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COMMONALITIES IN THE PATHOGENESIS
OF MOTOR, MOOD AND COGNITIVE
SYMPTOMS IN PARKINSON DISEASE
Nicolaas Bohnen, MD, PhD
Associate Professor
of Radiology & Neurology
University of Michigan
Ann Arbor, MI
UNIVERSITY OF MICHIGAN
Functional Neuroimaging, Cognitive and Mobility Laboratory
LANDMARKS IN PARKINSON DISEASE
• 1590 William Shakespeare, Henry VI, Dick “Why dost thou
quiver, man?”, Say: “The palsy and not fear provokes me”
• Franciscus de le Böe (1614-1672), Anatomist, University of
Leyden, first medical description of tremors
• 1817 James Parkinson, first description of PD
• 1912 Frederick Lewy describes cytoplasmic inclusions
• 1960 Hornykiewicz showed striatal dopaminergic depletion
in PD
• 1957-1967 Carlson, Cotzias: Clinical application of l-DOPA.
• 1970 Bjorkund: Development of neural transplantation
• 1976 Garnett: Development of 18F-FluoroDOPA (PET)
• 1987 Benabid et al. DBS surgery pioneers
NIGROSTRIATAL DOPAMINERGIC DENERVATION IS
CONSIDERED A KEY PATHOBIOLOGICAL EVENT IN PD
11C-(+)-DTBZ
NC
PET
PD
• PET or SPECT imaging can demonstrate presynaptic
dopaminergic denervation in PD. Striatal reductions are
asymmetrically more prominent in the posterior and
dorsal putamen.
CARDINAL MOTOR-DAT (-CFT) PET CORRELATIONS:
NIGROSTRIATAL DENERVATION IS INSUFFICIENT TO
EXPLAIN THE PARKINSONIAN SYNDROME
A. BRADYKINESIA
B. RIGIDITY
UPDRS brady -0.61 (P<0.01) UPDRS rigidity 0.11 ns
pegboard -0.52 (P=0.01)
foot tapper 0.45 (P=0.03)
C. IMBALANCE
D. TREMOR
fall risk
UP TREMOR -0.14 ns
Accelerometer -0.02 ns
ns
NON-MOTOR SYMPTOMS OF PD ARE OFTEN THE
GREATEST SOURCE OF DISABILITY
• Dysautonomia: Constipation, orthostatic hypotension, sexual
dysfunction, bladder dysfunction
• Personality changes: introversion, social viscosity, compulsive
behavior (side-effect dopaminergic medications)
• Anxiety
• Depression / Apathy
• Executive cognitive dysfunction & dementia
• Sleep disturbances / daytime somnolence
• Visual changes
• Hyposmia
CARDINAL MOTOR-DAT (-CFT) PET CORRELATIONS:
NIGROSTRIATAL DENERVATION IS INSUFFICIENT TO
EXPLAIN THE PARKINSONIAN SYNDROME
Smell
CES depression
Trait anxiety
MMSE
TMT BA
***P<0.001
DORSAL
STRIATUM
CAUDATE
NUCLEUS
0.65***
-0.04 ns
0.21 ns
-0.06 ns
-0.29 ns
0.62***
-0.06 ns
0.26 ns
-0.1 ns
-0.33 ns
PARADIGM SHIFT OF PD:
The BRAAK Hypothesis
LEWY BODY: FIRST DESCRIBED IN
THE NUCLEUS BASALIS OF MEYNERT
• Frederic Heinrich Lewy (1885-1950)
was the first person to describe the
neuronal inclusion bodies, later
renamed Lewy bodies, associated with
PD in Max Lewandowsky's Handbook
of Neurology in 1912
• However, he never seemed to make
note of the typical occurrence of the
inclusions in the substantia nigra of PD
patients. This finding was made in 1919
by C. Tretiakoff who was the first to
ascribe the name "Corps de Lewy" or
"Lewy bodies" to the inclusions.
Frederic Lewy
Heiko Braak
Braak Classification of Lewy Neurite/Body Deposition in PD:
A New Perspective On PD
Braak et al. 2004
(Braak et al. Cell Tiss Res 2004)
Clinical correlates of Braak PD staging
Braak
stage
Site of Lewy neurite formation
Clinical Features
I
Dorsal motor nucleus Vagus
VIP Neurons Aucherbach pl.
GI dysfunction, i.e., constipation
II
Locus Ceruleus, RF,
Raphe Nucleus
Sleep-wake disorders (RBD)
III
SNpc, amygdala, basolateral
nuclei, basal forebrain,
hypothalamus
Dysosmia, motor dysfunction, subtle
cognitive change
IV
Temporal mesocortex
Apparent dysautonomia,
neurocognitive change
V
Depigmentation of SN,
prefrontal/sensory assoc Cx
Mild dementia, hallucinations, motor
impairment
VI
Entire neocortex
Marked motor impairment, dementia
Nigrostriatal denervation is only the tip
of the PD iceberg (Langston, 2006)
PD = a “Centrosympathomyenteric
neuronopathy”
COGNITIVE IMPAIRMENT IN PD
• In PD, selective cognitive deficits, esp. executive
dysfunction with difficulties planning, innovating, and
sequencing (Bedard et al., 1999) are often present in the
absence of clinically diagnosable dementia.
• Because of the primary basal ganglia involvement in PD,
it has generally been asserted that executive impairment is
mainly attributable to a dopaminergic loss. The
contribution of dopamine to the working memory
processes in PD has been emphasized (Goldman-Rakic,
1998). However, more pure measures of executive
functioning do not show significant benefit with
dopaminergic treatment (Cooper et al., 1992). Therefore, it
is clear that the dopaminergic hypothesis cannot explain
why dopaminergic treatment generally does not reverse
the dysexecutive syndrome in PD.
COGNITIVE IMPAIRMENT IN PD:
THE CHOLINERGIC SYSTEM
• A more satisfying understanding of dysexecutive
syndrome in PD has come from pharmacological studies
of the cholinergic system.
• Dubois et al. (1997, 1999) reported that the use of anticholinergic medications in patients with PD led to severe
impairment on tests, such as the Wisconsin card sorting
task, digit span test, and a behavioral indifference scale .
Furthermore, anticholinergic drug administration caused a
transient dysexecutive syndrome in PD patients, but not in
normal controls, indicating specific anti-cholinergic
vulnerability in PD (Bedard et al., 1998).
DEMENTIA IN PARKINSON DISEASE
• Incidence of dementia in PD 40-50%.
• The causes of dementia in PD are probably manifold
but likely include direct cortical involvement as
evidenced by the presence of Lewy bodies and Lewy
neurites, dopaminergic degeneration, cholinergic
deficits from nucleus basalis atrophy, and concomitant
conditions such as Alzheimer disease (AD).
• Significant loss of cholinergic forebrain neurons has
also been reported in PD brains (Whitehouse et al.,
1983; Candy et al., 1983). Arendt et al. found greater
forebrain neuronal loss in PD than in AD (Arendt et al.,
1983), suggesting that cholinergic deficits may be at
least as prominent in (late-stage) PD as in AD.
IN VIVO CHOLINERGIC DENERVATION IS MORE
SEVERE AND EXTENSIVE IN PARKINSONIAN
DEMENTIA THAN IN PROTOTYPICAL ALZHEIMER
DISEASE
11C-PMP
AChE PET (Bohnen et al., 2003)
AChE PET CORRELATES OF EXECUTIVE
COGNITIVE IMPAIRMENT IN PD
Cholinergic denervation in PD is associated with cognitive
(executive, attention, working memory) changes.
DEPRESSION IN PD
• Depression is a frequent non-motor symptom in PD
(25-50%) and is a significant source of disability in this
disorder (Weintraub et al., 2004).
• There is converging evidence of serotonergic
hypofunction as a basis for depression in PD on the
basis of reduced 5-HIAA csf levels (D'Amato et al.,
1987; Birkmayer et al., 1987).
POST-MORTEM DATA: PROMINENT PRE- BUT NOT
POSTSYNAPTIC 5HT DEGENERATION IN PD
DEPRESSION IN PD: 5HT REVISITED?
• A recent meta-analysis on antidepressant studies in
PD found that this population may benefit less from
typical antidepressant treatment, particularly selective
serotonin reuptake inhibitors (SSRIs), than do patients
without PD (Weintraub, 2005).
• A recent study of acute tryptophan depletion also
failed to identify a specific serotonergic vulnerability for
depression in PD (Leentjens et al., 2006)
SEROTONERGIC DENERVATION IN PD
50%  20% ROSTRO-CAUDAL GRADIENT
11C-DASB
PET
(Courtesy Roger Albin)
DEPRESSION & COGNITION IN PD
• A relatively unique feature of depression in PD is that
mood disturbance is associated with a quantitative but
not qualitative worsening of cognitive deficits (Tröster et
al., 1995).
• Prospective studies have shown that depression may
be a risk factor for incident dementia in PD (Lieberman,
2006)
•This modulatory effect of depression on cognitive
impairment in PD suggests that a common mechanism
might underlie both types of symptoms.
CHOLINERGIC DENERVATION &
DEPRESSION IN PD
• Depressive symptomatology is associated with
cortical cholinergic denervation in PD that tends to be
more prominent when dementia is present.
• A significant inverse correlation between cortical AChE
activity and scores on the Cornell Scale for Depression
in Dementia (CSDD) (R=-0.50, P=0.007) which remained
significant after controlling for MMSE scores.
(Bohnen et al., 2007)
PHARMACOTHERAPY & DBS IN PD
MOTOR
UNIVERSITY OF MICHIGAN
MOTOR * 
INTERACTION

Functional Neuroimaging, Cognitive and Mobility Laboratory
MIND vs. BODY
Trade-Offs in PD pharmacotherapy
DA*ACh
“scale”
• Anti-cholinergic drugs have anti-rigid and anti-tremor
effects but may cause confusion or delirium.
• Cholinergic drugs may cause motor fluctuations and
worsen tremor but may help cognition
• Dopamine agnosits improve motor functions may lead to
psychosis
• DA receptor blockers (antipsychotics) may help
psychotic symptoms but may cause parkinsonism
PD & DBS SURGERY
DBS: NON-MOTOR SIDE-EFFECTS
• Cognitive deficits post DBS: verbal memory; verbal fluency; attention and
executive functions; working memory; mental speeds and response inhibition
(for review, Temel et al., 2006).
• Mood changes: depression, incl. suicide, mania, anxiety (for review, Temel et
al., 2006).
• Hypersexuality
• Pathological laughter
• Changes in personality, impulse control disorder
• Anatomically, cognitive and limbic information related to the basal ganglia is
processed by the associative and limbic circuits, respectively. These data
point towards a potent regulatory function of the STN in the processing of
associative and limbic information towards cortical and subcortical regions
with further evidence from functional neuroimaging studies (Temel et al. 2006;
Mallet et al. 2007).
• No major behavioral changes from Vim thalamic and GPi target stimulation.
Fig. 1. Method for localizing electrodes implanted in the brain of a patient with Parkinson's disease for
stimulation of the STN
Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666
Copyright ©2007 by the National Academy of Sciences
STN CONNECTIONS
(Temel et al., 2005)
STN DBS “on” vs “off” verbal fluency
• Number of words processed
Regions of decreased activation within the right orbitofrontal cortex and
the left inferior frontal cortex/insular cortex, the left inferior temporal
cortex during STN stimulation compared with the OFF state during the
fluency task (Schroeder et al., 2003)
“STN” (Nigral) DBS: Acute inducible depression
Only stimulation through contact 0 of the electrode
placed on the left side caused depression. The actual
time of each recording is indicated on the photograph.
Panel A shows the patient's usual expression while
receiving levodopa. Panel B shows a change in the
facial expression 17 seconds after stimulation began.
Panel C shows the patient crying and expressing
despair 4 minutes and 16 seconds after the start of
stimulation. Panel D shows the patient laughing 1
minute and 20 seconds after the stimulator was turned
off.
Bejjani et al. 1999 CONNECTIONS
The results of PET revealed activation of the left
orbitofrontal cortex, a finding consistent with involvement
of the nigrothalamic pathway, which extends to the left
amygdala and limbic structures and is implicated in the
processing of unpleasant feelings.
Fig. 3. Brain regions showing activation (red) or deactivation (green) during hypomania induced by
stimulation of the STN in patients with Parkinson's disease
Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666
Copyright ©2007 by the National Academy of Sciences
CONCLUSIONS
• PD is a multi-systems neurodegeneration syndrome that
cannot be fully explained by nigrostriatal dopaminergic
denervation. There is also post-mortem and in vivo
evidence of monoaminergic (5HT, NE) and cholinergic
denervation.
• Pharmacotherapy in PD may (adversely) effects DA, NE,
5HT or ACh neurochemical systems with respective nonmotor and motor consequences.
• DBS, in particular STN, may affect,because of its close
anatomic proximity, non-motor associative and
limbocortical circuits with consequences on mood,
cognition and behavior.