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1.
Sci Rep ; 14(1): 11268, 2024 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760448

RESUMEN

We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined the level of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer's Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Heterocigoto , Mutación , Tomografía de Emisión de Positrones , Presenilina-1 , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Femenino , Masculino , Presenilina-1/genética , Persona de Mediana Edad , Colombia , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Prosencéfalo Basal/diagnóstico por imagen , Imagen por Resonancia Magnética , Adulto , Atrofia , Anciano , Teorema de Bayes
2.
J Alzheimers Dis ; 99(1): 145-159, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38640150

RESUMEN

Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aß]-negative cognitively unimpaired, 6 Aß-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aß, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aß and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aß, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aß accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aß and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Prosencéfalo Basal , Cognición , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Proteínas tau/metabolismo , Prosencéfalo Basal/patología , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Estudios Retrospectivos , Cognición/fisiología , Estudios Transversales , Anciano de 80 o más Años , Estudios Longitudinales , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios de Cohortes
3.
Eur J Neurol ; 31(2): e16147, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37975786

RESUMEN

BACKGROUND AND PURPOSE: The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa-induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD-LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI). METHODS: Thirty-one PD-LID patients, 39 PD patients without LID (PD-nLID), and 28 healthy controls (HCs) underwent T1-weighted MRI, quantitative susceptibility mapping, multi-shell diffusion MRI, and resting-state functional MRI (rs-fMRI). Different measures characterizing the VP were obtained using a region-of-interest-based approach. RESULTS: The left VP in the PD-LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD-nLID and HC groups. Rs-MRI revealed that, compared with the PD-nLID group, the PD-LID group in the medication 'off' state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores. CONCLUSION: Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum-VP-mediodorsal thalamus-cortex network may be associated with pathophysiological mechanisms of PD-LID.


Asunto(s)
Prosencéfalo Basal , Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , Prosencéfalo Basal/patología , Imagen por Resonancia Magnética/métodos , Discinesia Inducida por Medicamentos/diagnóstico por imagen
4.
Brain ; 147(5): 1799-1808, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38109781

RESUMEN

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.


Asunto(s)
Prosencéfalo Basal , Cognición , Enfermedad de Parkinson , Humanos , Prosencéfalo Basal/patología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/metabolismo , Masculino , Femenino , Anciano , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/metabolismo , Persona de Mediana Edad , Estudios Transversales , Cognición/fisiología , Acetilcolina/metabolismo , Tomografía de Emisión de Positrones , Neuronas Colinérgicas/patología , Pruebas Neuropsicológicas
6.
Neurobiol Aging ; 132: 120-130, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37801885

RESUMEN

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-ß (Aß) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aß-PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and Aß status (Aß-, Aß+). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high Aß levels correlated with faster volume loss in the BF and hippocampus, and the effect of Aß varied within BF subregions. Compared to CU Aß+ individuals, Aß-related loss among CI Aß+ adults was much greater in the predominantly cholinergic subregion of Ch4p, whereas no difference was observed for the Ch1/Ch2 region. The findings support early and substantial vulnerability of the BF and further reveal distinctive degeneration of BF subregions during early AD.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/patología , Envejecimiento/patología , Péptidos beta-Amiloides , Imagen por Resonancia Magnética , Colinérgicos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Tomografía de Emisión de Positrones
7.
Neuroimage Clin ; 39: 103477, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37478584

RESUMEN

OBJECTIVES: Degeneration of the cholinergic basal forebrain nuclei (CBFN) system has been studied extensively in Alzheimer's disease (AD). White matter hyperintensities are a hallmark of aging as well as a common co-morbidity of AD, but their contribution to CBFN degeneration has remained unclear. Therefore, we explored the influence of white matter hyperintensities within cholinergic subcortical-cortical projection pathways on CBFN volumes and regional gray matter volumes in AD and age- and gender-matched controls. METHODS: We analyzed magnetic resonance images (MRI) from 42 patients with AD and 87 age- and gender-matched control subjects. We assessed the white matter hyperintensity burden within the cholinergic projection pathways using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and applied probabilistic anatomical maps for the analysis of CBFN volumes, i.e. the Ch1-3 compartment and the Ch4 cell group (nucleus basalis of Meynert), by diffeomorphic anatomical registration using exponentiated lie algebra analysis of voxel-based morphometry. Using multiple linear regression analyses, we explored correlations between regional gray matter volumes and the extent of white matter hyperintensities or CBFN volumes in both groups. RESULTS: In AD, all CBFN volumes were significantly smaller than in controls, and white matter hyperintensity burden within the cholinergic projection pathways was not correlated with CBFN volume. In controls, white matter hyperintensity burden within the cholinergic projection pathways was inversely correlated with CBFN volume when corrected for sex and total intracranial volume, but this correlation was no longer significant after correction for age. Voxel-wise multiple linear regression analyses using threshold-free cluster enhancement revealed that in controls, cholinergic pathway hyperintensities correlated with gray matter loss in perisylvian areas, whereas the were no effects in AD. Moreover, we found that CBFN volumes correlated with distinct regional cortical atrophy patterns in both groups. CONCLUSION: Our results indicate that white matter hyperintensities and AD pathology contribute independently but additively to the degeneration of cholinergic basal forebrain structures. Whereas AD is primarily associated with CBFN volume loss, cholinergic degeneration associated with white matter hyperintensities appears to involve disruption of cholinergic cortical projection fibers with less pronounced effects on CBFN volumes.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Sustancia Blanca , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen por Resonancia Magnética/métodos , Colinérgicos
8.
FASEB J ; 37(6): e22944, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37191946

RESUMEN

Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics in these disorders have been unsuccessful in slowing disease progression, likely due to poorly understood complex pathological interactions and dysregulated pathways. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration and has shown lifelong behavioral changes due to maternal choline supplementation (MCS). To test the impact of MCS on trisomic BFCNs, we performed laser capture microdissection to individually isolate choline acetyltransferase-immunopositive neurons in Ts65Dn and disomic littermates, in conjunction with MCS at the onset of BFCN degeneration. We utilized single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs. Leveraging multiple bioinformatic analysis programs on differentially expressed genes (DEGs) by genotype and diet, we identified key canonical pathways and altered physiological functions within Ts65Dn MSN BFCNs, which were attenuated by MCS in trisomic offspring, including the cholinergic, glutamatergic and GABAergic pathways. We linked differential gene expression bioinformatically to multiple neurological functions, including motor dysfunction/movement disorder, early onset neurological disease, ataxia and cognitive impairment via Ingenuity Pathway Analysis. DEGs within these identified pathways may underlie aberrant behavior in the DS mice, with MCS attenuating the underlying gene expression changes. We propose MCS ameliorates aberrant BFCN gene expression within the septohippocampal circuit of trisomic mice through normalization of principally the cholinergic, glutamatergic, and GABAergic signaling pathways, resulting in attenuation of underlying neurological disease functions.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Síndrome de Down , Ratones , Animales , Síndrome de Down/genética , Síndrome de Down/metabolismo , Ratones Transgénicos , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad , Colina/metabolismo , Suplementos Dietéticos
9.
Ann Clin Transl Neurol ; 10(5): 814-824, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37000969

RESUMEN

BACKGROUND: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. OBJECTIVE: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. METHODS: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD-FOG), 20 without FOG (PD-NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. RESULTS: Our study discovered that, compared to PD-NFOG, PD-FOG exhibited significant Ch4 atrophy (p = 4.6 × 10-5 ), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 × 10-5 ) and parahippocampal gyrus (p = 2.90 × 10-5 ). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD-FOG group (ß = -12.224, T = -2.556, p = 0.031). INTERPRETATION: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD-FOG.


Asunto(s)
Prosencéfalo Basal , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Trastornos Neurológicos de la Marcha/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/etiología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/patología , Atrofia/patología , Marcha
10.
Neurobiol Dis ; 180: 106070, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36898615

RESUMEN

BACKGROUND: It is not clear to which degree limbic TDP-43 pathology associates with a cholinergic deficit in the absence of Alzheimer's disease (AD) pathology. OBJECTIVE: Replicate and extend recent evidence on cholinergic basal forebrain atrophy in limbic TDP-43 and evaluate MRI based patterns of atrophy as a surrogate marker for TDP-43. METHODS: We studied ante-mortem MRI data of 11 autopsy cases with limbic TDP-43 pathology, 47 cases with AD pathology, and 26 mixed AD/TDP-43 cases from the ADNI autopsy sample, and 17 TDP-43, 170 AD, and 58 mixed AD/TDP-43 cases from the NACC autopsy sample. Group differences in basal forebrain and other brain volumes of interest were assessed using Bayesian ANCOVA. We assessed the diagnostic utility of MRI based patterns of brain atrophy using voxel-based receiver operating characteristics and random forest analyses. RESULTS: In the NACC sample, we found moderate evidence for the absence of a difference in basal forebrain volumes between AD, TDP-43, and mixed pathologies (Bayes factor(BF)10 = 0.324), and very strong evidence for lower hippocampus volume in TDP-43 and mixed cases compared with AD cases (BF10 = 156.1). The ratio of temporal to hippocampus volume reached an AUC of 75% for separating pure TDP-43 from pure AD cases. Random-forest analysis between TDP-43, AD, and mixed pathology reached only a multiclass AUC of 0.63 based on hippocampus, middle-inferior temporal gyrus, and amygdala volumes. Findings in the ADNI sample were consistent with these results. CONCLUSION: A comparable degree of basal forebrain atrophy in pure TDP-43 cases compared to AD cases encourages studies on the effect of cholinergic treatment in amnestic dementia due to TDP-43. A distinct pattern of temporo-limbic brain atrophy may serve as a surrogate marker to enrich samples in clinical trials for the presence of TDP-43 pathology.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Humanos , Enfermedad de Alzheimer/patología , Teorema de Bayes , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/patología , Imagen por Resonancia Magnética , Atrofia/patología , Proteínas de Unión al ADN/metabolismo , Colinérgicos
11.
Ann Neurol ; 93(5): 991-998, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36597786

RESUMEN

OBJECTIVES: Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non-motor outcome studies in Parkinson's disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample. METHODS: [18 F]-Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non-demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume-of-interest based correlation analysis. RESULTS: Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto-occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1-2. Correlations were also observed in the striatum, thalamus, and brainstem. INTERPRETATION: Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto-occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991-998.


Asunto(s)
Prosencéfalo Basal , Enfermedad de Parkinson , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Enfermedad de Parkinson/metabolismo , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Proteínas de Transporte Vesicular de Acetilcolina , Atrofia/patología , Colinérgicos/metabolismo
12.
Neurobiol Dis ; 177: 105983, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36586468

RESUMEN

Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Prosencéfalo Basal/patología , Núcleo Basal de Meynert/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Péptidos beta-Amiloides/metabolismo
13.
Nat Commun ; 13(1): 6543, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-36323689

RESUMEN

Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Síndromes de la Apnea del Sueño , Animales , Ratones , Humanos , Enfermedad de Alzheimer/patología , Prosencéfalo Basal/patología , Modelos Animales de Enfermedad , Síndromes de la Apnea del Sueño/complicaciones , Hipoxia/patología , Colinérgicos
14.
Neurobiol Aging ; 117: 24-32, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35640461

RESUMEN

Degeneration of cholinergic neurons in the basal forebrain (BF) contributes to cognitive impairment in Alzheimer's disease (AD) and other disorders. Atrophy of BF volume measured by structural MRI is thought to represent the loss of cholinergic neurons in this structure. As there are multiple types of neurons in the BF as well as glia and axons, whether this MRI measure actually reflects the change of cholinergic neurons has not been verified. In this study, we assessed BF cholinergic neuron number by histological counts and compared with the volume measurements by in vivo MRI in 3xTg mice, a model of familial AD. Both manual and template-based segmentation revealed atrophy of the medial septum (MS), consistent with a significant reduction in cholinergic neuron number. However, MRI-measured volume reduction did not correlate with the reduced cholinergic neuron number. To directly test whether specific loss of cholinergic neurons results in BF atrophy, we selectively ablated the cholinergic neurons in the MS. However, no detectable change in MRI volume was observed between lesioned and unlesioned mice. The results indicate that although loss of cholinergic neurons within the BF likely contributes to volume loss, this volume change cannot be taken as a direct biomarker of cholinergic neuron number.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Animales , Atrofia/patología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/patología , Colinérgicos , Neuronas Colinérgicas/patología , Modelos Animales de Enfermedad , Imagen por Resonancia Magnética/métodos , Ratones
15.
Eur J Neurol ; 29(5): 1394-1401, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35122358

RESUMEN

BACKGROUND AND PURPOSE: Currently, the extent of cholinergic basal forebrain atrophy in relatively pure limbic TAR DNA-binding protein 43 (TDP-43) pathology compared with relatively pure Alzheimer disease (AD) is unclear. METHODS: We compared antemortem magnetic resonance imaging (MRI)-based atrophy of the basal forebrain and medial and lateral temporal lobe volumes between 10 autopsy cases with limbic TDP-43 pathology and 33 cases with AD pathology on postmortem neuropathologic examination from the Alzheimer's Disease Neuroimaging Initiative cohort. For reference, we studied MRI volumes from cognitively healthy, amyloid positron emission tomography-negative subjects (n = 145). Group differences were assessed using Bayesian analysis of covariance. In addition, we assessed brain-wide regional volume changes using partial least squares regression (PLSR). RESULTS: We found extreme evidence (Bayes factor [BF]01  > 600) for a smaller basal forebrain volume in both TDP-43 and AD cases compared with amyloid-negative controls, and moderate evidence (BF01  = 4.9) that basal forebrain volume was not larger in TDP-43 than in AD cases. The ratio of hippocampus to lateral temporal lobe volumes discriminated between TDP-43 and AD cases with an accuracy of 0.78. PLSR showed higher gray matter in lateral temporal lobes and cingulate and precuneus, and reduced gray matter in precentral and postcentral gyri and hippocampus in TDP-43 compared with AD cases. CONCLUSIONS: Atrophy of the cholinergic basal forebrain appears to be similarly pronounced in cases with limbic TDP-43 pathology as in AD. This suggests that a clinical trial of the efficacy of cholinesterase inhibitors in amyloid-negative cases with amnestic dementia and an imaging signature of TDP-43 pathology may be warranted.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Enfermedad de Alzheimer/patología , Atrofia/patología , Prosencéfalo Basal/diagnóstico por imagen , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Teorema de Bayes , Colinérgicos/metabolismo , Proteínas de Unión al ADN , Humanos , Imagen por Resonancia Magnética
16.
J Neurosci ; 42(6): 1020-1034, 2022 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-34911797

RESUMEN

Aging is often associated with cognitive decline and recurrent cellular and molecular impairments. While life-long caloric restriction (CR) may delay age-related cognitive deterioration as well as the onset of neurologic disease, recent studies suggest that late-onset, short-term intermittent fasting (IF), may show comparable beneficial effects as those of life-long CR to improve brain health. We used a new optogenetic aging model to study the effects of late-onset (>18 months), short-term (four to six weeks) IF on age-related changes in GABAergic synaptic transmission, intracellular calcium (Ca2+) buffering, and cognitive status. We used male mice from a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R [VGAT-ChR2(H134R)-EYFP] in a reduced synaptic preparation that allows for specific optogenetic light stimulation on GABAergic synaptic terminals across aging. We performed quantal analysis using the method of failures in this model and show that short-term IF reverses the age-related decrease in quantal content of GABAergic synapses. Likewise, short-term IF also reversed age-related changes in Ca2+ buffering and spontaneous GABAergic synaptic transmission in basal forebrain (BF) neurons of aged mice. Our findings suggest that late-onset short-term IF can reverse age-related physiological impairments in mouse BF neurons but that four weeks IF is not sufficient to reverse age-related cognitive decline.SIGNIFICANCE STATEMENT Here, we demonstrate plasticity of the aging brain and reversal of well-defined hallmarks of brain aging using short-term intermittent fasting (IF) initiated later in life. Few therapeutics are currently available to treat age-related neurologic dysfunction although synaptic dysfunction occurs during aging and neurologic disease is a topic of intense research. Using a new reduced synaptic preparation and optogenetic stimulation we are able to study age-related synaptic mechanisms in greater detail. Several neurophysiological parameters including quantal content were altered during aging and were reversed with short-term IF. These methods can be used to identify potential therapies to reverse physiological dysfunction during aging.


Asunto(s)
Envejecimiento/patología , Prosencéfalo Basal/fisiología , Calcio/metabolismo , Ayuno/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Envejecimiento/fisiología , Animales , Prosencéfalo Basal/patología , Masculino , Ratones , Ratones Transgénicos , Neuronas/patología , Optogenética
17.
J Alzheimers Dis ; 85(3): 1267-1282, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34924387

RESUMEN

BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aß42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aß42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.


Asunto(s)
Enfermedad de Alzheimer/patología , Prosencéfalo Basal/patología , Biomarcadores , Colinérgicos , Inflamación/patología , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/patología , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino
18.
Parkinsonism Relat Disord ; 90: 27-32, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34348192

RESUMEN

INTRODUCTION: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD. METHODS: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions. RESULTS: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (߈slope= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (߈slope= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time. CONCLUSION: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.


Asunto(s)
Prosencéfalo Basal/patología , Cognición , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Olfato , Anciano , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Prosencéfalo Basal/diagnóstico por imagen , Neuronas Colinérgicas/patología , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/patología , Evaluación Geriátrica , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Tamaño de los Órganos , Enfermedad de Parkinson/fisiopatología
19.
Sci Rep ; 11(1): 13589, 2021 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-34193944

RESUMEN

Social behaviour is a complex construct that is reported to include several components of social approach, interaction and recognition memory. Alzheimer's disease (AD) is mainly characterized by progressive dementia and is accompanied by cognitive impairments, including a decline in social ability. The cholinergic system is a potential constituent for the neural mechanisms underlying social behaviour, and impaired social ability in AD may have a cholinergic basis. However, the involvement of cholinergic function in social behaviour has not yet been fully understood. Here, we performed a selective elimination of cholinergic cell groups in the basal forebrain in mice to examine the role of cholinergic function in social interaction and social recognition memory by using the three-chamber test. Elimination of cholinergic neurons in the medial septum (MS) and vertical diagonal band of Broca (vDB) caused impairment in social interaction, whereas ablating cholinergic neurons in the nucleus basalis magnocellularis (NBM) impaired social recognition memory. These impairments were restored by treatment with cholinesterase inhibitors, leading to cholinergic system activation. Our findings indicate distinct roles of MS/vDB and NBM cholinergic neurons in social interaction and social recognition memory, suggesting that cholinergic dysfunction may explain social ability deficits associated with AD symptoms.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Prosencéfalo Basal/metabolismo , Conducta Animal , Neuronas Colinérgicas/metabolismo , Memoria , Conducta Social , Interacción Social , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Prosencéfalo Basal/patología , Prosencéfalo Basal/fisiopatología , Neuronas Colinérgicas/patología , Ratones , Ratones Transgénicos
20.
Neurobiol Aging ; 106: 37-44, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34233212

RESUMEN

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia.


Asunto(s)
Prosencéfalo Basal/patología , Neuronas Colinérgicas/patología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Electroencefalografía , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Anciano , Atrofia , Prosencéfalo Basal/citología , Prosencéfalo Basal/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Enfermedad de Parkinson/diagnóstico
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