Intrinsic and Extrinsic Mechanisms of Thalamic Pathology in Multiple Sclerosis.

OBJECTIVE: Thalamic atrophy is among the earliest brain changes detected in patients with multiple sclerosis (MS) and the degree of thalamic atrophy is a strong predictor of disability progression. The causes of thalamic atrophy are not fully understood. Here, we investigate the contributions of thalamic demyelinated lesions, thalamic neuronal loss, and cerebral white matter (WM) lesions to thalamic volume. METHODS: We used postmortem in situ magnetic resonance imaging (MRI) scans of 95 subjects with MS to correlate thalamic lesion volumes with global MRI metrics. We histologically characterized thalamic demyelination patterns and compared neuronal loss and neuritic pathology in the thalami with the extremes of volume. RESULTS: Grossly apparent thalamic discolorations in cm-thick brain slices were T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1-hypointense, and appeared as perivascular demyelinated lesions with dystrophic neurons/axons. Subependymal demyelinated lesions with axonal loss and microglial/macrophage activation were also observed. The 12 subjects with the least thalamic volume had a 17.6% reduction of median neuronal density in the dorsomedial/ventrolateral and pulvinar nuclei compared with the 14 subjects with the greatest thalamic volume (p = 0.03). After correcting for age, disease duration, sex, and T2 lesion volume, the total (p = 0.20), ovoid (p = 0.31), or subependymal (p = 0.44) MRI thalamic lesion volumes correlated with thalamic volume. Thalamic volume correlated with cerebral T2 lesion volume (Spearman's rho = -0.65, p < 0.001; p < 0.0001 after correcting for age, disease duration, and sex). INTERPRETATION: Our findings suggest the degeneration of efferent/afferent thalamic projections and/or a neurodegenerative process as greater contributors to thalamic atrophy than thalamic demyelinating lesions. ANN NEUROL 2020 ANN NEUROL 2020;88:81-92.

The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis.

BACKGROUND: Episodic memory loss is one of the most common cognitive symptoms in patients with multiple sclerosis (MS), but the pathophysiology of this symptom remains unclear. Both the hippocampus and thalamus have been implicated in episodic memory and show regional atrophy in patients with MS. OBJECTIVE: In this work, we used functional magnetic resonance imaging (fMRI) during a verbal episodic memory task, lesion load, and volumetric measures of the hippocampus and thalamus to assess the relative contributions to verbal and visual-spatial episodic memory. METHODS: Functional activation, lesion load, and volumetric measures from 32 patients with MS and 16 healthy controls were used in a predictive analysis of episodic memory function. RESULTS: After adjusting for disease duration, immediate recall performance on a visual-spatial episodic memory task was significantly predicted by hippocampal volume ( p < 0.003). Delayed recall on the same task was significantly predicted by volume of the left thalamus ( p < 0.003). For both memory measures, functional activation of the thalamus during encoding was more predictive than that of volume measures ( p < 0.002). CONCLUSION: Our results suggest that functional activation may be useful as a predictive measure of episodic memory loss in patients with MS.

Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4.

Intraperitoneal injection of the Gram-negative bacterial endotoxin lipopolysaccharide (LPS) elicits a rapid innate immune response. While this systemic inflammatory response can be destructive, tolerable low doses of LPS render the brain transiently resistant to subsequent injuries. However, the mechanism by which microglia respond to LPS stimulation and participate in subsequent neuroprotection has not been documented. In this study, we first established a novel LPS treatment paradigm where mice were injected intraperitoneally with 1.0 mg/kg LPS for four consecutive days to globally activate CNS microglia. By using a reciprocal bone marrow transplantation procedure between wild-type and Toll-like receptor 4 (TLR4) mutant mice, we demonstrated that the presence of LPS receptor (TLR4) is not required on hematogenous immune cells but is required on cells that are not replaced by bone marrow transplantation, such as vascular endothelia and microglia, to transduce microglial activation and neuroprotection. Furthermore, we showed that activated microglia physically ensheathe cortical projection neurons, which have reduced axosomatic inhibitory synapses from the neuronal perikarya. In line with previous reports that inhibitory synapse reduction protects neurons from degeneration and injury, we show here that neuronal cell death and lesion volumes are significantly reduced in LPS-treated animals following experimental brain injury. Together, our results suggest that activated microglia participate in neuroprotection and that this neuroprotection is likely achieved through reduction of inhibitory axosomatic synapses. The therapeutic significance of these findings rests not only in identifying neuroprotective functions of microglia, but also in establishing the CNS location of TLR4 activation.