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1.
Adv Sci (Weinh) ; : e2309021, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38923244

ABSTRACT

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.

2.
bioRxiv ; 2024 May 31.
Article in English | MEDLINE | ID: mdl-38853978

ABSTRACT

Current therapeutic strategies for Alzheimer's disease (AD) target amyloid-beta (Aß) fibrils and high molecular weight protofibrils associated with plaques, but other bioactive species may directly contribute to neural systems failure in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in young mice expressing human Aß and Aß oligomers, we reveal marked impairments of hippocampal function long before amyloid plaques predominate. In slow wave sleep (SWS), Aß increased the proportion of hypoactive cells and reduced place-cell reactivation. During awake behavior, Aß impaired theta-gamma phase-amplitude coupling (PAC) and drove excessive synchronization of place cell calcium fluctuations with hippocampal theta. Remarkably, the on-line impairment of hippocampal theta-gamma PAC correlated with the SWS impairment of place-cell reactivation. Together, these results identify toxic effects of Aß on memory encoding and consolidation processes before robust plaque deposition and support targeting soluble Aß-related species to treat and prevent AD.

3.
Epilepsia ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38752861

ABSTRACT

OBJECTIVE: The increased amplitude of ictal activity is a common feature of epileptic seizures, but the determinants of this amplitude have not been identified. Clinically, ictal amplitudes are measured electrographically (using, e.g., electroencephalography, electrocorticography, and depth electrodes), but these methods do not enable the assessment of the activity of individual neurons. Population signal may increase from three potential sources: (1) increased synchrony (i.e., more coactive neurons); (2) altered active state, from bursts of action potentials and/or paroxysmal depolarizing shifts in membrane potential; and (3) altered subthreshold state, which includes all lower levels of activity. Here, we quantify the fraction of ictal signal from each source. METHODS: To identify the cellular determinants of the ictal signal, we measured single cell and population electrical activity and neuronal calcium levels via optical imaging of the genetically encoded calcium indicator (GECI) GCaMP. Spontaneous seizure activity was assessed with microendoscopy in an APP/PS1 mouse with focal cortical injury and via widefield imaging in the organotypic hippocampal slice cultures (OHSCs) model of posttraumatic epilepsy. Single cell calcium signals were linked to a range of electrical activities by performing simultaneous GECI-based calcium imaging and whole-cell patch-clamp recordings in spontaneously seizing OHSCs. Neuronal resolution calcium imaging of spontaneous seizures was then used to quantify the cellular contributions to population-level ictal signal. RESULTS: The seizure onset signal was primarily driven by increased subthreshold activity, consistent with either barrages of excitatory postsynaptic potentials or sustained membrane depolarization. Unsurprisingly, more neurons entered the active state as seizure activity progressed. However, the increasing fraction of active cells was primarily driven by synchronous reactivation and not from continued recruitment of new populations of neurons into the seizure. SIGNIFICANCE: This work provides a critical link between single neuron activity and population measures of seizure activity.

4.
Alzheimers Dement ; 20(6): 4234-4249, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38764252

ABSTRACT

INTRODUCTION: Sleep disturbances are common in Alzheimer's disease (AD) and may reflect pathologic changes in brain networks. To date, no studies have examined changes in sleep functional connectivity (FC) in AD or their relationship with network hyperexcitability and cognition. METHODS: We assessed electroencephalogram (EEG) sleep FC in 33 healthy controls, 36 individuals with AD without epilepsy, and 14 individuals with AD and epilepsy. RESULTS: AD participants showed increased gamma connectivity in stage 2 sleep (N2), which was associated with longitudinal cognitive decline. Network hyperexcitability in AD was associated with a distinct sleep connectivity signature, characterized by decreased N2 delta connectivity and reversal of several connectivity changes associated with AD. Machine learning algorithms using sleep connectivity features accurately distinguished diagnostic groups and identified "fast cognitive decliners" among study participants who had AD. DISCUSSION: Our findings reveal changes in sleep functional networks associated with cognitive decline in AD and may have implications for disease monitoring and therapeutic development. HIGHLIGHTS: Brain functional connectivity (FC) in Alzheimer's disease is altered during sleep. Sleep FC measures correlate with cognitive decline in AD. Network hyperexcitability in AD has a distinct sleep connectivity signature.


Subject(s)
Alzheimer Disease , Brain , Electroencephalography , Sleep , Humans , Alzheimer Disease/physiopathology , Male , Female , Aged , Sleep/physiology , Brain/physiopathology , Brain/diagnostic imaging , Cognitive Dysfunction/physiopathology , Cognition/physiology , Sleep Wake Disorders/physiopathology , Epilepsy/physiopathology , Machine Learning , Neuropsychological Tests/statistics & numerical data , Middle Aged
5.
Neurology ; 102(12): e209460, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38815233

ABSTRACT

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) copathologies of ß-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. METHODS: This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid ß-amyloid (A) and tau (T) were acquired. The association of functional cognition, ß-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. RESULTS: Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. DISCUSSION: In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aß does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.


Subject(s)
Amyloid beta-Peptides , Hippocampus , Lewy Body Disease , Positron-Emission Tomography , tau Proteins , Humans , Lewy Body Disease/metabolism , Lewy Body Disease/diagnostic imaging , Lewy Body Disease/pathology , Female , Male , Aged , tau Proteins/metabolism , Hippocampus/diagnostic imaging , Hippocampus/pathology , Hippocampus/metabolism , Cross-Sectional Studies , Amyloid beta-Peptides/metabolism , Longitudinal Studies , Magnetic Resonance Imaging , Aged, 80 and over , Neuropsychological Tests , Cohort Studies , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Middle Aged
6.
Alzheimers Dement ; 20(3): 2298-2308, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38265159

ABSTRACT

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.


Subject(s)
Lewy Body Disease , Humans , Lewy Body Disease/diagnosis , Lewy Body Disease/therapy
7.
Mov Disord ; 39(2): 267-272, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38226487

ABSTRACT

The link between smoking and a lower risk of Parkinson's disease (PD) is one of the strongest environmental or lifestyle associations in neuroepidemiology. Growing evidence supports the hypothesis that the association is based on a neuroprotective effect of smoking on PD, despite the plausible alternative that smoking serves as a marker for a proximal protective influence without itself conferring benefit. But how smoking could protect against neurodegeneration in PD is not well understood. Of several candidate molecules and mechanisms that have been nominated, nicotine has received the most attention. However, randomized controlled clinical trials of nicotine in PD have failed to demonstrate benefit on motor endpoints, including the NIC-PD study in which recently diagnosed participants were randomly assigned to placebo or nicotine treatment for 1 year. Given these results, the time is right to evaluate the neuroprotective potential of other molecules and biochemical cascades triggered by smoking. Here, we review the evidence supporting smoking's possible protective effect on PD, compounds in tobacco and smoke that might mediate such benefit, and non-causal classes of explanation, including reverse causation and the prospect of shared genetic determinants of smoking and PD resistance. The therapeutic potential of non-nicotine components of smoke is suggested by studies supporting multiple alternative mechanisms ranging from monoamine oxidase inhibitors to gut microbiome disruption to antioxidant response induction by chronic exposure to low levels of carbon monoxide. Rigorous investigation is warranted to evaluate this molecule and others for disease-preventing and disease-modifying activity in PD models and, if warranted, in clinical trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Subject(s)
Nicotine , Parkinson Disease , Smoking , Humans , Nicotine/adverse effects , Parkinson Disease/genetics , Randomized Controlled Trials as Topic , Smokers , Smoking/adverse effects
8.
Mol Neurodegener ; 18(1): 93, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38041158

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. METHODS: We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression. RESULTS: APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid ß (Aß) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice. CONCLUSIONS: In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aß by microglia in an AD mouse model.


Subject(s)
Alzheimer Disease , Humans , Mice , Animals , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Microglia/metabolism , Mice, Transgenic , Optogenetics , Calcium/metabolism , Sleep , GABAergic Neurons/metabolism , Disease Models, Animal , Amyloid beta-Protein Precursor/genetics
9.
Neurology ; 101(17): e1708-e1717, 2023 10 24.
Article in English | MEDLINE | ID: mdl-37657939

ABSTRACT

BACKGROUND AND OBJECTIVES: In a proportion of patients, dementia with Lewy bodies (DLB) is associated with Alzheimer disease (AD) copathology, which is linked to accelerated cognitive decline and more extensive cortical atrophy. The objective was to evaluate the relationship between a biomarker of AD copathology, plasma tau phosphorylated at residue 181 (ptau181), and the treatment effects of the p38α kinase inhibitor neflamapimod, which targets the cholinergic degenerative process in DLB. METHODS: The AscenD-LB study was a phase 2a, randomized (1:1), 16-week, placebo-controlled clinical trial of neflamapimod in DLB, the main results of which have been published. After the study was completed (i.e., post hoc), pretreatment plasma ptau181 levels were determined and participants were grouped based on a cutoff for AD pathology of 2.2 pg/mL (established in a separate cohort to identify AD from healthy controls). Clinical outcomes for the comparison of placebo with neflamapimod 40 mg three times daily (TID; the higher and more clinically active of 2 doses studied) were analyzed using mixed models for repeated measures within each subgroup (baseline plasma ptau181 < and ≥2.2 pg/mL). RESULTS: Pretreatment plasma ptau181 levels were determined in eighty-five participants with mild-to-moderate DLB receiving cholinesterase inhibitors, with 45 participants below and 40 above the 2.2 pg/mL cutoff at baseline. In the 16-week treatment period, in the comparison of placebo with neflamapimod 40 mg TID, for all end points evaluated, improvements with neflamapimod treatment were greater in participants below the cutoff, compared with those above the cutoff. In addition, participants below the ptau181 cutoff at baseline showed significant improvement over placebo in an attention composite measure (+0.42, 95% CI 0.07-0.78, p = 0.023, d = 0.78), the Clinical Dementia Rating Scale Sum of Boxes (-0.60, 95% CI -1.04 to -0.06, p = 0.031, d = 0.70), the Timed Up and Go test (-3.1 seconds, 95% CI -4.7 to -1.6, p < 0.001, d = 0.74), and International Shopping List Test-Recognition (+1.4, 95% CI 0.2-2.5, p = 0.024, d = 1.00). DISCUSSION: Exclusion of patients with elevated plasma ptau181, potentially through excluding patients with extensive cortical neurodegeneration, enriches for a patient with DLB population that is more responsive to neflamapimod. More generally, plasma biomarkers of AD copathology at study entry should be considered as stratification variables in DLB clinical trials. TRIAL REGISTRATION INFORMATION: NCT04001517 at ClinicalTrials.gov.


Subject(s)
Alzheimer Disease , Lewy Body Disease , Humans , Alzheimer Disease/pathology , Biomarkers , Cholinesterase Inhibitors/therapeutic use , Lewy Body Disease/drug therapy , Lewy Body Disease/complications , Postural Balance , Protein Kinase Inhibitors/therapeutic use , Time and Motion Studies
10.
Sci Rep ; 13(1): 13075, 2023 08 11.
Article in English | MEDLINE | ID: mdl-37567942

ABSTRACT

Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP/PS1 mice. The power but not the frequency of astrocytic calcium transients was reduced in APP/PS1 mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.


Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/pathology , Optogenetics/adverse effects , Calcium , Astrocytes/metabolism , Mice, Transgenic , Calcium, Dietary , Disease Models, Animal , Brain/metabolism , Disease Progression , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics
11.
Res Sq ; 2023 Apr 25.
Article in English | MEDLINE | ID: mdl-37163040

ABSTRACT

Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP mice. The power but not the frequency of astrocytic calcium transients was reduced in APP mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

12.
J Alzheimers Dis ; 91(4): 1557-1572, 2023.
Article in English | MEDLINE | ID: mdl-36641682

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. OBJECTIVE: To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. METHODS: We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. RESULTS: SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. CONCLUSION: SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Dementia , Humans , Alzheimer Disease/complications , Sleep, REM/physiology , Entropy , Electroencephalography , Dementia/complications
13.
Res Sq ; 2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38196602

ABSTRACT

Background: Associations between phenotypic traits, environmental exposures, and Parkinson's disease have largely been evaluated one-by-one, piecemeal, and pre-selections. A comprehensive picture of comorbidities, phenotypes, exposures, and polypharmacy characterizing the complexity and heterogeneity of real-world patients presenting to academic movement disorders clinics in the US is missing. Objectives: To portrait the complexity of features associated with patients with Parkinson's disease in a study of 933 cases and 291 controls enrolled in the Harvard Biomarkers Study. Methods: The primary analysis evaluated 64 health features for associations with Parkinson's using logistic regression adjusting for age and sex. We adjusted for multiple testing using the false discovery rate (FDR) with £ 0.05 indicating statistical significance. Exploratory analyses examined feature correlation clusters and feature combinations. Results: Depression (OR = 3.11, 95% CI 2.1 to 4.71), anxiety (OR = 3.31, 95% CI 2.01-5.75), sleep apnea (OR 2.58, 95% CI 1.47-4.92), and restless leg syndrome (RLS; OR 4.12, 95% CI 1.81-12.1) were significantly more common in patients with Parkinson's than in controls adjusting for age and sex with FDR £ 0.05. The prevalence of depression, anxiety, sleep apnea, and RLS were correlated, and these diseases formed part of a larger cluster of mood traits and sleep traits linked to PD. Exposures to pesticides (OR 1.87, 95% CI 1.37-2.6), head trauma (OR 2.33, 95% CI 1.51-3.73), and smoking (OR 0.57, 95% CI 0.43-0.75) were significantly associated with the disease consistent with previous studies. Vitamin supplementation with cholecalciferol (OR 2.18, 95% CI 1.4-3.45) and coenzyme Q10 (OR 2.98, 95% CI 1.89-4.92) was more commonly used by patients than controls. Cumulatively, 43% (398 of 933) of Parkinson's patients had at least one psychiatric or sleep disorder, compared to 21% (60 of 291) of healthy controls. Conclusions: 43% of Parkinson's patients seen at Harvard-affiliated teaching hospitals have depression, anxiety, and disordered sleep. This syndromic cluster of mood and sleep traits may be pathophysiologically linked and clinically important.

14.
Sci Rep ; 12(1): 21022, 2022 12 05.
Article in English | MEDLINE | ID: mdl-36471155

ABSTRACT

The Alzheimer's disease-associated peptide amyloid-beta (Aß) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aß, here we show that Aß aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aß impaired hippocampal theta-gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aß reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aß-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aß alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aß induced hyperexcitability.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Hippocampus , Animals , Humans , Mice , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Calcium/metabolism , Disease Models, Animal , Hippocampus/physiopathology , Mice, Transgenic
15.
Nat Commun ; 13(1): 5308, 2022 09 21.
Article in English | MEDLINE | ID: mdl-36130946

ABSTRACT

The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.


Subject(s)
Alzheimer Disease , Basal Forebrain , Alzheimer Disease/metabolism , Animals , Basal Forebrain/metabolism , Cholinergic Neurons/metabolism , Cholinesterase Inhibitors/metabolism , Double-Blind Method , GTP Phosphohydrolases/metabolism , Humans , Mice , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
16.
Parkinsonism Relat Disord ; 85: 11-16, 2021 04.
Article in English | MEDLINE | ID: mdl-33639572

ABSTRACT

Neurofilament light chain (NFL) level in biofluids is a sensitive measure of axonal damage and a promising biomarker in neurodegenerative diseases. In Parkinson's disease (PD), NFL can distinguish PD from other parkinsonian disorders, and NFL concentration is associated with disease severity, risk of progression, and survival. To determine whether serum NFL at baseline in de novo PD predicts motor decline, differentially impacts specific motor features, predicts cognitive decline, and predicts loss of dopamine terminals, here we evaluated 376 de novo PD patients from the PPMI database and analyzed the effect of baseline serum NFL levels on progression over eight years of motor impairment measured with the UPDRS, cognitive function measured with the MoCA, and putamen dopamine transporter (DAT) binding ratio measured with DaTscan. In longitudinal mixed effects models that controlled for age, gender, disease duration, and levodopa equivalent drug dose, higher levels of serum NFL at baseline were associated with greater increases of UPDRS-III and total UPDRS scores, with greater worsening of postural instability and gait disorder (PIGD) scores but not tremor scores over time. In contrast, baseline serum NFL was not associated with significant progression of MoCA scores in this de novo PD cohort. Higher baseline serum NFL was associated with greater reduction of putamen DAT binding ratio over time. Together, these findings show that baseline serum NFL levels predict the rate of motor decline, the accumulation of PIGD clinical features, and the progression of dopamine transporter loss in the early stage of PD.


Subject(s)
Disease Progression , Dopamine Plasma Membrane Transport Proteins/pharmacokinetics , Neurofilament Proteins/blood , Parkinson Disease/blood , Parkinson Disease/diagnosis , Parkinson Disease/physiopathology , Putamen/diagnostic imaging , Aged , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Prognosis , Tomography, Emission-Computed, Single-Photon
17.
Brain ; 144(1): 266-277, 2021 02 12.
Article in English | MEDLINE | ID: mdl-33578418

ABSTRACT

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse.


Subject(s)
Basal Ganglia Diseases/pathology , Cerebral Cortex/pathology , Neural Pathways/pathology , Aged , Aged, 80 and over , Basal Ganglia Diseases/diagnostic imaging , Carbolines , Cerebral Cortex/diagnostic imaging , Female , Humans , Male , Middle Aged , Neural Pathways/diagnostic imaging , Positron-Emission Tomography/methods
18.
Front Neurol ; 12: 805135, 2021.
Article in English | MEDLINE | ID: mdl-35173668

ABSTRACT

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

19.
Neurology ; 95(6): e685-e696, 2020 08 11.
Article in English | MEDLINE | ID: mdl-32540937

ABSTRACT

OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.


Subject(s)
Glucosylceramidase/genetics , Mutation , Parkinson Disease/genetics , Aged , Aged, 80 and over , Cognition Disorders/etiology , Cross-Sectional Studies , Female , Follow-Up Studies , Genetic Association Studies , Glucosylceramidase/blood , Humans , Male , Middle Aged , Neurologic Examination , Parkinson Disease/enzymology , Parkinson Disease/physiopathology , Parkinson Disease/psychology , Quantitative Trait Loci , Severity of Illness Index
20.
J Parkinsons Dis ; 10(2): 505-510, 2020.
Article in English | MEDLINE | ID: mdl-32250320

ABSTRACT

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.


Subject(s)
Caffeine/administration & dosage , Parkinson Disease/metabolism , Uric Acid/blood , Aged , Biomarkers/metabolism , Case-Control Studies , Cross-Sectional Studies , Eating , Female , Humans , Male , Middle Aged , Parkinson Disease/blood , Sex Factors
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