Eidelberg-relayout_US Neurology 17/02/2010 13:13 Page 27
Imaging, Cognition, and Parkinson’s Disease—An Overview
motor and cognitive aspects of PD (see Figure 1).
7,19
These networks have Figure 1: Motor- and Cognition-related Metabolic Patterns
been demonstrated to be robust descriptors of disease processes.
in Parkinson’s Disease
The motor manifestations of PD are associated with a highly reproducible
PDRP PDCP
disease-related spatial covariance pattern (PDRP) characterized by Premotor cortex
relative metabolic increases in pallidal, ventral thalamic, and pontine
(BA6/8)
Thalamus (VL)
areas, associated with reductions in premotor and posterior cortical
Putamen/GP
association regions.
20
PDRP has been shown to be consistently correlated Prefrontal
with standardized ratings of motor disability, and has been extensively
cortex
(BA10)
validated as a treatment biomarker.
21–23
A separate cognition-related
Primary motor
spatial covariance pattern (PDCP) has also been identified and validated
cortex
in non-demented PD patients.
10
This pattern is characterized by metabolic
(BA4)
reductions in frontal and parietal association areas, associated with
relative metabolic increases in the cerebellum. Both the PDRP and PDCP
have excellent test–re-test reproducibility. The PDCP has been
demonstrated to correlate with neuropsychological measures specifically Parietal association
associated with subcortical dementia syndrome.
10
Network expression is
cortex
(BA40/7)
Precuneus (BA7)
most strongly associated with performance on tests of memory and
executive functioning. A relationship with visuospatial and perceptual
20
Left: Parkinson’s disease motor-related spatial covariance pattern (PDRP) characterized by
pallidothalamic, pontine, and motor cortical hypermetabolism, associated with relative
motor speed has also been found.
10
metabolic reductions in the lateral premotor and posterior parietal areas. Right: Parkinson’s
10
disease cognition-related spatial covariance pattern (PDCP) characterized by hypometabolism
of prefrontal cortex, rostral supplementary motor area, and superior parietal regions.
The PDCP does have some regional overlap with the PDRP. However,
Relative metabolic increases are displayed in red; relative metabolic decreases are displayed in
these network biomarkers are dissociable in multiple ways.
7,10,23,24
In a
blue. Both patterns were overlaid on a standard magnetic resonance imaging (MRI) brain
template. The left hemisphere was cut in the transverse plane at z=-5mm. The right
longitudinal study
7
we documented that PDRP expression is elevated in
hemisphere was displayed as a surface projection on the same brain template.
early disease, whereas a significant degree of PDCP network expression
®
Reprinted with permission of HighWire Press , a subsidiary of the Stanford University Libraries.
cannot be discerned until approximately six years after symptom onset.
In other words, network expression parallels symptom onset, with the
Figure 2: PDCP Expression for Subgroups of
Parkinson’s Disease Patients with Different
motor manifestations preceding cognitive dysfunction. In addition,
Degrees of Cognitive Functioning
PDRP expression is sensitive to pharmacological and surgical therapies
directed at the motor manifestations of the disease.
22,25
On the other
PDCP expression
hand, PDCP expression remains stable with these interventions,
20
consistent with the lack of a treatment effect on cognitive functioning
based on repeated psychometric testing.
10,23 15
Subsequent studies have suggested that the PDCP is sensitive to early
10
cognitive decline, as characterized by mild cognitive impairment
MCI (-) MCI (-) MCI (-)
(MCI).
26,27
PDCP activity was found to increase in a stepwise fashion, with
5
n=15 n=15 n=20
PDCP expression
t=2 y t=4 y t=7.42 y
worsening cognitive categorization (see Figure 2). Healthy control
0
subjects had lower PDCP expression than PD patients without MCI, who
MCI (s) MCI (m) Dementia
in turn had lower values than those with cognitive impairment. n=21 n=28 n=9
-5
Moreover, patients with single-domain MCI maintained an intermediate
t=10.5 y t=12 y t=14.9 y
position between those with involvement of multiple cognitive domains
-10
and those without cognitive impairment. PDD patients exhibit further
PDCP elevations than MCI subjects.
Plots of Parkinson’s disease cognition-related spatial covariance pattern (PDCP) expression
(mean±SE) for subgroups of PD patients with different degrees of cognitive functioning. (-) is
normal cognition; (s) is single-domain mild cognitive impairment (MCI); (m) is multiple-domain
The anatomical regions that contribute most to the PDCP network are
MCI. t represents the mean duration of illness for each of the groups. With increasing cognitive
impairment there is a concomitant reduction in cortical metabolic activity (positive network
the medial aspects of the lateral frontal and parietal association areas,
values). These metabolic reductions do not appear to be evident prior to seven years after the
and are therefore somewhat reminiscent of the ‘default mode
onset of motor symptoms.
network.’
28
Therefore, it is possible that abnormal elevations in PDCP
activity denote reduced capacity to allocate neural resources, as well as changes in non-dopaminergic systems. Indeed, cholinergic deficits have
a diminution in cognitive reserve. Given the lack of a significant effect of been documented in multiple PDCP areas.
10,14,30
To date, there has been
levodopa on PDCP expression,
10
this network is unlikely to be a simple no direct comparison of PDCP expression and cholinergic functioning.
reflection of mesocortical dopaminergic dysfunction. Moreover, PDCP
regions do not generally display α-synuclein aggregation until later in Dopaminergic Imaging
the clinical course of disease.
29
It is therefore possible that in early The development of several ligands for use with PET has helped
stages of disease, this cognition-related pattern reflects functional elucidate the role of different mechanisms associated with cognitive
US NEUROLOGY
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