Patterns of neuronal Rhes as a novel hallmark of tauopathies.

The farnesyltransferase inhibitor, Lonafarnib, reduces tau inclusions and associated atrophy in familial tauopathy models through activation of autophagy, mediated by the inhibition of farnesylation of the Ras GTPase, Rhes. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tauopathy. We examined histological slides of allocortex and neocortex from multiple postmortem cases in five different tauopathies, FTLD-TDP, and healthy controls using immunofluorescence for Rhes, several tau post-translational modifications, and phospho-TDP-43. Single nucleus RNA data suggest that Rhes is found in all cortical neuron subpopulations but not in glia. Histologic investigation showed that nearly all neurons in control brains display a pattern of diffuse cytoplasmic Rhes positivity. However, in the presence of abnormal tau, but not abnormal TDP-43, the patterns of neuronal cytoplasmic Rhes tend to present as either punctiform or entirely absent. This observation reinforces the relevance of findings that link Rhes changes and tau pathology from the in vivo and in vitro models of tauopathy. The results here support a potential clinical application of Lonafarnib to tauopathies.

Serotonergic innervation of the human amygdala and evolutionary implications.

OBJECTIVES: The serotonergic system is involved in the regulation of socio-emotional behavior and heavily innervates the amygdala, a key structure of social brain circuitry. We quantified serotonergic axon density of the four major nuclei of the amygdala in humans, and examined our results in light of previously published data sets in chimpanzees and bonobos. MATERIALS AND METHODS: Formalin-fixed postmortem tissue sections of the amygdala from six humans were stained for serotonin transporter (SERT) utilizing immunohistochemistry. SERT-immunoreactive (ir) axon fiber density in the lateral, basal, accessory basal, and central nuclei of the amygdala was quantified using unbiased stereology. Nonparametric statistical analyses were employed to examine differences in SERT-ir axon density between amygdaloid nuclei within humans, as well as differences between humans and previously published data in chimpanzees and bonobos. RESULTS: Humans displayed a unique pattern of serotonergic innervation of the amygdala, and SERT-ir axon density was significantly greater in the central nucleus compared to the lateral nucleus. SERT-ir axon density was significantly greater in humans compared to chimpanzees in the basal, accessory basal, and central nuclei. SERT-ir axon density was greater in humans compared to bonobos in the accessory basal and central nuclei. CONCLUSIONS: The human pattern of SERT-ir axon distribution in the amygdala complements the redistribution of neurons in the amygdala in human evolution. The present findings suggest that differential serotonergic modulation of cognitive and autonomic pathways in the amygdala in humans, bonobos, and chimpanzees may contribute to species-level differences in social behavior.

Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases.

Importance: Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena. Objectives: To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP). Design, Setting, and Participants: This longitudinal cohort study enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals from the Memory and Aging Center of the University of California, San Francisco, between August 22, 2008, and December 31, 2020. Participants received electroencephalographic and polysomnographic sleep assessments. Postmortem neuronal analyses of brainstem hypothalamic wake-promoting neurons were performed and were included in the clinicopathological correlation analysis. No eligible participants were excluded from the study. Exposures: Electroencephalographic and polysomnographic assessment of sleep and postmortem immunohistological stereological analysis of 3 wake-promoting nuclei (noradrenergic locus coeruleus [LC], orexinergic lateral hypothalamic area [LHA], and histaminergic tuberomammillary nucleus [TMN]). Main Outcomes and Measures: Nocturnal sleep variables, including total sleep time, sleep maintenance, rapid eye movement (REM) latency, and time spent in REM sleep and stages 1, 2, and 3 of non-REM (NREM1, NREM2, and NREM3, respectively) sleep, and wake after sleep onset. Neurotransmitter, tau, and total neuronal counts of LC, LHA, and TMN. Results: Among 19 patients included in the clinicopathological correlation analysis, the mean (SD) age at death was 70.53 (7.75) years; 10 patients (52.6%) were female; and all patients were White. After adjusting for primary diagnosis, age, sex, and time between sleep analyses and death, greater numbers of LHA and TMN neurons were correlated with decreased homeostatic sleep drive, as observed by less total sleep time (LHA: r = -0.63; P = .009; TMN: r = -0.62; P = .008), lower sleep maintenance (LHA: r = -0.85; P < .001; TMN: r = -0.78; P < .001), and greater percentage of wake after sleep onset (LHA: r = 0.85; P < .001; TMN: r = 0.78; P < .001). In addition, greater numbers of LHA and TMN neurons were correlated with less NREM2 sleep (LHA: r = -0.76; P < .001; TMN: r = -0.73; P < .001). A greater number of TMN neurons was also correlated with less REM sleep (r = -0.61; P = .01). A greater number of LC neurons was mainly correlated with less total sleep time (r = -0.68; P = .008) and greater REM latency (r = 0.71; P = .006). The AD-predominant group had significantly greater sleep drive, including higher total sleep time (mean [SD], 0.49 [1.18] vs -1.09 [1.37]; P = .03), higher sleep maintenance (mean [SD], 0.18 [1.22] vs -1.53 [1.78]; P = .02), and lower percentage of wake after sleep onset during sleep period time (mean [SD], -0.18 [1.20] vs 1.49 [1.72]; P = .02) than the PSP-predominant group based on unbiased k-means clustering and principal component analyses. Conclusions and Relevance: In this cohort study, subcortical wake-promoting neurons were significantly correlated with sleep phenotypes in patients with AD and PSP, suggesting that the loss of wake-promoting neurons among patients with neurodegenerative conditions may disturb the control of sleep-wake homeostasis. These findings suggest that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases.

Tau-driven degeneration of sleep- and wake-regulating neurons in Alzheimer's disease.

Disturbances of the sleep/wake cycle in Alzheimer's disease (AD) are common, frequently precede cognitive decline, and tend to worsen with disease progression. Sleep is critical to the maintenance of homeostatic and circadian function, and chronic sleep disturbances have significant cognitive and physical health consequences that likely exacerbate disease severity. Sleep-wake cycles are regulated by neuromodulatory centers located in the brainstem, the hypothalamus, and the basal forebrain, many of which are vulnerable to the accumulation of abnormal protein deposits associated with neurodegenerative conditions. In AD, while sleep disturbances are commonly attributed to the accumulation of amyloid beta, patients often first experience sleep issues prior to the appearance of amyloid beta plaques, on a timeline that more closely corresponds to the first appearance of abnormal tau neurofibrillary tangles in sleep/wake regulating areas of the brainstem. Sleep disturbances also occur in pure tauopathies, providing further support that tau is a major contributor. Here, we provide an overview of the neuroanatomy of sleep/wake centers discovered in animal models, and review the evidence that tau-driven neuropathology is a primary driver of sleep disturbance in AD.

Decreased density of cholinergic interneurons in striatal territories in Williams syndrome.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25-28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.

Decreased Neuron Density and Increased Glia Density in the Ventromedial Prefrontal Cortex (Brodmann Area 25) in Williams Syndrome.

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25⁻28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS.

A postmortem stereological study of the amygdala in Williams syndrome.

Perturbations to the amygdala have been observed in neurological disorders characterized by abnormalities in social behavior, such as autism and schizophrenia. Here, we quantitatively examined the amygdala in the postmortem human brains of male and female individuals diagnosed with Williams Syndrome (WS), a neurodevelopmental disorder caused by a well-defined deletion of ~ 26 genes, and accompanied by a consistent behavioral profile that includes profound hypersociability. Using unbiased stereological sampling, we estimated nucleus volume, number of neurons, neuron density, and neuron soma area in four major amygdaloid nuclei- the lateral nucleus, basal nucleus, accessory basal nucleus, and central nucleus- in a sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. Boundaries of the four nuclei examined were drawn on Nissl-stained coronal sections as four separate regions of interest for data collection. We found that the lateral nucleus contains significantly more neurons in WS compared to TD. WS and TD do not demonstrate significant differences in neuron number in the basal, accessory basal, or central nuclei, and there are no significant differences between WS and TD in nuclei volume, neuron density, and neuron soma area in any of the four nuclei. A similarly designed study reported a decrease in lateral nucleus neuron number in autism, mirroring the opposing extremes of the two disorders in the social domain. These results suggest that the number of neurons in the lateral nucleus may contribute to pathological disturbances in amygdala function and sociobehavioral phenotype.

Increased glia density in the caudate nucleus in williams syndrome: Implications for frontostriatal dysfunction in autism.

Williams syndrome (WS) is a rare neurodevelopmental disorder with a well-described, known genetic etiology. In contrast to Autism Spectrum Disorders (ASD), WS has a unique phenotype characterized by global reductions in IQ and visuospatial ability, with relatively preserved language function, enhanced reactivity to social stimuli and music, and an unusual eagerness to interact socially with strangers. A duplication of the deleted region in WS has been implicated in a subset of ASD cases, defining a spectrum of genetic and behavioral variation at this locus defined by these opposite extremes in social behavior. The hypersociability characteristic of WS may be linked to abnormalities of frontostriatal circuitry that manifest as deficits in inhibitory control of behavior. Here, we examined the density of neurons and glia in associative and limbic territories of the striatum including the caudate, putamen, and nucleus accumbens regions in Nissl stained sections in five pairs of age, sex, and hemisphere-matched WS and typically-developing control (TD) subjects. In contrast to what is reported in ASD, no significant increase in overall neuron density was observed in this study. However, we found a significant increase in the density of glia in the dorsal caudate nucleus, and in the ratio of glia to neurons in the dorsal and medial caudate nucleus in WS, accompanied by a significant increase in density of oligodendrocytes in the medial caudate nucleus. These cellular abnormalities may underlie reduced frontostriatal activity observed in WS, with implications for understanding altered connectivity and function in ASD. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 531-545, 2018.

Neuron density is decreased in the prefrontal cortex in Williams syndrome.

Williams Syndrome (WS) is a rare neurodevelopmental disorder associated with a hemideletion in chromosome 7, which manifests a distinct behavioral phenotype characterized by a hyperaffiliative social drive, in striking contrast to the social avoidance behaviors that are common in Autism Spectrum Disorder (ASD). MRI studies have observed structural and functional abnormalities in WS cortex, including the prefrontal cortex (PFC), a region implicated in social cognition. This study utilizes the Bellugi Williams Syndrome Brain Collection, a unique resource that comprises the largest WS postmortem brain collection in existence, and is the first to quantitatively examine WS PFC cytoarchitecture. We measured neuron density in layers II/III and V/VI of five cortical areas: PFC areas BA 10 and BA 11, primary motor BA 4, primary somatosensory BA 3, and visual area BA 18 in six matched pairs of WS and typically developing (TD) controls. Neuron density in PFC was lower in WS relative to TD, with layers V/VI demonstrating the largest decrease in density, reaching statistical significance in BA 10. In contrast, BA 3 and BA 18 demonstrated a higher density in WS compared to TD, although this difference was not statistically significant. Neuron density in BA 4 was similar in WS and TD. While other cortical areas were altered in WS, prefrontal areas appeared to be most affected. Neuron density is also altered in the PFC of individuals with ASD. Together these findings suggest that the PFC is targeted in neurodevelopmental disorders associated with sociobehavioral alterations. Autism Res 2017, 10: 99-112. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Basal Dendritic Morphology of Cortical Pyramidal Neurons in Williams Syndrome: Prefrontal Cortex and Beyond.

Williams syndrome (WS) is a unique neurodevelopmental disorder with a specific behavioral and cognitive profile, which includes hyperaffiliative behavior, poor social judgment, and lack of social inhibition. Here we examined the morphology of basal dendrites on pyramidal neurons in the cortex of two rare adult subjects with WS. Specifically, we examined two areas in the prefrontal cortex (PFC)-the frontal pole (Brodmann area 10) and the orbitofrontal cortex (Brodmann area 11)-and three areas in the motor, sensory, and visual cortex (BA 4, BA 3-1-2, BA 18). The findings suggest that the morphology of basal dendrites on the pyramidal neurons is altered in the cortex of WS, with differences that were layer-specific, more prominent in PFC areas, and displayed an overall pattern of dendritic organization that differentiates WS from other disorders. In particular, and unlike what was expected based on typically developing brains, basal dendrites in the two PFC areas did not display longer and more branched dendrites compared to motor, sensory and visual areas. Moreover, dendritic branching, dendritic length, and the number of dendritic spines differed little within PFC and between the central executive region (BA 10) and BA 11 that is part of the orbitofrontal region involved into emotional processing. In contrast, the relationship between the degree of neuronal branching in supra- versus infra-granular layers was spared in WS. Although this study utilized tissue held in formalin for a prolonged period of time and the number of neurons available for analysis was limited, our findings indicate that WS cortex, similar to that in other neurodevelopmental disorders such as Down syndrome, Rett syndrome, Fragile X, and idiopathic autism, has altered morphology of basal dendrites on pyramidal neurons, which appears more prominent in selected areas of the PFC. Results were examined from developmental perspectives and discussed in the context of other neurodevelopmental disorders. We have proposed hypotheses for further investigations of morphological changes on basal dendrites in WS, a syndrome of particular interest given its unique social and cognitive phenotype.