Structural and Functional Brain Changes beyond Visual System in Patients with Advanced Glaucoma

 

A major characteristic of glaucomatous degeneration is the loss of RGCs and their axons, which leads to progressive blindness. However, some MRI studies show that neural abnormalities in glaucoma are not limited to the RGCs and are more extensive, extending to the entire visual pathway.

Histological evidence of neurodegeneration of the visual system in experimental glaucoma supports in-vivo MRI data and suggests that MRI-derived findings could reflect the extent of neuroaxonal damage along the entire visual system.

Frezzotti et al., have performed MRI studies and assessed across the whole brain: i) changes in microstructural integrity of white matter (WM) tracts by tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) measures, ii) structural changes in grey matter (GM) volume by VBM-style analysis, iii) functional connectivity (FC) changes of brain networks by resting-fMRI, and iv) how brain changes could be related to visual impairment. The study found changes such as reduced microstructural integrity of the optic radiations, decreased volume of the visual cortex, and altered FC of the visual network.

TBSS analysis of DTI diffusivities confirmed the presence of an altered integrity of the WM tracts in POAG patients with respect to normal controls (NC). Such abnormalities were present along the visual pathway, but also beyond the visual pathway, namely in the middle cerebellar peduncle, posterior limb of the internal capsule mapping on the corticospinal tract, anterior thalamic radiation on the right, and superior longitudinal fascicle (SLF).

In several distinct brain regions GM volume was lower in POAG patients than in NC. Patients also showed GM volume decrease in the cerebellum on the left, temporal lobe (hippocampus bilaterally), frontal lobe (fronto-orbital cortex, subcallosal cortex and frontal pole on the left) and parietal lobe (superior parietal lobule on the right, postcentral gyrus on the left).

POAG patients had lower FC in an extrastriate region of the visual network (lingual gyrus on the right) in the working memory network (superior frontal gyrus on the left supramarginal gyrus and LOC on the right) and in the dorsal attention network (LOC bilaterally, pre- and postcentral gyrus on the left).

POAG patients had higher FC than NC in the visual network (LOC bilaterally and temporo-occipital fusiform cortex on the left) and in the medial part of the executive network (superior frontal gyrus, parancigulate gyrus and anterior cingulate).

GM atrophy was found in the most anterior and medial parts of the visual cortex (anterior lingual gyrus), and also in the most posterior and lateral regions (LOC). Another recent study has found reduced cortical thickness in primary and secondary visual cortex in a heterogeneous group of POAG patients.

Other WM tracts and cortical GM regions that are not part of the typical visual pathway, such as the anterior thalamic radiation, corticospinal tract and middle cerebellar peduncle were also found altered in POAG patients in Frezzotti’s study.

POAG patients showed GM atrophy in regions involved in cognitive processing such as the hippocampus (memory), fronto-orbital cortex (decision-making) and superior parietal lobule (spatial orientation).

In addition to brain structural abnormalities, POAG patients also had functional connectivity changes in different resting state networks (RSNs). In patients with severe impairment of visual field, decreased FC in visual and working memory networks could be interpreted as due to maladaptation, thus contributing to clinical deficits.

The findings of widespread brain abnormalities observed in the present study delineate POAG as a more complex disorder than classically thought, capable of involving, at least in advanced stages, unanticipated brain structures and functions.

Therefore, glaucoma could be interpreted as the expression of a complex neurodegenerative process at cerebral level. The diffuse involvement of different distinct structures and functions could be an expression of the spread of neurodegeneration, similarly to what is found in typical neurodegenerative conditions such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease.

There is evidence indicating a close link between glaucoma and neurodegenerative conditions on the basis of the similarities in the loss of selective neuron populations, in the trans-synaptic disease spreading from injured neurons to connected and distant neurons, and in the common mechanisms of apoptosis, including oxidative injury, glutamate excitotoxicity and abnormal protein accumulation.

The prevalence of glaucoma was found to be much higher in different cohorts of patients with Alzheimer disease than in NC and this was independent from the IOP values.

By using a multimodal MRI approach, this exploratory study demonstrates that patients with advanced POAG have structural and functional changes that go well beyond the visual system, suggesting that POAG can be considered a vision disorder falling within the group of neurodegenerative disorders and, as such, spreading throughout the brain.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105931