Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, is viewed as a ...relatively pure form of AD with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), and vascular brain injury (VBI) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z = 3.00, p = 0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p = 0.33; LBD: 49% versus 42%, p = 0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p = 0.02). In contrast, LATE (35% versus 8%, p < 0.001), HS (15% versus 3%, p = 0.02), AGD (58% versus 41%, p = 0.052), and VBI (65% versus 39%, p = 0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI -2.5, -0.2) and Clinical Dementia Rating - Sum of Boxes (1.15 point/pathology, 95%CI 0.45, 1.84), across the EOAD and the LOAD cohorts. The effect of sex on the number of copathologies was not significant (p = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of copathologies (+0.40, 95%CI 0.01, 0.79, p = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to men, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.
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.
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.
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 specifically social stimuli, and is likely rooted in part in abnormalities of frontostriatal circuitry. Recent research has demonstrated that selective ablation of striatal cholinergic interneurons (SCINs) results in significant increases in compulsive conspecific‐directed, but not object‐focused, exploratory behavior in mice, indicating a role for SCINs in social approach behavior. Here, we examined the density of SCINs and parvalbumin‐positive interneurons in the striatum of five postmortem specimens from subjects with WS and five typically‐developing (TD) subjects. We found a significant reduction in the density of SCINs in the medial caudate nucleus, an important region receiving cortical projections from the orbitofrontal and ventromedial prefrontal cortex in circuitry involved in language and reward systems. This pattern of decreased SCIN density in WS is contrasted by anatomical findings in other disorders, including Tourette syndrome and schizophrenia, where differing patterns of SCIN depletion are found. Taken together with findings from neuroimaging, differences in the brains of individuals with WS at both the macro‐ and microstructural level further indicate a role for frontostriatal circuitry in the disorder's distinctive behavioral phenotype.
Support or Funding Information
This research is supported in part by NIH #P01NICHD033113, #1R03MH103697‐01(KS), and a Wenner Gren Dissertation Fieldwork Grant (KLH).
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
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