Thalamus Is a Prime Target for Neurodegeneration in MS, Study Suggests

In patients with multiple sclerosis (MS), degeneration of thalamic projections and/or a neurodegenerative process appears to make a greater contribution to thalamic atrophy than thalamic demyelinating lesions, according to Kedar Mahajan, MD, PhD, a neurologist in Cleveland Clinic’s Department of Neurosciences and Mellen Center for MS Treatment and Research.

He and Cleveland Clinic colleagues conducted postmortem in situ MRI studies in 95 subjects with MS and compared thalamic lesion volume with pathologic examination findings identifying thalamic demyelination and microglial/macrophage activation. Results were published in the Annals of Neurology (2020 Apr 14 [Epub ahead of print]).

“Thalamic atrophy is one of the earliest brain changes seen in patients with MS and is associated with cognitive impairment, physical disability and fatigue,” Dr. Mahajan reports. “In addition, the extent of atrophy is correlated with progression of disability, which makes it a potential marker for neurodegeneration.”

The investigators made several key findings:

• Thalamic lesions were detected in the majority of the postmortem cohort: 68% upon examination of tissue slices and 98% by MRI.
• Immunohistochemistry revealed several distinct patterns of demyelination. “We were most impressed by a pattern of demyelination in the subependymal region of the brain, where there appeared to be considerably more damage to axons and neurons than we could observe around perivascular lesions,” says Dr. Mahajan. This pattern of demyelination is not well recognized and could be caused by inflammatory factors within the cerebrospinal fluid.
• When comparing cases with the most thalamic volume to the least, the team found that there were significantly fewer neurons present than could be accounted for by differences in volume. “This suggests that neurons were being lost out of proportion to the observed volume,” Dr. Mahajan notes.
• Extensive analyses of MRI measures were correlated with thalamic volume after adjusting for age, sex, disease duration and race, revealing that the lesion burden throughout the brain correlated better with thalamic volume than did the number of lesions found just within the thalamus.

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Figure 1. The left panels show an MRI of a subject with a sizeable thalamic lesion measuring 1.4 cm3 and a thalamic volume of 18.4 cm3. The expected thalamic volume for the subject’s age is 18.0 cm3, which suggests that even large thalamic lesions do not necessarily correlate with thalamic volume. The right panel shows staining of tissue from the same subject for myelin with proteolipid protein. The demyelinated lesion is outlined in green.

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Figure 2. The left MRI is from a subject with one of the greatest thalamic volumes in the study (16.6 cm3), whereas the right MRI is from a subject with one of the lowest thalamic volumes (10.2 cm3) — a 1.6-fold difference. The white matter lesion burden was 2.5-fold higher in the subject on the right versus the one on the left (57.6 vs. 23.4). The white outlines indicate the borders of the thalamus in each subject.

“Our findings suggest that the thalamus is a particular target for neurodegeneration, which is likely because of its extensive connectivity to the rest of the brain,” Dr. Mahajan says. “Axons injured by any number of lesions throughout the brain have a greater likelihood of tracking back to the thalamus compared with other structures.”

Brain donation program yields singular insights

One of the most notable aspects of this study was its use of the Cleveland Clinic MS Rapid Brain Donation Program, to which patients with MS have elected to donate tissue after death for use in neuroscience research.

“Although there are a few other MS brain donation programs in the world, ours is unique because of its extensive 24/7/365 collaboration among departments — including our Imaging Institute, Mellen Center and Departments of Pathology, Biomedical Engineering and Neurosciences — and its rapid tissue processing using multiple techniques for high-quality research,” says Dr. Mahajan.

Clinical implications

The relationship between lesions and neurodegeneration is of particular interest in MS. Current highly efficacious MS therapies work well in stopping new and enlarging lesions, but they do not help with neurodegeneration directly. The results of the current study suggest that stopping disease activity in early MS by using effective therapies, followed by monitoring with MRI and adjusting therapies if breakthrough activity occurs, will likely impact neurodegeneration by limiting overall lesion burden. Measures such as whole brain and thalamic volumes have seen increasing use in clinical trials in the past few years because of their correlation with neuroperformance measures such as walking speed, manual dexterity, cognition, mood and fatigue.

“Our work supports the involvement of structures such as the thalamus in MS, and we are currently exploring the relationship of individual thalamic subregions with clinical disability,” says Dr. Mahajan. “The hope is that therapeutics may emerge in the not-too-distant future that could repair and decrease the extent of injury within lesions and be ‘neuroprotective,’” he explains, adding that having MRI measures in place to capture neurodegeneration along with lesion volumes will aid in evaluating the efficacy of such therapeutics.