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.

Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

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.

Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery.

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

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.

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.

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.

Degeneration of cholinergic white matter pathways and nucleus basalis of Meynert in individuals with objective subtle cognitive impairment.

We evaluated alterations in the nucleus basalis of Meynert (NBM) volume and integrity of cholinergic white matter pathways in objective subtle cognitive impairment (Obj-SCI) individuals. NBM segmentation and cholinergic pathways tracking were conducted at baseline, 12-, 24-, and 48-month follow-ups in 41 Obj-SCI individuals and 61 healthy controls (HC). The baseline and 4-year rate of change in NBM volume and cholinergic pathways mean diffusivity were compared. Associations between cholinergic index changes and pathological processes and cognitive performance were evaluated. After controlling for age, sex, APOE genotype, and total intracranial volume, Obj-SCI individuals exhibited reduced NBM volume and increased medial pathway mean diffusivity compared to HC at baseline. Furthermore, amyloid-positive Obj-SCI individuals exhibited a steeper longitudinal decline in NBM volume than HC. Additionally, decreases in NBM volume and cholinergic pathways integrity were associated with amyloid and vascular pathologies and cognitive decline. Overall, degeneration of the cholinergic system plays an important role in cognitive impairment during the preclinical stage of Alzheimer's disease, which may provide a significant target for early therapeutic interventions.

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.

Neuronal loss of the nucleus basalis of Meynert in primary progressive aphasia is associated with Alzheimer's disease neuropathological changes.

INTRODUCTION: Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment. Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking. METHODS: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals. RESULTS: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbM-related pretangles were associated with nbM neuronal loss. DISCUSSION: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss.

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.

Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis.

Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Anticholinergic drugs and forebrain magnetic resonance imaging changes in cognitively normal people and those with mild cognitive impairment.

BACKGROUND AND PURPOSE: Anticholinergic (AC) medication use is associated with cognitive decline and dementia, which may be related to an AC-induced central hypocholinergic state, but the exact mechanisms remain to be understood. We aimed to further elucidate the putative link between AC drug prescription, cognition, and structural and functional impairment of the forebrain cholinergic nucleus basalis of Meynert (NBM). METHODS: Cognitively normal (CN; n = 344) and mildly cognitively impaired (MCI; n = 224) Alzheimer's Disease Neuroimaging Initiative Phase 3 participants with good quality 3-T magnetic resonance imaging were included. Structural (regional gray matter [GM] density) and functional NBM integrity (functional connectivity [FC]) were compared between those on AC medication for > 1 year (AC+ ) and those without (AC- ) in each condition. AC burden was classed as mild, moderate, or severe. RESULTS: MCI AC+ participants (0.55 ± 0.03) showed lower NBM GM density compared to MCI AC- participants (0.56 ± 0.03, p = 0.002), but there was no structural AC effect in CN. NBM FC was lower in CN AC+ versus CN AC- (3.6 ± 0.5 vs. 3.9 ± 0.6, p = 0.001), and in MCI AC+ versus MCI AC- (3.3 ± 0.2 vs. 3.7 ± 0.5, p < 0.001), with larger effect size in MCI. NBM FC partially mediated the association between AC medication burden and cognition. CONCLUSIONS: Our findings provide novel support for a detrimental effect of mild AC medication on the forebrain cholinergic system characterized as functional central hypocholinergic that partially mediated AC-related cognitive impairment. Moreover, structural tissue damage suggests neurodegeneration, and larger effect sizes in MCI point to enhanced susceptibility for AC medication in those at risk of dementia.

Postural and gait symptoms in de novo Parkinson's disease patients correlate with cholinergic white matter pathology.

INTRODUCTION: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes. METHODS: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity. RESULTS: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance. CONCLUSIONS: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.

Plasticity in Intrinsic Excitability of Hypothalamic Magnocellular Neurosecretory Neurons in Late-Pregnant and Lactating Rats.

Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nuclei. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant, and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant, and lactating rats, and blockade of osmosensitive ΔN-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant, and lactating rats. Furthermore, supraoptic nucleus ΔN-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that sustained activity of ΔN-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer's Disease.

Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer's disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer's disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer's disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer's disease and potential therapeutic implications.

Altered multimodal magnetic resonance parameters of basal nucleus of Meynert in Alzheimer's disease.

OBJECTIVES: We aimed to examine how gray matter volume (GMV), regional blood flow (rCBF), and resting-state functional connectivity (FC) of the basal nucleus of Meynert (BNM) are altered in 40 patients with AD, relative to 30 healthy controls (HCs). METHODS: We defined the BNM on the basis of a mask histochemically reconstructed from postmortem human brains. We examined GMV with voxel-based morphometry of high-resolution structural images, rCBF with arterial spin labeling imaging, and whole-brain FC with published routines. We performed partial correlations to explore how the imaging metrics related to cognitive and living status in patients with AD. Further, we employed receiver operating characteristic analysis to compute the "diagnostic" accuracy of these imaging markers. RESULTS: AD relative to HC showed lower GMV and higher rCBF of the BNM as well as lower BNM connectivity with the right insula and cerebellum. In addition, the GMVs of BNM were correlated with cognitive and daily living status in AD. Finally, these imaging markers predicted AD (vs. HC) with an accuracy (area under the curve) of 0.70 to 0.86. Combination of BNM metrics provided the best prediction accuracy. CONCLUSIONS: By combining multimode MR imaging, we demonstrated volumetric atrophy, hyperperfusion, and disconnection of the BNM in AD. These findings support cholinergic dysfunction as an etiological marker of AD and related dementia.

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies.

Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes. Post-mortem nbM tissue was stained for Complex I or IV and quantitated relative to porin with immunofluorescence using confocal microscopy of individual cells from LBD (303 neurons, 8 cases), control (362 neurons, 8 cases) and asymptomatic incidental LBD (iLBD) cases (99 neurons, 2 cases). Additionally, α-synuclein, tau and amyloid-ß pathology were analysed using quantitative immunohistochemistry, and respiratory chain markers were compared in cells with Lewy bodies (N = 134) and unaffected cells (N = 272). The expression of Complex I normalised to mitochondrial mass was significantly lower in LBD compared to control and iLBD cases and this was unrelated to local neuropathological burdens but trended toward a relationship with neuronal loss. Furthermore, Complex I expression was higher in cells with Lewy bodies compared to adjacent cells without α-synuclein aggregates. These findings suggest that Complex I deficits in the nbM occur in symptomatic LBD cases and may relate to neuronal loss, but that contrary to the view that Lewy body formation underlies neuronal dysfunction and damage in LBD, Lewy bodies are associated with higher Complex I expression than neurons without Lewy bodies. One could speculate that Lewy bodies may provide a mechanism to encapsulate damaged mitochondria and/or α-synuclein oligomers, thus protecting neurons from their cytotoxic effects.

Evaluation of the pre-treatment effect of Centella asiatica medicinal plants on long-term potentiation (LTP) in rat model of Alzheimer's disease.

The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer's disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats' brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.