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68 HUFFMAN ET. AL

Recent efforts to overcome this limitation have shown While the exact cause of DPS is not fully known,
promise utilizing mathematical models to define fluid some suggest that perivascular spaces become dilated
shifts (61), yet additional work is needed for clinical when ISF fluid is retained as a result of impaired
application. drainage (12,65). This impaired fluid movement could
further exacerbate the buildup of proteins along path-
CLINICAL SIGNIFICANCE OF THE ways and intensify the reduction in arterial pulses,
PERIVASCULAR SPACE creating a feed-forward cycle and increasing the
Previous studies in animals have reported dys- amount of Aβ deposits (4,12). Increased deposits of
function within perivascular pathways in advanced Aβ may exacerbate the dilation of perivascular spaces,
aging though the etiology of this pathological marker causing constriction of the surrounding cerebral
remains unclear (45). Dilated perivascular spaces arteries and thus impairing overall neurovascular cir-
(DPS) can be present in healthy adults of all ages culation and fluid movement (21). Correspondingly,
(22,46) and have traditionally been considered a animal models have exhibited significant decreases
benign variation in brain anatomy. Recent stud- in ISF flow following the buildup of Aβ (4). Previous
ies have established links between pathology of studies have linked CAA to the development of AD
the perivascular space and clinical disorders such (24,73), with disruption of perivascular flow possi-
as AD, small vessel disease, and multiple sclerosis bly present in both conditions. Further, Aβ and tau
(15,19,56,60,78) though the causal direction of the proteins are present in the interstitial space and are
association remains unclear. On MRI, DPS are com- thought to be cleared along perivascular pathways
monly observed in three primary anatomical loca- (59,76,80). Collectively, these results suggest that the
tions: 1) along the lenticulostriate arteries as they impact of aging on perivascular function may be a
penetrate the basil ganglia, 2) the centrum semiovale, critical mechanism associated with AD pathology.
along the medullary arteries as they project into the Kress and colleagues have observed a sizable
cortical gray matter and extend into the white matter, decrease in Aβ clearance in aging mice (45). These
and 3) the midbrain (30,58). DPS evident in the basal older mice also displayed significantly reduced
ganglia are more commonly attributed to vascular concentrations of AQP4 in astrocyte endfeet (45).
dementia (25), while DPS in white matter may be The redistribution of AQP4 has been linked to the
more indicative of AD (60). pathology of AD (82), as it is required for CSF-ISF
Perivascular pathways are responsible for the interchanges and the clearance of Aβ. As mentioned
clearance of proteins and metabolic waste from the previously, the AQP4 knockout mice exhibit an ~65%
interstitium, and their dilation has been implicated in reduction in the clearance of Aβ (36), suggesting that
dysregulated CSF flow, possibly due to the buildup of the decreased expression within these channels is
amyloid deposits (21). The accumulation of Aβ in the involved in protein aggregation and plaque formation.
cerebral arteries, a condition referred to as cerebral Dilated perivascular spaces, protein accumulation,
amyloid angiopathy (CAA), is frequently observed in and mislocalization of AQP4 are all pathological
the aging brain. Buildup of Aβ leads to plaque forma- features observed in AD though it is likely they are
tion within the perivascular space and is likely caused less specific to AD and broadly applicable as a con-
by the impaired drainage of Aβ (65,76). One leading sequence of advanced aging.
hypothesis for the development of CAA is based on Recent advances in imaging techniques may allow
gradual hardening of cerebral vessels, resulting in a further insight into the functional implications of
significant decrease in the rates of arterial pulsation perivascular dysfunction. Given the small size of peri-
(29,45). Decreases in arterial pulsation are thought vascular spaces, the advent of 7T MRI has shown the
to slow the drainage of solutes from the perivascu- potential in enhancing detection and visibility of DPS
lar pathways, leading to Aβ deposition and protein (9,42,84). Clearer imaging may allow for quantitative
aggregation within the leptomeningeal and cortical measuring of DPS, which would aid in our under-
arteries (29,36,41,59). standing of the pathology of DPS in illnesses such as