Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer’s Disease Spectrum

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 Aβ 42/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 Aβ 42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its rostrocaudal axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from rostral and caudal BFCNs over a one-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Rostral BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Caudal tail BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.

Divergent Connectivity Changes in Gray Matter Structural Covariance Networks in Subjective Cognitive Decline, Amnestic Mild Cognitive Impairment, and Alzheimer’s Disease

Alzheimer’s disease (AD) has a long preclinical stage that can last for decades prior to progressing toward amnestic mild cognitive impairment (aMCI) and/or dementia. Subjective cognitive decline (SCD) is characterized by self-experienced memory decline without any evidence of objective cognitive decline and is regarded as the later stage of preclinical AD. It has been reported that the changes in structural covariance patterns are affected by AD pathology in the patients with AD and aMCI within the specific large-scale brain networks. However, the changes in structural covariance patterns including normal control (NC), SCD, aMCI, and AD are still poorly understood. In this study, we recruited 42 NCs, 35 individuals with SCD, 43 patients with aMCI, and 41 patients with AD. Gray matter (GM) volumes were extracted from 10 readily identifiable regions of interest involved in high-order cognitive function and AD-related dysfunctional structures. The volume values were used to predict the regional densities in the whole brain by using voxel-based statistical and multiple linear regression models. Decreased structural covariance and weakened connectivity strength were observed in individuals with SCD compared with NCs. Structural covariance networks (SCNs) seeding from the default mode network (DMN), salience network, subfields of the hippocampus, and cholinergic basal forebrain showed increased structural covariance at the early stage of AD (referring to aMCI) and decreased structural covariance at the dementia stage (referring to AD). Moreover, the SCN seeding from the executive control network (ECN) showed a linearly increased extent of the structural covariance during the early and dementia stages. The results suggest that changes in structural covariance patterns as the order of NC-SCD-aMCI-AD are divergent and dynamic, and support the structural disconnection hypothesis in individuals with SCD.

Target-specific control of olfactory bulb periglomerular cells by GABAergic and cholinergic basal forebrain inputs

The olfactory bulb (OB), the first relay for odor processing, receives dense GABAergic and cholinergic long-range projections from basal forebrain (BF) nuclei that provide information about the internal state and behavioral context of the animal. However, the targets, impact and dynamics of these afferents are still unclear. I studied how BF synaptic inputs modulate activity in diverse subtypes of periglomerular (PG) interneurons using optogenetic stimulation and loose cell-attached or whole-cell patch-clamp recording in OB slices from adult mice. GABAergic BF inputs potently blocked PG cells firing except in a minority of calretinin-expressing cells in which GABA release elicited spiking. Parallel cholinergic projections excited a previously overlooked PG cell subtype via synaptic activation of M1 muscarinic receptors. Low frequency stimulation of the cholinergic axons drove persistent firing in these PG cells thereby increasing tonic inhibition in principal neurons. Taken together, these findings suggest that modality-specific BF inputs can orchestrate inhibition in OB glomeruli using multiple, potentially independent, inhibitory or excitatory target-specific pathways.

Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia

A potential pathophysiological mechanism of cognitive difficulties in schizophrenia is a dysregulated cholinergic system. Particularly, the cholinergic basal forebrain nuclei (BFCN), the source of cortical cholinergic innervation, support multiple cognitive functions, ranging from attention to decision-making. We hypothesized that BFCN structural integrity is altered in schizophrenia and associated with patients’ attentional deficits. We assessed gray matter (GM) integrity of cytoarchitectonically defined BFCN region-of-interest in 72 patients with schizophrenia and 73 healthy controls, matched for age and gender, from the COBRE open-source database, via structural magnetic resonance imaging (MRI)–based volumetry. MRI-derived measures of GM integrity (i.e., volumes) were linked with performance on a symbol coding task (SCT), a paper-pencil-based metric that assesses attention, by correlation and mediation analysis. To assess the replicability of findings, we repeated the analyses in an independent dataset comprising 26 patients with schizophrenia and 24 matched healthy controls. BFCN volumes were lower in patients (t(139)=2.51, p = 0.01) and significantly associated with impaired SCT performance (r = 0.31, p = 0.01). Furthermore, lower BFCN volumes mediated the group difference in SCT performance. When including global GM volumes, which were lower in patients, as covariates-of-no-interest, these findings disappeared, indicating that schizophrenia did not have a specific effect on BFCN relative to other regional volume changes. We replicated these findings in the independent cohort, e.g., BFCN volumes were lower in patients and mediated patients’ impaired SCT performance. Results demonstrate lower BFCN volumes in schizophrenia, which link with patients’ attentional deficits. Data suggest that a dysregulated cholinergic system might contribute to cognitive difficulties in schizophrenia via impaired BFCN.