**5. Conclusion and future directions**

*Connectivity and Functional Specialization in the Brain*

the brain parenchyma.

pathology.

*4.2.3 Multiple sclerosis*

lesion formation.

secondary consequence [105].

Some authors have suggested that this spread could be through a hematogenous pathway [95]. Although PD patients in Braak stage 1 have their axon terminals outside the BBB, this same structure protects the somas of those axons, which reside in the central nervous system. Cerebrovascular disease also plays a part in PD, as both vascular disease and vascular risk factors aggravate motor and cognitive symptoms [96]. This may explain the BBB leakiness observed in these patients, as a recent study observed in the post-commissural putamen of PD patients, using histologic markers of serum protein, iron, and erythrocyte extravasation [97]. Regarding the extravasation of molecules through the cerebral vascular system, the histological analysis of PD patients reveals BBB breakdown in the striatum as shown by capillary leakages and accumulation of perivascular fibrinogen, immunoglobulins deposits, hemosiderin, red blood cells extravasation and leukocyte infiltration [98]. Increased BBB permeability and inducing inflammatory and necrotic processes in

In patients with PD, a dysregulation of the transport systems has also been observed in the BBB, recent studies reveal that α-syn crosses the BBB, which could signify an important contributory event in PD pathogenesis (neurodegeneration) [99]. The α-syn oligomers crossed the BBB into the brain, in parenchyma where α-syn amplification and strain-specific pathology and neurotoxic phenotypes. In the other hand, regarding the clearance of the α-syn, this molecule is capable of inhibiting Aβ efflux suggesting and the endothelial LRP1 is a only potential efflux transporter for α-syn, however, LRP1 is similarly downregulated in PD [100], this could result in impaired α-syn BBB clearance and accumulation in brain, suggesting that the high levels of α-syn produced peripherally can enter the brain in the presence of BBB breakdown, which may also contribute to development of PD

Multiple sclerosis (MS) is an autoimmune disease with an early BBB disruption pattern. One clear indication is the presence of Gadolinium-enhancing lesions on magnetic resonance, which translates in extravasation of intravascular contrast due to brain parenchyma and its associated active inflammation. Moreover, an increasing amount of evidence shows this disruption could not be restricted to Gd-enhancing lesions, as observed in non-enhancing areas in postmortem MS brains [101]. As the entry of inflammatory infiltrate occurs in the brain's perivascular regions, it is intuitive to think BBB disruption is very likely an early event in

There is also evidence of maladaptive changes in the NVU's components. One great example is ECs, which upregulate adhesion molecules and display chemokines on their luminal surface, to promote transcellular immune cell migration [102]. Also, in MS, TJ abnormalities can be seen, as one study observed abnormal ZO-1 at TJs in sections of primary progressive MS patients' cortical grey matter [101]. The BM in these patients' lesions also appears discontinuous. MRI studies have shown hypoperfusion in early and advanced stages of MS, suggesting the presence of metabolic injury in the brain parenchyma in a hypoxia-like fashion [103]. Regarding a primary BBB dysfunction, studies have focused on astrocytes and pericytes, whose maladaptive changes could explain the reduction in capillary blood flow and further hypoxia. D'haeseleer et al. observed that the hypoperfusion in MS could be mediated by astrocyte's released endothelin-1 (ET-1), as it can be normalized with an ET-1 antagonist [104]. This body of evidence conveys heterogeneous pathophysiology in MS, one that included BBB breakdown as a primary event and not only as a

**36**

The relevance of the NVU in the support of cerebral homeostasis of the BBB is being partly established with recent evidence. The multifactorial interactions between their components are extremely refined, expressing the complexity of the central CNS physiology. The knowledge of each of the components and their respective pathways are critical to understanding various neurovascular diseases, such as cerebrovascular injury (e.g. stroke) and neurological disorders (e.g. Alzheimer's). Although despite current knowledge, many questions about the role of each component NVU, pathways and crosstalking still have no answer. These advances have uncovered gaps in our knowledge of neurovascular health and have provided us with the roadmap to ask new questions that should be addressed by the future studies. Finally, based on the current state of our knowledge, it is probably time to think about BBB not only as an impermeable cellular membrane which protects brain from peripheral influences and should be breached for therapeutic CNS drug delivery, but also as an enormous source of understudied molecular and cellular targets in the pathophysiological states, which if explored could change the paradigm about brain diseases therapy and could lead to development of novel BBB-based personalized approaches to treat them.
