A−. only, S-BAG S+FC associated advanced pathology lower performance. Conclusions: Both are participants. However, FC also capture complementary signals. Specifically, may unique biphasic response pathology, while pathological progression decline stage. A age-prediction improves sensitivity healthy differences. Funding: This work supported by National Institutes Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, U19-AG032438), BrightFocus Foundation (A2022014F), Alzheimer’s Association (SG-20-690363-DIAN).

Язык: Английский

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Resting-state oscillations reveal disturbed excitation–inhibition ratio in Alzheimer’s disease patients

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Май 7, 2023

An early disruption of neuronal excitation-inhibition (E-I) balance in preclinical animal models Alzheimer's disease (AD) has been frequently reported, but is difficult to measure directly and non-invasively humans. Here, we examined known novel neurophysiological measures sensitive E-I patients across the AD continuum. Resting-state magnetoencephalography (MEG) data 86 amyloid-biomarker-confirmed subjects continuum (17 diagnosed with subjective cognitive decline, 18 mild impairment (MCI) 51 dementia due probable (AD dementia)), 46 healthy elderly 20 young control were reconstructed source-space. was investigated by detrended fluctuation analysis (DFA), a functional E/I (fE/I) algorithm, aperiodic exponent power spectrum. We found disrupted ratio specifically, lower DFA, shift towards higher excitation, fE/I exponent. Healthy showed ratios (< 1.0) than reported previous literature, not explained age or choice an arbitrary threshold parameter, which warrants caution interpretation results. Correlation analyses that DFA (E-I imbalance) (more excitation) associated worse score patients. In contrast, hippocampi MCI score. This MEG-study imbalance, likely increased dementia, stage To accurately determine direction balance, validations currently used markers additional vivo are required.

Язык: Английский

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Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review

Neuropsychology Review, Год журнала: 2023, Номер 34(1), С. 338 - 361

Опубликована: Март 6, 2023

Abstract Despite the numerous pharmacological interventions targeting dementia, no disease-modifying therapy is available, and prognosis remains unfavorable. A promising perspective involves tackling high-frequency gamma-band (> 30 Hz) oscillations involved in hippocampal-mediated memory processes, which are impaired from early stages of typical Alzheimer’s Disease (AD). Particularly, positive effects entrainment on mouse models AD have prompted researchers to translate such findings into humans using transcranial alternating current stimulation (tACS), a methodology that allows endogenous cortical frequency-specific manner. This systematic review examines state-of-the-art use gamma-tACS Mild Cognitive Impairment (MCI) dementia patients shed light its feasibility, therapeutic impact, clinical effectiveness. search two databases yielded 499 records resulting 10 included studies total 273 patients. The results were arranged single-session multi-session protocols. Most demonstrated cognitive improvement following gamma-tACS, some showed neuropathological markers, suggesting feasibility these anyhow far strong evidence available for models. Nonetheless, small number their wide variability terms aims, parameters, measures, make it difficult draw firm conclusions. We discuss methodological limitations studies, proposing possible solutions future avenues improve research dementia.

Язык: Английский

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Combining aperiodic 1/f slopes and brain simulation: An EEG/MEG proxy marker of excitation/inhibition imbalance in Alzheimer's disease

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Год журнала: 2023, Номер 15(3)

Опубликована: Июль 1, 2023

Accumulation and interaction of amyloid-beta (Aβ) tau proteins during progression Alzheimer's disease (AD) are shown to tilt neuronal circuits away from balanced excitation/inhibition (E/I). Current available techniques for noninvasive interrogation E/I in the intact human brain, example, magnetic resonance spectroscopy (MRS), highly restrictive (i.e., limited spatial extent), have low temporal resolution suffer ability distinguish accurately between different neurotransmitters complicating its interpretation. As such, these methods alone offer an incomplete explanation E/I. Recently, aperiodic component neural power spectrum, often referred literature as '1/f slope', has been described a promising scalable biomarker that can track disruptions potentially underlying spectrum clinical conditions, such autism, schizophrenia, or epilepsy, well developmental changes seen aging.

Язык: Английский

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Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Journal of Cellular and Molecular Medicine, Год журнала: 2023, Номер 28(2)

Опубликована: Окт. 17, 2023

Alzheimer's disease (AD) is a heterogeneous neurodegenerative with multifaceted neuropathological disorders. AD characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned the degradation clearance Aβ. Indeed, defective neuronal pathway due to dysfunction enzymes might be possible mechanism for Aβ subsequent progression neuropathology. NEP one most imperative metalloproteinase involved in This review aimed highlight role inhibitors AD. The combination sacubitril valsartan which called angiotensin receptor blocker inhibitor (ARNI) may produce beneficial deleterious effects on increase risk inhibition clearance, brain bradykinin (BK) natriuretic peptides (NPs), augment pathogenesis These verdicts come from animal model studies, though they not applied humans. However, clinical studies revealed promising safety findings regarding use ARNI. Moreover, increases various neuroprotective inflammation, glucose homeostasis nerve conduction. Also, inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin glucagon-like peptide 1 (GLP-1) levels. proposed that have protective effect against development increasing GLP-1, neuropeptide Y (NPY) substance P, BK. Preclinical recommended this regard.

Язык: Английский

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In vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(23)

Опубликована: Май 30, 2024

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I remains unknown. Here, we noninvasively estimate a putative marker whole-cortex by fitting large-scale biophysically plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our generates realistic dynamics in the Human Connectome Project. Next, show estimated sensitive gamma-aminobutyric acid (GABA) agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced changes are spatially consistent with positron emission tomography measurement receptor density. then investigate relationship between and neurodevelopment. find declines heterogeneously across cerebral cortex youth, greatest reduction occurring sensorimotor systems relative association systems. Importantly, among children same chronological age, lower (especially cortex) linked better cognitive performance. This result replicated North American (8.2 23.0 y old) Asian (7.2 7.9 cohorts, suggesting more mature indexes improved cognition normative development. Overall, findings open door studying how disrupted trajectories may lead dysfunction psychopathology emerges youth.

Язык: Английский

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