The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Parvalbumin neurons in the entorhinal cortex of subjects diagnosed with bipolar disorder or schizophrenia.

BACKGROUND: Growing evidence indicates that the entorhinal cortex (ECx) might be affected in schizophrenia (SZ) and bipolar disorder (BD). To test whether distinct interneuronal subpopulations might be altered, numbers of parvalbumin-immunoreactive (PVB-IR) neurons were measured in the ECx of BD and SZ subjects. These neurons play a pivotal role within ECx intrinsic circuits. METHODS: Numbers, numerical density, and soma size of PVB-IR neurons were measured in the ECx of normal control (n = 16), BD (n = 10), and SZ (n = 10) subjects. The volume of the ECx was measured in Nissl-stained sections. RESULTS: In BD, decreases of total numbers (p = .02) and numerical densities (p = .01) of PVB-IR neurons were detected in the ECx. Within distinct subregions, reductions were detected in the superficial layers of the lateral (p = .02), intermediate (p = .04), and caudal (p = .01) ECx. In SZ, total numbers and numerical densities were not altered. A reduction of soma size was present in the intermediate ECx (p = .01). Volume was unaffected in either disorder. CONCLUSIONS: In BD, a decrease of PVB-IR neurons may alter intrinsic inhibitory networks within the superficial layers of the ECx. The likely consequence is a disruption of integration and transfer of information from the cerebral cortex to the hippocampus.     

The neurochemistry of Alzheimer's disease

Our knowledge of the neurochemical pathology of AD has increased immensely the last years. Although it is now clear that mutations in the APP gene can cause some rare hereditary forms of AD, and that ApoE4 is a prominent risk factor for AD, we at present know little about the underlying cause of AD in the general population and the biochemical mechanisms by which the apolipoprotein E4 isoform affects AD pathogenesis. It is hoped that the near future will see a resolution of the current controversies in AD research, including: 1) whether APP mutations cause Alzheimer's disease by affecting Aβ deposition or the function of APP itself; 2) whether abnormal phosphorylation of tau is a central pathogenetic event, or whether it occurs as epiphenomena that reflect general neurodegeneration in a variety of disease processes; 3) Whether Aβ deposition in the brain is the central event in AD or whether it occurs as epiphenomena in a variety of brain disorders such as head trauma; and 4) whether altered tau phosphorylation occurs secondary to Aβ deposition or vice versa, and what the link is (if any) between the two processes.     

The St. George's dementia bed investigation study: a comparison of clinical and pathological diagnosis.

Sixty-four elderly patients who had been admitted to the St. George's Hospital Alzheimer's disease evaluation project during 1981-1989 were followed up to postmortem examination. Comparison between clinical diagnoses and neuropathological diagnoses indicated positive predictive values for the antemortem diagnoses of 50-67%. Existing clinical criteria may not be accurate enough to permit firm antemortem diagnosis of older people for either research or clinical purposes.     

Electron-cytochemical investigation of the brain mitochondria at various times after death

An electron-cytochemical investigation was made of oxidation of 3,3-diaminobenzidine (DAB) in the brain of rats and man at different times after death. The oxidation product of DAB was localized in the mitochondria, lipofuscin granules, and erythrocytes. Oxidation of DAB by rat and human brain mitochondria was shown to be only very slightly depressed even 2 days after death.Laboratory of Experimental Pathology and Pathomorphology of the Brain, Institute of Psychiatry, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. V. Snezhnevskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 6, pp. 757–759, June, 1976.     

Postmortem Stability of SARS-CoV-2 in Nasopharyngeal Mucosa

Analyses of infection chains have demonstrated that severe acute respiratory syndrome coronavirus 2 is highly transmissive. However, data on postmortem stability and infectivity are lacking. Our finding of nasopharyngeal viral RNA stability in 79 corpses showed no time-dependent decrease. Maintained infectivity is supported by virus isolation up to 35 hours postmortem.     

生前与死后伤的区别——用免疫组化法检测损伤组织中的免疫球蛋白G

目的 :研究损伤组织中的免疫球蛋白 G(Ig G)的分布以区别生前与死后伤。方法 :卵白素—生物素过氧化物酶复合物技术 (ABC法 ) ,直接用辣根过氧化物酶标记单一特异性抗体 (直接法 )检测人体生前与死后损伤皮肤组织中的 Ig G。结果 :生前损伤标本均阳性 ,死后损伤标本均阴性。应用本方法可以检测极短时间 (<1 0 min)内死亡的生前伤。钝器伤 Ig G阳性反应分布范围比锐器伤广。结论 :应用 ABC法、直接法的免疫组化技术检测人体损伤皮肤组织中的 Ig G比较简便 ,该方法适用基层推广应用。     

Optimization and pharmacological characterization of receptor‐mediated Gi/o activation in postmortem human prefrontal cortex

The biochemical abnormalities in transmembrane signal transduction mediated through G protein‐coupled receptors (GPCRs) have been postulated as underlying pathophysiology of psychiatric diseases such as schizophrenia and mood disorders. In the present study, the experimental conditions of agonist‐induced [³⁵S]GTPγS binding in postmortem human brain membranes were optimized, and the responses induced by a series of agonists were pharmacologically characterized. The [³⁵S]GTPγS binding assay was performed in postmortem human prefrontal cortical membranes by means of filtration techniques, and standardized as to GDP concentration, membrane protein content, MgCl₂ and NaCl concentrations in assay buffer, incubation period and effect of white matter contamination. Under the standard assay conditions, the specific [³⁵S]GTPγS binding was stimulated by the addition of 15 compounds in a concentration‐dependent manner. Of these agonists, R(+)‐8‐OH‐DPAT, UK‐14,304, DAMGO and DPDPE showed apparently biphasic concentration‐response curves. As for these four responses, only higher‐potency site was pharmacologically characterized. The receptors involved in the responses investigated were 5‐HT_1A receptor (probed with R(+)‐8‐OH‐DPAT or 5‐HT), α_2A‐adrenoceptor (UK‐14,304 or (?)‐epinephrine), M₂/M₄ mAChRs (carbachol), adenosine A₁ receptor (adenosine), histamine H₃ receptor (histamine), group II mGlu (l ‐glutamate), GABA_B receptor (baclofen), μ‐opioid receptor (DAMGO or endomophin‐1), δ‐opioid receptor (DPDPE or SNC‐80) and NOP (nociceptin). Although dopamine also activated specific [³⁵S]GTPγS binding, this response was likely mediated via α_2A‐adrenoceptor, but not dopamine receptor subtypes. The present study provides us with fundamental aspects of the strategy for elucidation of probable abnormalities of neural signalling mediated by G proteins activated through multiple GPCRs in the brain of psychiatric patients.