Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Degeneration in Nucleus basalis of Meynert signals earliest stage of Alzheimer's disease progression.

Nucleus Basalis of Meynert (NbM), a crucial source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), has shown sensitivity to neurofibrillary degeneration in the early stages of Alzheimer's Disease. Using deformation-based morphometry (DBM) on up-sampled MRI scans from 1447 Alzheimer's Disease Neuroimaging Initiative participants, we aimed to quantify NbM degeneration along the disease trajectory. Results from cross-sectional analysis revealed significant differences of NbM volume between cognitively normal and early mild cognitive impairment cohorts, confirming recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. Longitudinal linear mixed-effect models were then used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results indicated the earliest deviations in NbM volumes from the cognitively healthy trajectory, challenging the prevailing idea that Alzheimer's originates in the EC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

Abnormally decreased functional connectivity of the right nucleus basalis of Meynert in Alzheimer's disease patients with depression symptoms.

Dysfunction of the basal forebrain is the main pathological feature in patients with Alzheimer's disease (AD). The aim of this study was to explore whether depressive symptoms cause changes in the functional network of the basal forebrain in AD patients. We collected MRI data from depressed AD patients (n = 24), nondepressed AD patients (n = 14) and healthy controls (n = 20). Resting-state functional magnetic resonance imaging data and functional connectivity analysis were used to study the characteristics of the basal forebrain functional network of the three groups of participants. The functional connectivity differences among the three groups were compared using ANCOVA and post hoc analyses. Compared to healthy controls, depressed AD patients showed reduced functional connectivity between the right nucleus basalis of Meynert and the left supramarginal gyrus and the supplementary motor area. These results increase our understanding of the neural mechanism of depressive symptoms in AD patients.

Nucleus Basalis of Meynert Degeneration Predicts Cognitive Decline in Corticobasal Syndrome.

BACKGROUND: Cognitive changes are common in corticobasal syndrome (CBS) and significantly impact quality of life and caregiver burden. However, relatively few studies have investigated the neural substrates of cognitive changes in CBS, and reliable predictors of cognitive impairment are currently lacking. The nucleus basalis of Meynert (NbM), which serves as the primary source of cortical cholinergic innervation, has been functionally associated with cognition. This study aimed to explore whether patients with CBS exhibit reduced NbM volumes compared with healthy control participants and whether NbM degeneration can serve as a predictor of cognitive impairment in patients with CBS. METHODS: In this study, we investigated in vivo volumetric changes of the NbM in 38 patients with CBS and 84 healthy control participants. Next, we assessed whether gray matter degeneration of the NbM evaluated at baseline could predict cognitive impairment during a 12-month follow-up period in patients with CBS. All volumetric analyses were performed using 3T T1-weighted images obtained from the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Patients with CBS displayed significantly lower NbM volumes than control participants (p < .001). Structural damage of the NbM also predicted the development of cognitive impairment in patients with CBS as assessed by longitudinal measurements of the Clinical Dementia Rating Sum of Boxes (p < .001) and Mini-Mental State Examination (p = .035). CONCLUSIONS: Our findings suggest that NbM atrophy may represent a promising noninvasive in vivo marker of cognitive decline in CBS and provide new insights into the neural mechanisms that underlie cognitive impairment in CBS.

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study.

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

Structural degeneration of the nucleus basalis of Meynert in mild cognitive impairment and Alzheimer's disease - Evidence from an MRI-based meta-analysis.

Recent models of Alzheimer's disease (AD) suggest that neuropathological changes of the medial temporal lobe, especially entorhinal cortex, are preceded by degenerations of the cholinergic Nucleus basalis of Meynert (NbM). Evidence from imaging studies in humans, however, is limited. Therefore, we performed an activation-likelihood estimation meta-analysis on whole brain voxel-based morphometry (VBM) MRI data from 54 experiments and 2581 subjects in total. It revealed, compared to healthy older controls, reduced gray matter in the bilateral NbM in AD, but only limited evidence for such an effect in patients with mild cognitive impairment (MCI), which typically precedes AD. Both patient groups showed less gray matter in the amygdala and hippocampus, with hints towards more pronounced amygdala effects in AD. We discuss our findings in the context of studies that highlight the importance of the cholinergic basal forebrain in learning and memory throughout the lifespan, and conclude that they are partly compatible with pathological staging models suggesting initial and pronounced structural degenerations within the NbM in the progression of AD.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation of the nucleus basalis of Meynert modulates hippocampal-frontoparietal networks in patients with advanced Alzheimer's disease.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown potential for the treatment of mild-to-moderate Alzheimer's disease (AD). However, there is little evidence of whether NBM-DBS can improve cognitive functioning in patients with advanced AD. In addition, the mechanisms underlying the modulation of brain networks remain unclear. This study was aimed to assess the cognitive function and the resting-state connectivity following NBM-DBS in patients with advanced AD. METHODS: Eight patients with advanced AD underwent bilateral NBM-DBS and were followed up for 12 months. Clinical outcomes were assessed by neuropsychological examinations using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale. Resting-state functional magnetic resonance imaging and positron emission tomography data were also collected. RESULTS: The cognitive functioning of AD patients did not change from baseline to the 12-month follow-up. Interestingly, the MMSE score indicated clinical efficacy at 1 month of follow-up. At this time point, the connectivity between the hippocampal network and frontoparietal network tended to increase in the DBS-on state compared to the DBS-off state. Additionally, the increased functional connectivity between the parahippocampal gyrus (PHG) and the parietal cortex was associated with cognitive improvement. Further dynamic functional network analysis showed that NBM-DBS increased the proportion of the PHG-related connections, which was related to improved cognitive performance. CONCLUSION: The results indicated that NBM-DBS improves short-term cognitive performance in patients with advanced AD, which may be related to the modulation of multi-network connectivity patterns, and the hippocampus plays an important role within these networks. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022324. Registered 5 April 2019-Prospective registration. https://www.chictr.org.cn/showproj.aspx?proj=37712.

Increased functional connectivity between nucleus basalis of Meynert and amygdala in cognitively intact elderly along the Alzheimer's continuum.

BACKGROUND: A growing body of research reported the degeneration of the basal forebrain (BF) cholinergic system in the early course of Alzheimer's disease (AD). However, functional changes of the BF in asymptomatic individuals along the Alzheimer's continuum remain unclear. METHODS: A total of 229 cognitively intact participants were included from the Alzheimer's Disease Neuroimaging Initiative dataset and further divided into four groups based on the "A/T" profile using amyloid and tau positron emission tomography (PET). All A-T+ subjects were excluded. One hundred and seventy-three subjects along the Alzheimer's continuum (A-T-, A+ T-, A+ T+) were used for further study. The seed-based functional connectivity (FC) maps of the BF subregions (Ch1-3 and Ch4 [nucleus basalis of Meynert, NBM]) with whole-brain voxels were constructed. Analyses of covariance to detect the between-group differences and to further investigated the relations between FC values and AD biomarkers or cognition. RESULTS: We found increased FC between right Ch4 and bilateral amygdala among three groups, and the FC value could well distinguish between the A-T- group and the Alzheimer's continuum groups. Furthermore, increased FC between the Ch4 and amygdala was associated with higher pathological burden reflected by amyloid and tau PET in the entire population as well as better logistic memory function in A + T+ group. CONCLUSION: Our study demonstrated the NBM functional connectivity increased in cognitively normal elderly along the Alzheimer's continuum, which indicated a potential compensatory mechanism to counteract pathological changes in AD and maintain intact cognitive function.

Altered functional connectivity between the nucleus basalis of Meynert and anterior cingulate cortex is associated with declined attentional performance after total sleep deprivation.

BACKGROUND: Sleep deprivation can markedly influence vigilant attention. The nucleus basalis of Meynert (NBM), the main source of cholinergic projections to the cortex, plays an important role in wakefulness maintenance and attention control. However, the involvement of NBM in attentional impairments after total sleep deprivation (TSD) has yet to be established. The purpose of this study is to investigate the alterations in NBM functional connectivity and its association with the attentional performance following TSD. METHODS: Thirty healthy adult males were recruited in the study. Participants underwent two resting-state functional magnetic resonance imaging (rs-fMRI) scans, once in rested wakefulness (RW) and once after 36 h of TSD. Seed-based functional connectivity analysis was performed using rs-fMRI data for the left and right NBM. The vigilant attention was measured using a psychomotor vigilance test (PVT). Furthermore, Pearson correlation analysis was conducted to investigate the relationship between altered NBM functional connectivity and changed PVT performance after TSD. RESULTS: Compared to RW, enhanced functional connectivity was observed between right NBM and bilateral thalamus and cingulate cortex, while reduced functional connectivity was observed between left NBM and right superior parietal lobule following TSD. Moreover, altered NBM functional connectivity with the left anterior cingulate cortex was negatively correlated with PVT performance after TSD. CONCLUSION: Our results suggest that the disrupted NBM-related cholinergic circuit highlights an important role in attentional performance after TSD. The enhanced NBM functional connectivity with the anterior cingulate cortex may act as neural signatures for attentional deficits induced by sleep deprivation.

Role of the Nucleus Basalis as a Key Network Node in Temporal Lobe Epilepsy.

OBJECTIVE: To determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses. METHODS: We acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing. RESULTS: We observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures (r = -0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%). CONCLUSIONS: These results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder.

Resting state activity and connectivity of the nucleus basalis of Meynert and globus pallidus in Lewy body dementia and Parkinson's disease dementia.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two related diseases which can be difficult to distinguish. There is no objective biomarker which can reliably differentiate between them. The synergistic combination of electrophysiological and neuroimaging approaches is a powerful method for interrogation of functional brain networks in vivo. We recorded bilateral local field potentials (LFPs) from the nucleus basalis of Meynert (NBM) and the internal globus pallidus (GPi) with simultaneous cortical magnetoencephalography (MEG) in six PDD and five DLB patients undergoing surgery for deep brain stimulation (DBS) to look for differences in underlying resting-state network pathophysiology. In both patient groups we observed spectral peaks in the theta (2-8 Hz) band in both the NBM and the GPi. Furthermore, both the NBM and the GPi exhibited similar spatial and spectral patterns of coupling with the cortex in the two disease states. Specifically, we report two distinct coherent networks between the NBM/GPi and cortical regions: (1) a theta band (2-8 Hz) network linking the NBM/GPi to temporal cortical regions, and (2) a beta band (13-22 Hz) network coupling the NBM/GPi to sensorimotor areas. We also found differences between the two disease groups: oscillatory power in the low beta (13-22Hz) band was significantly higher in the globus pallidus in PDD patients compared to DLB, and coherence in the high beta (22-35Hz) band between the globus pallidus and lateral sensorimotor cortex was significantly higher in DLB patients compared to PDD. Overall, our findings reveal coherent networks of the NBM/GPi region that are common to both DLB and PDD. Although the neurophysiological differences between the two conditions in this study are confounded by systematic differences in DBS lead trajectories and motor symptom severity, they lend support to the hypothesis that DLB and PDD, though closely related, are distinguishable from a neurophysiological perspective.

Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert.

The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer's disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39-77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging.

Are Linear Measurements of the Nucleus Basalis of Meynert Suitable as a Diagnostic Biomarker in Mild Cognitive Impairment and Alzheimer Disease?

BACKGROUND AND PURPOSE: Cell loss within the nucleus basalis of Meynert is an early event in Alzheimer disease. The thickness of the nucleus basalis of Meynert (NBM) can be measured on structural MR imaging. We investigated NBM thickness in relation to cognitive state and biochemical markers. MATERIALS AND METHODS: Mean bilateral nucleus basalis of Meynert thickness was measured on coronal T1-weighted MR imaging scans from the Alzheimer's Disease Neuroimaging Initiative dataset. Three hundred and fifteen scans (80 controls, 79 cases of early mild cognitive impairment, 77 cases of late mild cognitive impairment and 79 cases of Alzheimer disease) were assessed. Alzheimer's Disease Assessment Scale-Cognitive scores, CSF tau, and amyloid quantification were extracted. Group differences in NBM thickness, their correlates and measurement reliability were assessed. RESULTS: Mean NBM thickness ± SD progressively declined from 2.9 ± 0.3, 2.5 ± 0.3, and 2.3 ± 0.3 to 1.8 ± 0.4 mm in healthy controls, patients with early mild cognitive impairment, late mild cognitive impairment and Alzheimer disease respectively (P < .001). NBM thickness was negatively correlated with Alzheimer's Disease Assessment Scale-Cognitive scores (r = -0.53, P < .001) and weakly positively correlated with CSF amyloid (r = 0.250, P < .001) respectively. No association with CSF tau was found. NBM thickness showed excellent diagnostic accuracy to differentiate Alzheimer disease (area under the curve, 0.986) and late mild cognitive impairment from controls (area under the curve, 0.936) with excellent sensitivity, but lower specificity 66.7%. Intra- and interrater reliability for measurements was 0.66 and 0.47 (P < .001). CONCLUSIONS: There is progressive NBM thinning across the aging-dementia spectrum, which correlates with cognitive decline and CSF markers of amyloid-ß pathology. We show high diagnostic accuracy but limited reliability, representing an area for future improvement. NBM thickness is a promising, readily available MR imaging biomarker of Alzheimer disease warranting diagnostic-accuracy testing in clinical practice.

Phase enhanced PSIR T1 weighted imaging improves contrast resolution of the nucleus basalis of Meynert at 7 T: a preliminary study.

BACKGROUND: The nucleus basalis of Meynert (NBM) provides the majority of cortical cholinergic innervation which is required for memory formation, maintaining attention and promoting learning. Neuronal loss within this area is implicated in a number of neurodegenerative disorders. Imaging the NBM is however limited by its small size and suboptimal contrast resolution at the base of the brain. PURPOSE: To develop a novel method of processing T1 weighted MRI data for improving contrast resolution and delineation of the NBM. STUDY TYPE: Technical development, case series. SUBJECTS: Five healthy volunteers. FIELD STRENGTH, SEQUENCE, ANALYSIS: Volunteers were scanned on a Philips 7 T Achieva imaging system. T1-weighted images were constructed from a double inversion phase sensitive inversion recovery (PSIR) sequence. Inversion recovery data were combined with the filtered phase data from the long inversion time image to produce a novel susceptibility weighted-PSIR (SW-PSIR) map. This process is similar to that used to combine T2* weighted image and phase maps to create susceptibility weighted images (SWI), but with the processing parameters optimized in terms of contrast-to-noise ratio to the NBM in the final SW-PSIR maps. Average NBM thickness was reported as mean ±â€¯standard deviation (SD). Intra-observer and inter-observer reliability were tested using intra-class correlation coefficient (ICC). RESULTS: 0.7mm3 isotropic resolution images were acquired in a 5 min and 50 s scan. The mean thickness ±â€¯SD of the left (right) NBM was 3.5 ±â€¯0.4 mm and 3.8 ±â€¯0.5 mm (3.6 ±â€¯0.5 mm and 3.7 ±â€¯0.5 mm) by the first and second observers respectively with excellent intra-observer and inter-observer agreement (>0.90). CONCLUSION: In this pilot study the SW-PSIR imaging approach improves delineation of the NBM between the ventral pallidum and chiasmatic cistern allowing accurate thickness measurement. The role of this sequence, in enabling robust morphometry of the NBM in health and disease, can be tested further in larger studies.

From eyes-closed to eyes-open: Role of cholinergic projections in EC-to-EO alpha reactivity revealed by combining EEG and MRI.

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system.

Severe Lesions Involving Cortical Cholinergic Pathways Predict Poorer Functional Outcome in Acute Ischemic Stroke.

Background and Purpose- The aim of the study was to assess the effect of lesion severity in cortical cholinergic pathways in acute ischemic stroke patients on functional outcomes. Methods- The study sample consisted of 214 men (70.9%) and 88 women (29.1%) with acute ischemic stroke. We used the Cholinergic Pathways Hyperintensities Scale (CHIPS) to assess the severity of lesions in cortical cholinergic pathways using brain magnetic resonance imaging. The other magnetic resonance imaging parameters included infarction, white matter lesions, and medial temporal lobe atrophy. Functional outcome was assessed using the Lawton activities of daily living (ADL) scale at 3 and 6 months after the index stroke. We also assessed disability status using the modified Rankin Scale. Results- Univariate analysis showed that patients with poor functional outcomes were older, more likely to be men, had a higher National Institutes of Health Stroke Scale (NIHSS) score on admission, and had more frequent histories of previous stroke and infection complications. They also had significantly more frequent cortical infarcts, left subcortical infarcts, a larger infarct volume, more severe medial temporal lobe atrophy, and periventricular hyperintensities, and higher CHIPS scores. In the multiple regression analysis, model 1 showed that age and NIHSS score on admission were significant predictors of poor ADL at 3 months, with an R2 of 45.4% fitting the model. Age, NIHSS score on admission and stroke subtype were also significant predictors of poor ADL at 6 months, with an R2 of 37.9% fitting the model. In model 2, sex, previous stroke, NIHSS score on admission, right cortical infarcts, left subcortical infarcts and CHIPS score were significant predictors for poor ADL at 3 months, with an R2 of 53.5%. NIHSS score on admission, stroke subtype, and CHIPS score were significant predictors for poor ADL at 6 months, with an R2 of 40.2%. After adjustment for confounders, CHIPS score was also a significant predictor for poor modified Rankin Scale, both at 3 and 6 months. Even after removing patients with moderate-to-severe white matter lesions, higher CHIPS scores still correlated with poorer ADL and modified Rankin Scale both at both 3 and 6 months. Conclusions- In patients with acute ischemic stroke, cortical cholinergic pathways impairment is common, and the severity of lesions in the cortical cholinergic pathways may significantly predict a poorer functional outcome. Clinical Trial Registration- URL: http://www.chictr.org.cn/index.aspx . Unique identifier: ChiCTR1800014982.

Altered Nucleus Basalis Connectivity Predicts Treatment Response in Mild Cognitive Impairment.

Purpose To determine whether functional connectivity (FC) mapping of nucleus basalis of Meynert (NBM) cholinergic network (hereafter, NBM FC) could provide a biomarker of central cholinergic deficits with predictive potential for response to cholinesterase inhibitor (ChEI) treatment. Materials and Methods The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All participants and their representatives gave written informed consent prior to data collection. NBM FC was examined in 33 healthy control participants, 102 patients with mild cognitive impairment (MCI), and 33 patients with AD by using resting-state functional MRI data from the ADNI database. NBM FC was compared between groups before and after 6 months of ChEI treatment in MCI. Associations between baseline NBM FC and baseline cognitive performance as well as cognitive outcomes after treatment were investigated. Results Compared with the healthy control group, NBM FC was decreased in patients with untreated MCI and increased in patients with AD treated with ChEI (corrected P ˂ .05). Global cognition (Alzheimer's Disease Assessment Scale-Cognitive subscale score) was associated with NBM FC (r = -0.349; P ˂ .001). NBM FC was higher 6 months after ChEI compared with before ChEI in treated MCI (corrected P ˂ .05), but did not change at 6 months in patients with untreated MCI (corrected P ˂ .05). Baseline NBM FC in MCI strongly predicted cognitive outcomes 6 months after ChEI (R2 = 0.458; P = .001). Conclusion Functional dissociation of the nucleus basalis of Meynert from a cortical network may explain the cognitive deficits in dementia and allow for the selection of individuals who are more likely to respond to cholinesterase inhibitors at early disease stages. © RSNA, 2018 Online supplemental material is available for this article.

Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson's disease.

Currently, no reliable predictors of cognitive impairment in Parkinson's disease exist. We hypothesized that microstructural changes at grey matter T1-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson's disease. We performed a cross-sectional comparison between patients with Parkinson's disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson's disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson's disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson's disease without cognitive impairment. These results were confirmed both with region of interest and voxel-based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson's disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson's disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.

Neuroanatomical Characteristics Associated With Response to Deep Brain Stimulation of the Nucleus Basalis of Meynert for Alzheimer's Disease.

OBJECTIVES: First reports on the application of deep brain stimulation (DBS) of the Nucleus basalis of Meynert (NBM) showed feasibility and safety of the intervention in patients with Alzheimer´s disease. However, clinical effects vary and the mechanisms of actions are still not well understood. The aim of this study was to characterize neuroimaging changes that are associated with the responsiveness to the treatment. MATERIALS AND METHODS: We examined preoperative T1-weighted MR images of ten patients with Alzheimer's disease (AD) treated with DBS of the NBM and correlated the clinical outcome with volumetric differences of cortical thickness. Subsequently, we sought to identify brain regions that carry out the clinical effects by correlating the outcome with streamlines connected to the volume of activated tissue. Clinical assessments at baseline, 6 and 12 months after the intervention included the AD Assessment Scale as well as the mini mental status examination. RESULTS: A fronto-parieto-temporal pattern of cortical thickness was found to be associated with beneficial outcome. Modulation of streamlines connected to left parietal and opercular cortices was associated with better response to the intervention. CONCLUSION: Our results indicate that patients with less advanced atrophy may profit from DBS of the NBM. We conclude that beneficial effects of the intervention are related to preserved fronto-parieto-temporal interplay.