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]. The trouble is that in the neurological literature, vascular parkinsonism, or VaP, has been taken to mean any progressive slowness of gait (“lower-body parkinsonism”) in the context of just about any increased signal on brain MRI (“vascular”) and, as enshrined in the 2004 Zijlmans’ Possible Criteria for the Clinical Diagnosis of Vascular Parkinsonism [
Never mind that these three pillars of the Ziljmans' criteria were created from clinico-pathologic data of only 17 patients, 12 of whom had nigral cell loss indicative of neurodegenerative parkinsonism (9 meeting criteria for Parkinson's disease, 2 multiple system atrophy, and 1 progressive supranuclear palsy). Collectively, these cases demonstrated no regional specificity: the severity of microscopic small-vessel disease did not differ between frontal, temporal, parietal, occipital, and striatal regions. More importantly, the criteria could be met with just about any clinical presentation: (1) with acute, delayed, or insidious onset; (2) with uni- or bilateral parkinsonism; (3) with focal or diffuse lesions; and (4) with strategic or non-strategic lesions [
]. Matsusue and colleagues subsequently confirmed that hyperintense periventricular lesions on brain MRI are often misattributed to small-vessel ischemic disease because of the absence of pathological correlation with microangiopathy [
]. This has explained a well-known paradox that a neuroimaging-reliant diagnosis of VaP could not resolve: extensive basal ganglia hyperintensities can be present in normal or asymptomatic individuals [
], and without a specific pathological pattern, struggling with the fundamental contradiction that large infarcts in the territory of the lenticulostriate arteries, the most paradigmatic of all strategic vascular injuries, are only rarely complicated with parkinsonism [
]. Is there a greater indictment to a vascular syndrome than the observation that the imaging hyperintensities which define it, regardless of burden or distribution, bear no associations with hypertension, diabetes, previous stroke, cardiac disease, cigarette smoking, or serum levels of cholesterol and triglycerides? [
As VaP may be neither vascular in etiology nor parkinsonian in phenotype, every clinical study of this entity must be interpreted with caution. In this issue of Parkinsonism and Related Disorders, Don Gueu Park and colleagues retrospectively reviewed the records of 63 of their VaP cases, with an additional selection criterion: a normal 18F-FP-CIT PET dopamine transporter (DAT) scan [
]. Using a semi-quantitative visual rating system, Park and colleagues found that the signal hyperintensities in the deep white matter and periventricular regions, but not of the basal ganglia or infratentorial regions, correlated with motor severity, as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). When comorbidities were entered into the model, type 2 diabetes significantly increased motor scores compared with non-diabetics and, in multivariate analysis, correlated with motor severity in patients with hyperintensities in the periventricular region but not in the other three regions. The authors concluded that periventricular hyperintensities and diabetes are independently associated with motor severity in VaP with normal DAT imaging.
Let's start from the comorbidity angle. It is well established that diabetes worsens any phenotype with which it coexists. If one assembles a cohort of rheumatoid arthritis patients and compares it to an arthritis cohort without diabetes, the diabetes-plus-arthritis cohort will appear worse than the arthritis-alone cohort. There is probably a reference for this, but I just didn't bother looking it up. Clinicians would be far more interested in any observation suggesting that the addition of one disorder to another makes the combination better, not worse (e.g., Parkinson's disease patients with gout exhibit a slower progression than those without [
]). In general, people with two or more pathologies are worse than those with only one.
But what is the implication of this report? That VaP has been explicitly accepted as a “DAT-negative parkinsonism.” The authors do not mention how many of their VaP diagnoses had a positive DAT scan. The assumption is that such a group may be rare, precluding the ability to compare their DAT-positive to their DAT-negative patients. I suspect, however, that most clinicians would rethink the working diagnosis of VaP in the context of a positive DAT scan –instead of creating a dual VaP-plus-neurodegenerative parkinsonism category, as proposed by Rektor and colleagues [
Here are the fundamental conceptual problems with VaP, which make the results of any studies on this construct hard to translate into clinical care:
Slowness does not necessarily mean Parkinsonism. The wide-based, short-stepped gait with freezing episodes described in patients with VaP and normal pressure hydrocephalus (NPH), with which it can be phenotypically indistinguishable, suggest a higher-level gait disorder of “cautious/disequilibrium” type (what our forebears described as apraxic or magnetic gait), a cognitive rather than a parkinsonian semiology [
]. In fact, if VaP were the manifestation of ischemic microangiopathy, clinicians would steer efforts into addressing any underlying hypertension, hypercholesterolemia, or hypercoagulability disorders. But there is no such evidence. A recent review on VaP management does not even include one sentence about the value of searching, let alone modifying vascular risk factors [
], yet most patients continue to progress insidiously, regardless of antiplatelet prophylaxis, cholesterol-lowering agents, or antihypertensive strategies.
Until more sophisticated imaging studies can uncover the underlying molecular biology of patients with confluent high signal abnormalities on T2-weighted or FLAIR MRI sequences, the use of clinical descriptors is preferable to the VaP designation to avoid false implications. Leukoaraiosis-associated higher-level gait disorder is a mouthful but describes what we see, without advocating for an unproven etiology (vascular) or an incorrect semiology (parkinsonism). Continuing to jump into VaP otherwise (1) falsely suggests the achievement of a final diagnosis, which discourages efforts into uncovering the underlying white matter disorder, such as an adult-onset genetic leukoencephalopathy due to any of a range of mutations in CSF1R, COL4A1, or other genes, and (2) suggests a therapeutic pathway with no return on investment. If true parkinsonism (confirmed by a positive DAT scan when in doubt) is associated with leukoaraiosis, it behooves us to rethink VaP (Fig. 1) and consider symptomatic treatment with levodopa rather than antiplatelets, statins, or antihypertensives. Rather than two disorders, one being “VaP”, patients with parkinsonism and leukoaraiosis are more likely to have one disorder explaining both findings, such as frontotemporal lobar degeneration [
Let's restrict vascular parkinsonism to the neurological outcome of ischemic or hemorrhagic strokes affecting the substantia nigra or the nigrostriatal pathway. For every other vascular parkinsonism, something else is missing –for an attentive clinician to uncover.
The drafting and review of this manuscript was undertaken alone, with minimal influence of wine as synaptic enhancer.
Declaration of competing interest
There are no competing interests for the subject matter in this editorial.
Dr. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Bexion, Kyowa Kirin, Sunovion, Supernus (formerly, USWorldMeds), and Herantis Pharma; honoraria from Acadia, Sunovion, Amneal, and Supernus; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He cofounded REGAIN Therapeutics (a biotech start-up developing nonaggregating peptide analogues as replacement therapies for neurodegenerative diseases) and is co-owner of a patent that covers synthetic soluble nonaggregating peptide analogues as replacement treatments in proteinopathies.
There was no funding for this manuscript.
Hemiparkinsonism with a discrete lacunar infarction in the contralateral substantia nigra.