Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence.

BACKGROUND: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. METHODS: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. RESULTS: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). CONCLUSIONS: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

Histochemical and immunohistochemical study on muscle fibers in human extraocular muscle spindles.

Human extraocular muscles are unique in several ways including their endowment with proprioceptive organs. Aim of this study was to establish a classification of intrafusal muscle fibers of human extraocular muscles based on their histochemical and immunohistochemical properties and to determine their relationship to extrafusal extraocular muscle fiber types in this respect. Using light microscopy, intrafusal muscle fibers were followed on consecutive cross-sections and classified according to the localization of their myonuclei and to their enzyme- and myosin-immunohistochemical characteristics. Sixteen muscle spindles in human extraocular muscles counted as 'true' spindles revealed 27% nuclear chain fibers [40.1 microm+/-10.4; perimeter+/-SD] and 73% anomalous fibers [44.1 microm+/-12]. Seven 'false' muscle spindles showed only anomalous fibers [43.8 microm+/-11.1] and entirely lacked nuclear chain fibers. Six fiber types were distinguished according to their histochemical and myosin heavy chain immunohistochemical properties. Fiber type 1 [46.3 microm+/-13.3] was made up of fast-twitch myosin heavy chain isoform. Fiber type 2 [39.5 microm+/-10] additionally expressed a developmental myosin heavy chain isoform. Fiber type 3 [42.8 microm+/-10.4] consisted of pure slow-twitch positive muscle fibers. Slow-twitch MHC and fast-twitch myosin heavy chain isoform were found in fiber type 4 [43.3 microm+/-9]. Fiber types 5 and 6 showed different myosin heavy chain patterns than fiber types 1-4. The vast majority of nuclear chain fibers displayed fiber type 2 features, but 12% of nuclear chain fibers were found to be of fiber type 1. Among anomalous fibers in true spindles the frequency of fiber type 1 was much higher than in false spindles. On the other hand, fiber type 4 was found more often in false than in true spindles. With regard to their histochemical and immunohistochemical properties intrafusal muscle fibers in human extraocular muscles differ both from intrafusal muscle fibers in other skeletal muscles and from extrafusal muscle fibers in extraocular eye muscles. These conspicuous differences to skeletal muscle spindles relate to their morphology and myosin heavy chain characteristics. In particular, the occurrence of anomalous fibers might reflect dynamic neuronal processes and might be necessary for modulating and adapting processes in advancing age, as well as maintaining proprioceptive input during the whole life.

Twitch and nontwitch motoneuron subgroups in the oculomotor nucleus of monkeys receive different afferent projections.

Motoneurons in the primate oculomotor nucleus can be divided into two categories, those supplying twitch muscle fibers and those supplying nontwitch muscle fibers. Recent studies have shown that twitch motoneurons lie within the classical oculomotor nucleus (nIII), and nontwitch motoneurons lie around the borders. Nontwitch motoneurons of medial and inferior rectus are in the C group dorsomedial to nIII, whereas those of inferior oblique and superior rectus lie near the midline are in the S group. In this anatomical study, afferents to the twitch and nontwitch subgroups of nIII have been anterogradely labeled by injections of tritiated leucine into three areas and compared. 1) Abducens nucleus injections gave rise to silver grain deposits over all medial rectus subgroups, both twitch and nontwitch. 2) Laterally placed vestibular complex injections that included the central superior vestibular nucleus labeled projections only in twitch motoneuron subgroups. However, injections into the parvocellular medial vestibular nucleus (mvp), or Y group, resulted in labeled terminals over both twitch and nontwitch motoneurons. 3) Pretectal injections that included the nucleus of the optic tract (NOT), and the olivary pretectal nucleus (OLN), labeled terminals only over nontwitch motoneurons, in the contralateral C group and in the S group. Our study demonstrates that twitch and nontwitch motoneuron subgroups do not receive identical afferent inputs. They can be controlled either in parallel, or independently, suggesting that they have basically different functions. We propose that twitch motoneurons primarily drive eye movements and nontwitch motoneurons the tonic muscle activity, as in gaze holding and vergence, possibly involving a proprioceptive feedback system.