UNIVERSITY OFMICHIGANUNIVERSITY OFMICHIGAN Functional Neuroimaging, Cognitive and Mobility Laboratory

COMMONALITIES IN THE PATHOGENESIS OF MOTOR, MOOD AND COGNITIVE SYMPTOMS IN PARKINSON

DISEASE

Nicolaas Bohnen, MD, PhDAssociate Professor

of Radiology & Neurology University of Michigan

Ann Arbor, MI

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

• PET or SPECT imaging can demonstrate presynaptic dopaminergic denervation in PD. Striatal reductions are asymmetrically more prominent in the posterior and dorsal putamen.

NC PD11C-(+)-DTBZ PET

NIGROSTRIATAL DOPAMINERGIC DENERVATION IS CONSIDERED A KEY PATHOBIOLOGICAL EVENT IN PD

CARDINAL MOTOR-DAT (-CFT) PET CORRELATIONS:NIGROSTRIATAL DENERVATION IS INSUFFICIENT TO

EXPLAIN THE PARKINSONIAN SYNDROME

A. BRADYKINESIA

UPDRS brady -0.61 (P<0.01)

pegboard -0.52 (P=0.01)

foot tapper 0.45 (P=0.03)

B. RIGIDITY

UPDRS rigidity 0.11 ns

C. IMBALANCE

fall risk ns

D. TREMOR

UP TREMOR -0.14 ns

Accelerometer -0.02 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

DORSAL CAUDATESTRIATUM NUCLEUS

Smell 0.65*** 0.62***CES depression -0.04 ns -0.06 nsTrait anxiety 0.21 ns 0.26 nsMMSE -0.06 ns -0.1 nsTMT BA -0.29 ns -0.33 ns

***P<0.001

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 LewyFrederic 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 stagingBraak

stageSite 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”

• 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.

• 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

• 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 anti-cholinergic 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).

COGNITIVE IMPAIRMENT IN PD: THE CHOLINERGIC SYSTEM

• 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.

DEMENTIA IN PARKINSON DISEASE

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 PD50% 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)

MOTOR MOTOR * INTERACTION

UNIVERSITY OFMICHIGANUNIVERSITY OFMICHIGAN Functional Neuroimaging, Cognitive and Mobility Laboratory

PHARMACOTHERAPY & DBS IN PD

MIND vs. BODYTrade-Offs in PD pharmacotherapy

• 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

DA*ACh“scale”

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.

Copyright ©2007 by the National Academy of Sciences

Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666

Fig. 1. Method for localizing electrodes implanted in the brain of a patient with Parkinson's disease for stimulation of the STN

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.

Copyright ©2007 by the National Academy of Sciences

Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666

Fig. 3. Brain regions showing activation (red) or deactivation (green) during hypomania induced by stimulation of the STN in patients with Parkinson's disease

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 non-motor 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.