Smaller Amygdala Subnuclei Volume in Schizophrenia Patients with Violent Behaviors

Objective To investigate the association between the volume of amygdala subnuclei and violent behaviors in patients with schizophrenia (SCZ). Methods In the present study, we recruited 40 SCZ patients with violent behaviors (VS), 26 SCZ patients without violent behaviors (NVS), and 28 matched healthy controls (HC) who completed T1-weighted magnetic resonance imaging. Both the total amygdala and amygdala subnuclei volumes were estimated with FreeSurfer. Results When comparing the whole SCZ patients with HC, SCZ patients had smaller volume of the left amygdala and the left basal nucleus. Further, the VS patients had smaller volume of the amygdala central nucleus as compared to the NVS group. Conclusions Our findings suggested that a smaller volume of the amygdala central nucleus might be relevant to violence risk in SCZ patients.

Cholinesterase Inhibitors Used for the Management of Alzheimer’s Disease: A Review

Alzheimer’s disease (AD) is defined as a progressive neurodegenerative disorder that has lately become the top reason for dementia in the elderly population (usually above 60-65 years). As mentioned before, most AD cases are sporadic and have a late onset. This disease is characterized by impairment of higher cognitive functions like deficits in memory, language comprehension, coordination, etc. The primary pathophysiology behind Alzheimer’s disease is loss of cholinergic innervation due to the formation of neuritic (senile) amyloid-beta plaques and tau protein-containing neurofibrillary tangles (NFTs) in parts of the brain associated with memory functions. These neurofibrillary tangles (NFTs) and amyloid β plaques can cause the induction of other aetiologies of Alzhedisease-likes like neuroinflammation and central hyperexcitability. The brain's main regions affected by Alzheimer’s disease are the neocortex, the basal nucleus of Meynert, and the hippocampus. These areas are associated with higher cognitive functions like memory, arousal, attention, sensory processing, etc. Thus, cholinesterase inhibitors have been widely used as first-line drug therapy for symptomatic relief in Alzheimer’s disease. They function by inhibiting acetylcholinesterase or catabolizing it and henceforth enhancing synaptic availability of Acetylcholine. The commonly prescribed drugs of this class include donepezil, galantamine, physostigmine, metrifonate, and rivastigmine. This article will discuss the widely used cholinesterase inhibitors (old & new) for managing AD symptoms in detail.

Correlation Between Amygdala Nuclei Volumes and Memory in Cognitively Normal Adults Carrying the ApoE ε3/ε3 Allele

The amygdala is known to be related to cognitive function. In this study, we used an automated approach to segment the amygdala into nine nuclei and evaluated amygdala and nuclei volumetric changes across the adult lifespan in subjects carrying the apolipoprotein E (ApoE) ε3/ε3 allele, and we related those changes to memory function alteration. We found that except the left medial nucleus (Me), whose volume decreased in the old group compared with the middle-early group, all other nuclei volumes presented a significant decline in the old group compared with the young group. Left accessory basal nucleus (AB) and left cortico-amygdaloid transition area (CAT) volumes were also diminished in the middle-late group. In addition, immediate memory recall is impaired by the process of aging, whereas delayed recall and delayed recognition memory functions were not significantly changed. We found significant positive correlations between immediate recall scores and volumes of the bilateral basal nucleus (Ba), AB, anterior amygdaloid area (AAA), CAT, whole amygdala, left lateral nucleus (La), left paralaminar nucleus (PL), and right cortical nucleus (Co). The results suggest that immediate recall memory decline might be associated with volumetric reduction of the amygdala and its nuclei, and the left AB and left CAT might be considered as potential imaging biomarkers of memory decline in aging.

Microcontact Printing of Cholinergic Neurons in Organotypic Brain Slices

Alzheimer's disease is a severe neurodegenerative disorder of the brain, characterized by beta-amyloid plaques, tau pathology, and cell death of cholinergic neurons, resulting in loss of memory. The reasons for the damage of the cholinergic neurons are not clear, but the nerve growth factor (NGF) is the most potent trophic factor to support the survival of these neurons. In the present study we aim to microprint NGF onto semipermeable 0.4 μm pore membranes and couple them with organotypic brain slices of the basal nucleus of Meynert and to characterize neuronal survival and axonal growth. The brain slices were prepared from postnatal day 10 wildtype mice (C57BL6), cultured on membranes for 2–6 weeks, stained, and characterized for choline acetyltransferase (ChAT). The NGF was microcontact printed in 28 lines, each with 35 μm width, 35 μm space between them, and with a length of 8 mm. As NGF alone could not be printed on the membranes, NGF was embedded into collagen hydrogels and the brain slices were placed at the center of the microprints and the cholinergic neurons that survived. The ChAT+ processes were found to grow along with the NGF microcontact prints, but cells also migrated. Within the brain slices, some form of re-organization along the NGF microcontact prints occurred, especially the glial fibrillary acidic protein (GFAP)+ astrocytes. In conclusion, we provided a novel innovative microcontact printing technique on semipermeable membranes which can be coupled with brain slices. Collagen was used as a loading substance and allowed the microcontact printing of nearly any protein of interest.

Anatomic survey of seeding in Alzheimer’s disease brains reveals unexpected patterns

Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The most common tauopathy, sporadic Alzheimer’s disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell–cell transfer of tau “seeds”, or assemblies, that serve as templates for their own replication. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology. We now expand this work to additional regions. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We measured tau seeding in each of the 500 samples using a cell-based tau “biosensor” assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We observed a progressive increase in tau seeding according to NFT stage. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. In conclusion, tau histopathology and seeding are complementary analytical tools. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD.

Amygdala Abnormalities Are Related to Anxiety in Patients With Sporadic Amyotrophic Lateral Sclerosis

To explore selective atrophy patterns and resting-state functional connection (FC) alterations in the amygdala at different stages of amyotrophic lateral sclerosis (ALS), and to determine any correlations between amygdala abnormalities and neuropsychiatric symptoms. We used the King’s clinical staging system for ALS to divide 83 consecutive patients with ALS into comparable subgroups at different disease stages. We investigated the pattern of selective amygdala subnucleus atrophy and analysed amygdala-based whole-brain FC analysis in the patients and 94 healthy controls (HCs). Cognitive and emotional functions were also evaluated using a neuropsychological test battery. There were no significant differences between King’s stage 1 ALS patients and HCs for any amygdala subnucleus volumes. Compared with HCs, King’s stage 2 patients had significantly lower left accessory basal nucleus and cortico-amygdaloid transition volumes after Bonferroni correction. Furthermore, after Bonferroni correction, King’s stage 3 patients demonstrated significant reductions in most subnucleus volumes as well as global amygdala volume compared with HCs. Notably, amygdala-based resting-state FC was unaltered in ALS patients until King’s stage 3. Specific subnucleus volumes were significantly associated with Mini-Mental State Examination scores and Hamilton Anxiety Rating Scale scores in ALS patients. In conclusions, our study provides a comprehensive profile of amygdala abnormalities in ALS patients. The pattern of amygdala abnormalities in ALS patients differed across King’s clinical disease stages, and our findings suggest that amygdala abnormalities are an important feature of patients with ALS. Moreover, amygdala volume may play an important role in anxiety and cognitive dysfunction in ALS patients.

Altered Functional Connectivity of the Basal Nucleus of Meynert in Subjective Cognitive Impairment, Early Mild Cognitive Impairment, and Late Mild Cognitive Impairment

Background: The spectrum of early Alzheimer's disease (AD) is thought to include subjective cognitive impairment, early mild cognitive impairment (eMCI), and late mild cognitive impairment (lMCI). Choline dysfunction affects the early progression of AD, in which the basal nucleus of Meynert (BNM) is primarily responsible for cortical cholinergic innervation. The aims of this study were to determine the abnormal patterns of BNM-functional connectivity (BNM-FC) in the preclinical AD spectrum (SCD, eMCI, and lMCI) and further explore the relationships between these alterations and neuropsychological measures.Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate FC based on a seed mask (BNM mask) in 28 healthy controls (HC), 30 SCD, 24 eMCI, and 25 lMCI patients. Furthermore, the relationship between altered FC and neurocognitive performance was examined by a correlation analysis. The receiver operating characteristic (ROC) curve of abnormal BNM-FC was used to specifically determine the classification ability to differentiate the early AD disease spectrum relative to HC (SCD and HC, eMCI and HC, lMCI and HC) and pairs of groups in the AD disease spectrum (eMCI and SCD, lMCI and SCD, eMCI and lMCI).Results: Compared with HC, SCD patients showed increased FC in the bilateral SMA and decreased FC in the bilateral cerebellum and middle frontal gyrus (MFG), eMCI patients showed significantly decreased FC in the bilateral precuneus, and lMCI individuals showed decreased FC in the right lingual gyrus. Compared with the SCD group, the eMCI group showed decreased FC in the right superior frontal gyrus (SFG), while the lMCI group showed decreased FC in the left middle temporal gyrus (MTG). Compared with the eMCI group, the lMCI group showed decreased FC in the right hippocampus. Interestingly, abnormal FC was associated with certain cognitive domains and functions including episodic memory, executive function, information processing speed, and visuospatial function in the disease groups. BNM-FC of SFG in distinguishing eMCI from SCD; BNM-FC of MTG in distinguishing lMCI from SCD; BNM-FC of the MTG, hippocampus, and cerebellum in distinguishing SCD from HC; and BNM-FC of the hippocampus and MFG in distinguishing eMCI from lMCI have high sensitivity and specificity.Conclusions: The abnormal BNM-FC patterns can characterize the early disease spectrum of AD (SCD, eMCI, and lMCI) and are closely related to the cognitive domains. These new and reliable findings will provide a new perspective in identifying the early disease spectrum of AD and further strengthen the role of cholinergic theory in AD.

The Altered Anatomical Distribution of ACE2 in the Brain With Alzheimer’s Disease Pathology

The whole world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through angiotensin-converting enzyme 2 (ACE2). Neurological manifestations in COVID-19 patients suggested the invasion of SARS-CoV-2 into the central nervous system. The present study mapped the expression level of ACE2 in 12 brain regions through immunohistochemistry and detected ACE2 in endothelial cells and non-vascular cells. The comparison among brain regions found that pons, visual cortex, and amygdala presented a relatively high level of ACE2. In addition, this study demonstrates that the protein level of ACE2 was downregulated in the basal nucleus, hippocampus and entorhinal cortex, middle frontal gyrus, visual cortex, and amygdala of the brain with Alzheimer’s disease (AD) pathology. Collectively, our results suggested that ACE2 was expressed discriminatorily at different human brain regions, which was downregulated in the brain with AD pathology. This may contribute to a comprehensive understanding of the neurological symptoms caused by SARS-CoV-2 and provide clues for further research on the relationship between COVID-19 and AD.

Cortical granularity shapes information flow to the amygdala and its striatal targets in nonhuman primate

The prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala and also the scope of amygdalo-striatal efferents, including projections beyond the 'classic' ventral striatum. To further interrogate this triad and define the 'limbic (amygdala-recipient) striatum', we conducted tract tracing studies in two cohorts of primates to define the scope of cortico-amygdalo-striatal (indirect) and cortico-'limbic' striatal (direct) paths originating in the entire PFC and insula. With larger data sets and a quantitative approach, we found that the level of cortical granularity predicts the complexity and location of projections to both the amygdala and striatum. Remarkably, 'cortical-like' basal nucleus subdivisions also followed these rules in their projections to the striatum. In both 'direct' and 'indirect' paths to the 'limbic' striatum, agranular cortices formed a 'foundational', broad projection, and were joined by inputs from progressively more differentiated cortices. In amygdalo-striatal paths, the ventral basal nucleus was the 'foundational' input, with progressively more dorsal basal nucleus regions gradually adding inputs as the 'limbic striatum' extended caudally. Together, the 'indirect' and 'direct' paths follow consistent rules dictating projection strength and complexity to their targets. In the 'indirect' path, the agranular 'interoceptive' cortices consistently dominate amygdala inputs to the striatum. In contrast, 'direct' cortical inputs to the 'limbic' (amygdala-recipient) striatum create gradual shifts in connectivity fingerprints to provide clues to functional differences in the classic versus caudal ventral 'limbic' striatum.

Volumetric trajectories of hippocampal subfields and amygdala nuclei influenced by adolescent alcohol use and lifetime trauma

Alcohol use and exposure to psychological trauma frequently co-occur in adolescence and share many risk factors. Both exposures have deleterious effects on the brain during this sensitive developmental period, particularly on the hippocampus and amygdala. However, very little is known about the individual and interactive effects of trauma and alcohol exposure and their specific effects on functionally distinct substructures within the adolescent hippocampus and amygdala. Adolescents from a large longitudinal sample (N = 803, 2684 scans, 51% female, and 75% White/Caucasian) ranging in age from 12 to 21 years were interviewed about exposure to traumatic events at their baseline evaluation. Assessments for alcohol use and structural magnetic resonance imaging scans were completed at baseline and repeated annually to examine neurodevelopmental trajectories. Hippocampal and amygdala subregions were segmented using Freesurfer v6.0 tools, followed by volumetric analysis with generalized additive mixed models. Longitudinal statistical models examined the effects of cumulative lifetime trauma measured at baseline and alcohol use measured annually on trajectories of hippocampal and amygdala subregions, while controlling for covariates known to impact brain development. Greater alcohol use, quantified using the Cahalan scale and measured annually, was associated with smaller whole hippocampus (β = −12.0, pFDR = 0.009) and left hippocampus tail volumes (β = −1.2, pFDR = 0.048), and larger right CA3 head (β = 0.4, pFDR = 0.027) and left subiculum (β = 0.7, pFDR = 0.046) volumes of the hippocampus. In the amygdala, greater alcohol use was associated with larger right basal nucleus volume (β = 1.3, pFDR = 0.040). The effect of traumatic life events measured at baseline was associated with larger right CA3 head volume (β = 1.3, pFDR = 0.041) in the hippocampus. We observed an interaction between baseline trauma and within-person age change where younger adolescents with greater trauma exposure at baseline had smaller left hippocampal subfield volumes in the subiculum (β = 0.3, pFDR = 0.029) and molecular layer HP head (β = 0.3, pFDR = 0.041). The interaction also revealed that older adolescents with greater trauma exposure at baseline had larger right amygdala nucleus volume in the paralaminar nucleus (β = 0.1, pFDR = 0.045), yet smaller whole amygdala volume overall (β = −3.7, pFDR = 0.003). Lastly, we observed an interaction between alcohol use and baseline trauma such that adolescents who reported greater alcohol use with greater baseline trauma showed smaller right hippocampal subfield volumes in the CA1 head (β = −1.1, pFDR = 0.011) and hippocampal head (β = −2.6, pFDR = 0.025), yet larger whole hippocampus volume overall (β = 10.0, pFDR = 0.032). Cumulative lifetime trauma measured at baseline and alcohol use measured annually interact to affect the volume and trajectory of hippocampal and amygdala substructures (measured via structural MRI annually), regions that are essential for emotion regulation and memory. Our findings demonstrate the value of examining these substructures and support the hypothesis that the amygdala and hippocampus are not homogeneous brain regions.