Tackling vascular risk factors as a possible disease modifying intervention in Parkinson’s disease

Abstract

The trialed treatment landscape of Parkinson’s disease (PD) is extensive, but up to now, there is no disease-modifying therapy. As the pathophysiology of PD becomes untangled further, new targets for intervention may arise. Substantial evidence points to alpha-synuclein as a possibly important pathogenic protein in this disease, making it a therapeutically interesting target . However, just as we have seen in the field of Alzheimer’s disease, where targeting the most prominent pathological deposits (amyloid) yielded disappointing results , the mechanisms contributing to neurodegeneration in PD are complex and extend well beyond alpha-synuclein aggregation. Indeed, several recent trials that specifically targeted alpha-synuclein showed no signs of a disease-modifying effect on either clinical scales or imaging outcomes , casting doubt on the viability of an anti-alpha-synuclein-only approach . The question arises whether targeting a single pathogenic target will ever be sufficient to modify the course of PD and whether a complementary, more multifaceted, and comprehensive therapeutic approach would be more effective. Here, we propose additional therapeutic options from a different angle, namely targeting risk factors that contribute to cerebral small vessel disease (SVD), including lacunar infarcts and white matter lesions. PD and SVD are both common conditions and their incidence increases with age. Importantly, SVD is commonly seen in neuroimaging in PD. Such vascular lesions may be identified during the first assessment in de novo patients, but appear more commonly later on in the course of the disease . Both the severity and progression of SVD have been independently associated with incident parkinsonism . When SVD is present in PD, it negatively impacts the clinical symptoms of PD. This includes a worsening of gait, cognition, and mood, and it may well be associated with a further hastening of the already progressive course of PD . The severity of SVD correlates with the Hoehn and Yahr motor score . Several disease mechanisms may underlie the interaction between SVD and PD. The first option is structural SVD lesions located in strategic brain regions, e.g. the basal ganglia. A second option is hypoperfusion in cerebral small vessels. Both of these mechanisms may result in widespread dysfunction of multiple brain pathways, including the disruption of dopaminergic and non-dopaminergic pathways involved in the pathophysiology of motor and non-motor symptoms in parkinsonism . Third, there is increasing evidence that the permeability of the blood–brain barrier is increased in SVD. Strikingly, alterations in the blood–brain barrier have also been observed in mesencephalic regions (including the substantia nigra) of patients with PD. This might represent a mechanistic link . Specifically, blood–brain barrier dysfunction disrupts astrocyte integrity, which impairs interstitial fluid exchange and decreases neuronal energy supply. It also stops oligodendrocyte precursor cells from maturation, which impairs the formation and repair of myelin and energy support to axons . Fourth, cerebral hypoperfusion could also induce alpha-synuclein aggregation leading to PD pathology with subsequent soluble alpha-synuclein depletion . We hypothesize that the course of PD might be slowed down by an individually tailored and multicomponent intervention, targeting vascular, and lifestyle-related risk factors for SVD. The optimal target group for such an intervention would be patients with PD and radiologically proven SVD (defined as small subcortical (lacunar) infarcts (of deep gray nuclei and deep white matter), microhemorrhages, diffuse white matter changes, and enlarged perivascular spaces). Possible target risk factors are diabetes mellitus, hypertension, dyslipidemia, overweight, unhealthy diet, physical inactivity, sleep apnea, and smoking (Table 1 ). A combined pharmacological and non-pharmacological approach could be used. Table 1 Risk factors for comorbid cerebral small vessel disease in Parkinson’s disease Full size table

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