CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis.

Multiple sclerosis (MS) is characterized by heterogeneity in disease course and prediction of long-term outcome remains a major challenge. Here, we investigate five myeloid markers - CHIT1, CHI3L1, sTREM2, GPNMB and CCL18 - in the cerebrospinal fluid (CSF) at diagnostic lumbar puncture in a longitudinal cohort of 192 MS patients. Through mixed-effects and machine learning models, we show that CHIT1 is a robust predictor for faster disability progression. Integrative analysis of 11 CSF and 26 central nervous system (CNS) parenchyma single-cell/nucleus RNA sequencing samples reveals CHIT1 to be predominantly expressed by microglia located in active MS lesions and enriched for lipid metabolism pathways. Furthermore, we find CHIT1 expression to accompany the transition from a homeostatic towards a more activated, MS-associated cell state in microglia. Neuropathological evaluation in post-mortem tissue from 12 MS patients confirms CHIT1 production by lipid-laden phagocytes in actively demyelinating lesions, already in early disease stages. Altogether, we provide a rationale for CHIT1 as an early biomarker for faster disability progression in MS.

Optical coherence tomography as a prognostic tool for disability progression in MS: a systematic review.

Since multiple sclerosis (MS) is characterized by an unpredictable disease course, accurate prognosis and personalized treatment constitute an important challenge in clinical practice. We performed a qualitative systematic review to assess the predictive value of retinal layer measurement by spectral-domain optical coherence tomography (SD-OCT) in MS patients. Longitudinal MS cohort studies that determined the risk of clinical deterioration based on peripapillary retinal nerve fiber layer (pRNFL) and/or macular ganglion cell-inner plexiform layer (mGCIPL) atrophy were included. Our search strategy and selection process yielded eight articles in total. Of those, five studies only focused on patients with a relapsing-remitting disease pattern (RRMS). After correction for confounders such as disease duration, we found that (1) cross-sectional measurement of pRNFL thickness ≤ 88 µm; (2) cross-sectional measurement of mGCIPL thickness < 77 µm; (3) longitudinal measurement of pRNFL thinning > 1.5 µm/year; and (4) longitudinal measurement of mGCIPL thinning ≥ 1.0 µm/year is associated with an increased risk for disability progression in subsequent years. Longitudinal mGCIPL assessment consistently resulted in the highest risk estimates in our analysis. Within these studies, inclusion and exclusion criteria accounted for the retinal degeneration inherent to (acute) optic neuritis (ON). This small systematic review provides additional evidence that OCT-measured pRNFL and/or mGCIPL atrophy can predict disability progression in RRMS patients. We therefore recommend close clinical follow-up or initiation/change of treatment in RRMS patients with increased risk for clinical deterioration based on retinal layer thresholds, in particular when other poor prognostic signs co-occur.

The temporoinsular projection system: an anatomical study.

OBJECTIVE: Connections between the insular cortex and the amygdaloid complex have been demonstrated using various techniques. Although functionally well connected, the precise anatomical substrate through which the amygdaloid complex and the insula are wired remains unknown. In 1960, Klingler briefly described the "fasciculus amygdaloinsularis," a white matter tract connecting the posterior insula with the amygdala. The existence of such a fasciculus seems likely but has not been firmly established, and the reported literature does not include a thorough description and documentation of its anatomy. In this fiber dissection study the authors sought to elucidate the pathway connecting the insular cortex and the mesial temporal lobe. METHODS: Fourteen brain specimens obtained at routine autopsy were dissected according to Klingler's fiber dissection technique. After fixation and freezing, anatomical dissections were performed in a stepwise progressive fashion. RESULTS: The insula is connected with the opercula of the frontal, parietal, and temporal lobes through the extreme capsule, which represents a network of short association fibers. At the limen insulae, white matter fibers from the extreme capsule converge and loop around the uncinate fasciculus toward the temporal pole and the mesial temporal lobe, including the amygdaloid complex. CONCLUSIONS: The insula and the mesial temporal lobe are directly connected through white matter fibers in the extreme capsule, resulting in the appearance of a single amygdaloinsular fasciculus. This apparent fasciculus is part of the broader network of short association fibers of the extreme capsule, which connects the entire insular cortex with the temporal pole and the amygdaloid complex. The authors propose the term "temporoinsular projection system" (TIPS) for this complex.

White matter tract anatomy in the rhesus monkey: a fiber dissection study.

Brain connectivity in non-human primates (NHPs) has been mainly investigated using tracer techniques and functional connectivity studies. Data on structural connections are scarce and come from diffusion tensor imaging (DTI), since gross anatomical white matter dissection studies in the NHP are lacking. The current study aims to illustrate the course and topography of the major white matter tracts in the macaque using Klingler's fiber dissection. 10 hemispheres obtained from 5 primate brains (Macaca mulatta) were studied according to Klingler's fiber dissection technique. Dissection was performed in a stepwise mesial and lateral fashion exposing the course and topography of the major white matter bundles. Major white matter tracts in the NHP include the corona radiata, tracts of the sagittal stratum, the uncinate fasciculus, the cingulum and the fornix. Callosal fiber topography was homologous to the human brain with leg motor fibers running in the posterior half of the corpus callosum. The relative size of the anterior commissure was larger in the NHP. NHPs and humans share striking homologies with regard to the course and topography of the major white matter tracts.