Parkinsonism and Related Disorders 94 (2022) 132–134
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Parkinsonism and Related Disorders
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Editorial
What the VaP? The meaning of “vascular parkinsonism”☆
A R T I C L E I N F O
Keywords
Vascular parkinsonism
Higher-level gait disorder
Leukoaraiosis
Leukoencephalopathy
What is vascular parkinsonism? The rapid appearance of hemi­
parkinsonism due to contralateral strokes in the cerebral peduncle of the
midbrain, affecting the region occupied by the substantia nigra [1]. The
trouble is that in the neurological literature, vascular parkinsonism, or
VaP, has been taken to mean any progressive slowness of gait (“low­
er-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 [2], “a
relationship between the above two.”
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 demon­
strated 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 [2]. 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 micro­
angiopathy [3]. 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 in­
dividuals [4].
In the nearly two decades since the proposed diagnostic criteria, VaP
remains a nosological entity without a specific imaging pattern [4,5],
without a specific gait impairment pattern (which is similar in cases with
versus without white matter hyperintensities) [6], and without a specific
pathological pattern, struggling with the fundamental contradiction that
☆
Editorial for: Park DG et al., Factors Associated with Motor Severity in Vascular Parkinsonism with Normal Dopamine Transporter Imaging – Parkinsonism
and Related Disorders.
https://doi.org/10.1016/j.parkreldis.2021.12.008
Available online 15 December 2021
1353-8020/© 2021 Published by Elsevier Ltd.
large infarcts in the territory of the lenticulostriate arteries, the most
paradigmatic of all strategic vascular injuries, are only rarely compli­
cated with parkinsonism [7]. 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? [8].
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 [9]. Using a semi-quantitative
visual rating system, Park and colleagues found that the signal hyper­
intensities 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 peri­
ventricular 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 dis­
order to another makes the combination better, not worse (e.g.,
Editorial Parkinsonism and Related Disorders 94 (2022) 132–134

Parkinson’s disease patients with gout exhibit a slower progression than
those without [10]). 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 [11].
Here are the fundamental conceptual problems with VaP, which
make the results of any studies on this construct hard to translate into
clinical care:
o 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 [12,13]. The literature has misattributed patients with
higher-level gait disorders, apathetic depression, and pyramidal
slowness to “parkinsonism” [14].
o Leukoaraiosis does not necessarily mean Vascular. Not all that
shines on imaging is vascular [15]. In fact, if VaP were the mani­
festation 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 sen­
tence about the value of searching, let alone modifying vascular risk
factors [16]. Vascular risk factors are common in VaP [17], 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. Leu­
koaraiosis-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 anti­
platelets, 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 fronto­
temporal lobar degeneration [18]; similarly, patients with parkinsonism
and hydrocephalus are more likely to have one disorder, such as pro­
gressive supranuclear palsy [19]. The corollary of this story is that the
presence of leukoaraiosis and/or hydrocephalus requires further studies
[20]. Calling them “VaP” or “NPH,” or, as I once wrongly conceived, the
‘spectrum’ of both [21], truncates clinical reasoning.
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

Fig. 1. Suggested flow diagram to rethink “vascular parkinsonism”. Only ischemic or hemorrhagic strokes affecting the substantia nigra and/or nigrostriatal
pathway result in true vascular parkinsonism. For leukoaraiosis in any other distribution, vascular parkinsonism likely represents other entities leading to a higher-
level gait disorder not a ‘lower body parkinsonian’ phenotype, with examples of the most prevalent shown here. CADASIL: cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy; CSF1R: Colony Stimulating Factor 1 Receptor gene; COL4A1: Collagen Type IV Alpha 1 Chain gene; DAT:
Dopamine transporter; PET: positron emission tomography; PD: Parkinson’s disease; NPH: normal pressure hydrocephalus; VPS: ventriculoperitoneal shunt; WMH:
white matter hyperintensities.

133
Editorial
else is missing –for an attentive clinician to uncover.
Author contributions
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.
Full disclosures
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, Suno­
vion, Amneal, and Supernus; and publishing royalties from Lippincott
Williams & Wilkins, Cambridge University Press, and Springer. He
cofounded REGAIN Therapeutics (a biotech start-up developing non­
aggregating peptide analogues as replacement therapies for neurode­
generative diseases) and is co-owner of a patent that covers synthetic
soluble nonaggregating peptide analogues as replacement treatments in
proteinopathies.
Funding
There was no funding for this manuscript.
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Alberto J. Espay
James J. and Joan A. Gardner Family Center for Parkinson’s Disease and
Movement Disorders, Department of Neurology, University of Cincinnati,
260 Stetson St., Suite 2300, Cincinnati, OH, USA
E-mail addresses: alberto.espay@uc.edu, aespay@gmail.com,
aespay@gmail.com.