Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis

Abstract

The deep and periventricular white matter is preferentially affected in several neurological disorders, including cerebral small vessel disease (SVD) and multiple sclerosis (MS), suggesting that common pathogenic mechanisms may be involved in this injury. Here we consider the potential pathogenic role of tissue hypoxia in lesion development, arising partly from the vascular anatomy of the affected white matter. Specifically, these regions are supplied by a sparse vasculature fed by long, narrow end arteries/arterioles that are vulnerable to oxygen desaturation if perfusion is reduced (as in SVD, MS and diabetes) or if the surrounding tissue is hypoxic (as in MS, at least). The oxygen crisis is exacerbated by a local preponderance of veins, as these can become highly desaturated 'sinks' for oxygen that deplete it from surrounding tissues. Additional haemodynamic deficiencies, including sluggish flow and impaired vasomotor reactivity and vessel compliance, further exacerbate oxygen insufficiency. The cells most vulnerable to hypoxic damage, including oligodendrocytes, die first, resulting in demyelination. Indeed, in preclinical models, demyelination is prevented if adequate oxygenation is maintained by raising inspired oxygen concentrations. In agreement with this interpretation, there is a predilection of lesions for the anterior and occipital horns of the lateral ventricles, namely regions located at arterial watersheds, or border zones, known to be especially susceptible to hypoperfusion and hypoxia. Finally, mitochondrial dysfunction due to genetic causes, as occurs in leucodystrophies or due to free radical damage, as occurs in MS, will compound any energy insufficiency resulting from hypoxia. Viewing lesion formation from the standpoint of tissue oxygenation not only reveals that lesion distribution is partly predictable, but may also inform new therapeutic strategies.

Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

“…It has been uncertain whether the reduced perfusion is a physiological response to reduced demand, or whether the reduced perfusion may be causing functional and structural damage, but the evidence that the perfusion deficits are associated with reduced cortical oxygenation indicates that the mismatch between perfusion (oxygen delivery) and oxygen demand is, therefore, responsible for causing damage. The perfusion deficits may expose vulnerable niches in the brain to such severe hypoxia that the local oligodendrocytes die, resulting in pattern III demyelination . The evidence for hypoxia in MS is in agreement with earlier results from microarray and immunohistochemical studies .…”

“…To the best of our knowledge, this is the first study examining perfusion within the spinal cord in rats with EAE, and it has revealed that the expression of neurological deficit is closely related to hypoperfusion of the spinal cord, and that remission from functional deficits is accompanied by improved perfusion. Hypoperfusion is well established in MS with delayed arterial bolus arrival time, increased mean vascular transit time, and long circulation time . It has been uncertain whether the reduced perfusion is a physiological response to reduced demand, or whether the reduced perfusion may be causing functional and structural damage, but the evidence that the perfusion deficits are associated with reduced cortical oxygenation indicates that the mismatch between perfusion (oxygen delivery) and oxygen demand is, therefore, responsible for causing damage.…”

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part III: Oligodendrocyte and Myelin

“…In regard to the transitional zone between cortical grey and white matter, the subcortical white matter may represent a region in the brain that is less vascularized [15][16][17]. Interestingly, our observational findings regarding vascularity in the cortex revealed that there are usually 2-4 neurovascular units (NVU) capillaries per grid examined and in the transitional zone described there was usually only one NVU capillary at the most with a preponderance of no NVU capillaries per grid examined.…”

Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis?

“…At some point—often around age 40–50—the clinical phenotype may transition to a progressive phase, 64–67 during which further mechanisms, over and above focal inflammatory demyelination, contribute to disease evolution. 68 69 These include mitochondrial dysfunction, 68 hypoxia, 70 iron accumulation 68 and fibrogen deposition, 71 and contribute to amplify neurodegeneration, 68 72 particularly in late-stage disease or older patients, where inflammation is less prominent 53 73 and neuronal loss seems to be relatively independent from demyelination. 10 …”

“…Although the association between vascular disease and MS is not fully understood, it is possible that vascular risk factors 94 95 or vascular pathology can cause additional damage to the brains of people with MS, over and above that caused by MS alone. 70 96 97 Although this needs further confirmation, information about patients’ vascular status should be incorporated into clinical trials. MS is a heterogeneous disease, and at the individual level the time to reach the secondary progressive phase is variable.…”