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

Cholinergic Pathway SNPs and Postural Control in 477 Older Adults

Objective: To determine whether single nucleotide polymorphisms (SNPs) of the cholinergic system and quantitative parameters of postural control are associated in healthy older adults. This is a cross-sectional analysis from the TREND study.Methods: All participants performed a static postural control task for 30 s on a foam pad in semitandem stance and eyes closed. We analyzed mean power frequency (MPF), area, acceleration, jerk, and velocity from a mobile sensor worn at the lower back using a validated algorithm. Genotypes of four SNPs in genes involved in the cholinergic system (SLC5A7, CHAT, BCHE, CHRNA4) were extracted from the NeuroX chip. All participants present a normal neurological examination and a Minimental state examination score >24.Results: Four hundred and seventy seven participants were included. Mean age was 69 years, 41% were female. One SNP of the cholinergic pathway was significantly associated with a quantitative postural control parameter. The minor allele of rs6542746 in SLC5A7 was associated with lower MPF (4.04 vs. 4.22 Hz; p = 3.91 × 10-4). Moreover, the following associations showed trends toward significance: minor allele of rs6542746 in SLC5A7 with higher anteroposterior acceleration (318 vs. 287 mG; p = 0.005), and minor allele of rs3810950 in CHAT with higher mediolateral acceleration [1.77 vs. 1.65 log(mG); p = 0.03] and velocity [1.83 vs. 1.74 log(mm/s); p = 0.019]. Intraindividual occurrence of rs6542746 and rs3810950 minor alleles was dose-dependently related with lower MPF (p = 0.004).Conclusion: This observational study suggests an influence of SNPs of the cholinergic pathway on postural control in older adults

Recent Advances in Cholinergic Imaging and Cognitive Decline—Revisiting the Cholinergic Hypothesis of Dementia

Purpose of Review Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Recent Findings Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning, and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson’s disease. Summary The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration

Cognitive efficiency in late midlife is linked to lifestyle characteristics and allostatic load

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process

Clinical Characteristics and Neuroanatomical Predictors of Acute Antidepressant Outcome for Patients with Comorbid Depression and Mild Cognitive Impairment

Background: Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. The classification of cognitive impairment severity continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Previous studies have found associations between treatment outcome and both cortical thickness and white matter hyperintensities (WMH), though report inconsistent directionality and affected regions. In this study, we examined baseline clinical characteristics and neuroanatomical features as prognostic indicators for older adults with comorbid DEP and CI participating in an open antidepressant trial. EMCI is hypothesized to have greater cortical thickness and global cognition than LMCI. Antidepressant treatment remitters and responders are hypothesized to have greater cortical thickness and lower WMH burden than non-remitters and non-responders. Methods: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HDRS) score \u3e14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. All patients underwent a baseline MRI scan and received open antidepressant treatment for 8 weeks. Cortical thickness was extracted using an automated brain segmentation and reconstruction program (FreeSurfer). Vertex-wise analyses were conducted using general linear models to evaluate the relationships between cortical thickness and clinical variables. Results: 79 DEP-CI patients were recruited, of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9 and mean HDRS was 23.0. LMCI patients had significantly worse global cognition and smaller right hippocampal volume compared to EMCI patients. EMCI patients had thicker right medial orbitofrontal cortex than LMCI. MRI indices of cerebrovascular disease did not differ between MCI subtypes. Remitters had greater deep WMH burden, left medial orbitofrontal gyrus thickness, and right superior frontal gyrus thickness than non-remitters. Greater HDRS depressive severity was positively correlated with right pars triangularis thickness. Stronger ADAS-Cog global cognitive performance was positively correlated with thickness in diffuse cortical areas. Conclusions: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer’s disease. Samples of DEP-CI exhibit unique patterns of cortical thickness and WMHs compared to their non-CI peers. Cortical thickness may serve as predictor of treatment remission and relates to both depressive severity and global cognition

Η επίδραση μιας πρώιμης εμπειρίας στο χολινεργικό σύστημα του επίμυ

Oι πρώιμες εμπειρίες, δηλαδή οι εμπειρίες κατά τα πρώτα στάδια της μεταγεννητικής ζωής, έχουν μεγάλη αξία για τη διαμόρφωση της συμπεριφοράς του ατόμου. Στις λειτουργίες μνήμης, μάθησης και προσοχής παίζουν λειτουργικό ρόλο περιοχές όπως ο προμετωπιαίος φλοιός, ο ιππόκαμπος και η αμυγδαλή. Στο εργαστήριο Βιολογίας/Βιοχημείας αναπτύχθηκε η δοκιμασία λαβυρίνθου σχήματος «Ταυ» κατά τη νεογνική ζωή, η οποία φαίνεται να επηρεάζει τις γνωστικές λειτουργίες των επίμυων. Στόχος της παρούσας διατριβής μεταπτυχιακού διπλώματος εξειδίκευσης ήταν η εξέταση της επίδρασης της δοκιμασίας λαβυρίνθου σχήματος Τ, μιας πρώιμης εμπειρίας ανταμοιβής ή παρεμπόδισης λήψης ανταμοιβής στο χολινεργικό σύστημα του επίμυ. Για το σκοπό αυτό εξετάστηκε η λειτουργία των ενζύμων σύνθεσης και αποικοδόμησης του νευροδιαβιβαστή ακετυλοχολίνη (χολινοακετυλοτρανσφεράση- ChAT και ακετυλοχολινεστεράση- AChE). Στο σύμπλεγμα «Μέσο διάφραγμα - Κάθετο σκέλος της διαγώνιας ταινίας του Broca » και στην περιοχή του οριζόντιου σκέλους της διαγώνιας ταινίας του Broca ανιχνεύθηκε σημαντική διαφορά μεταξύ των πειραματικών μας ομάδων για τον αριθμό των ανοσοθετικών κυττάρων για το ένζυμο ChAT. Αναφορικά με το ένζυμο AChE ανιχνεύθηκε μείωση στον έξω βασικό αμυγδαλικό πυρήνα στην ομάδα DER. Συνεπώς, τα δεδομένα της παρούσας έρευνας υποστηρίζουν την υπόθεση ότι η εκπαίδευση κατά την νεογνική ηλικία υπό συνθήκες άρνησης ή λήψης της αναμενόμενης επαφής με τη μητέρα, στον λαβύρινθο Τ, οδηγεί σε μακροχρόνιες αλλαγές στο μεταιχμιακό σύστημα του εγκεφάλου και πιο συγκεκριμένα στο βασικό πρόσθιο χολινεργικό σύστημα αυτού.Objectives: The nervous system is a very sensitive system for early life experiences. We studied the basal forebrain cholinergic system (BFCS) in adult male rats, in order to test whether the T-maze learning experience (a novel early experience developed in our lab) affects the cholinergic system, which participates in cognitive functions, including attention, learning and memory. Methods: Rat pups learn a T-maze during postnatal days 10-13 and either recieve the expected reward withough maternal contact (RER group) or are denied this reard (DER group). We determined immunohistochemically the levels of the synthesizing and degrading enzymes of acetylcholine, Choline-Acetyl-Transferase (ChAT) and Acetyl-Cholinesterase (AChE) in the primary cholinergic regions of the (BFCS). Results: The number of ChAT positive cells was significantly reduced in DER animals at the complex of MS-VDB (medial septum- vertical limb of the diagonal band of Broca) and HDB (horizontal limb of the diagonal band of Broca) compared to both controls and RER animals. Regarding the AChE activity, we did not detect any significant differences with the exception of the basolateral nucleus of amygdala (BLA) of the DER group, in comparison to both RER and control groups. Conclusions: The findings of the present study support the hypothesis that training in a T- maze task at the neonatal period under denial or receipt of expected reward through maternal contact leads to long-term changes in the mesolimbic circuit of the brain, especially in the BFCS, which may result in behavioral changes even in adult life

The integrity of the cholinergic system determines memory performance in healthy elderly

The cholinergic system plays a central role in episodic memory-related processes in health and disease. Cerebral acetylcholinesterase (AChE) activity, a measure of the integrity of the cholinergic system, can be assessed in vivo using positron emission tomography (PET) and [11C]N-methyl-4-piperidyl acetate (MP4A). A close relationship between the kinetic constant k3 of MP4A and mnestic functions has been demonstrated for patients suffering from amnestic mild cognitive impairment and Alzheimer's disease. Under the hypothesis that AChE activity and memory are intimately linked in older age, we obtained MP4A-PET and structural magnetic resonance images as well as neuropsychological data from fourteen healthy older adults. Multiple regression analysis revealed that AChE activity in areas previously implicated in mnestic functions predicted episodic memory performance irrespective of cortical atrophy. Data suggest that in older adults the integrity of the cholinergic system underlies inter-individual variability in memory function

EFFECTS OF ESTRADIOL AND SELECTIVE ESTROGEN RECEPTOR AGONISTS ON BIOCHEMICAL ENDPOINTS IN THE BRAIN: A COMPARISON BETWEEN TRANSITIONAL AND SURGICAL MENOPAUSE RAT MODELS

Women spend the last third of their lifetime postmenopause, with cessation of ovarian activity and diminished production of systemic estrogen. The loss of ovarian estrogen production is correlated with age-related cognitive decline, dementia and a shift in brain metabolism from glucose to ketone bodies. Estrogen treatment may prevent or reverse these changes. Our goal is to understand how the loss of ovarian function and estrogen replacement therapy affect metabolism and function of brain regions that are involved in cognitive functions. In this study, we evaluated the differences between surgical (ovariectomized, OVX) to transitional (ovatotoxin-treated, 4-vinylcyclohexene diepoxide, VCD) menopause rat models in comparison to normally cycling rats and with agonists treatments for the selective activation of estrogen receptor α (ERα), ERβ and G-protein coupled estrogen receptor 1 (GPER-1). Our endpoints were chosen to represent pivotal targets in major metabolic, energy, cytoskletal and neurological pathways which are modulated by estrogens with corresponding effects on neuronal or cognitive functions. Overall these studies established a highly reliable method to relatively quantify proteins in brain homogenates, a direct comparison of metabolic endpoints between OVX, VCD and cycling animals as well as the effects of ER agonists between OVX and VCD rats in two time points of continuous treatment (1- and 6- weeks) and three brain regions: hippocampus (HPC), frontal cortex (FCX) and striatum (STR). These studies illustrates that type and onset of menopause have versatile impact on brain metabolism, glucose utilization, cytoskeletal and cholinergic endpoints. We also demonstrated the differences in response to selective activation of different estrogen receptors and provided an insight into changes that occur in across duration of treatment, menopause models and treatments with selective estrogen receptor agonists. These can serve as a pre-clinical map for the development of more selective estrogen replacement therapy for postmenopausal women