Parkinsons Disease: Cognitive Sequelae

Fiona Pilate Neuropsychology of Aging CLP 7934

Abbreviations

PD = Parkinsons Disease

PDD = Parkinsons Disease Dementia

RAC = Dopamine Receptors NDD = Neurodegenerative diseases

NC = Normal Control
AD = Alzheimers Disease DLB = Dementia with Lewy Bodies MCI = Mild Cognitive Impairment DB S = Deep Brain Stimulation STN = subthalamic nucleus

Parkinsons Disease: Introduction

Progressive neurodegenerative disorder that causes motor and nonmotor dysfunction Characterized by loss of dopaminergic neurons in substantia nigra pars compacta Can affect other areas of the nervous system including the autonomic2 and enteric nervous systems Second most common neurodegenerative disorder after Alzheimers disease Affects 1 to 1.5 million people in the United States alone

Parkinsons Disease Epidemiology

A Widespread Problem
As many as one million Americans suffer from Parkinson's disease This is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease (ALS) Incidence of Parkinsons increases with age, but an estimated 15 percent of people with PD are diagnosed before the age of 50 Approximately 40,000 Americans are diagnosed with Parkinson's disease each year: This number does not reflect the thousands of cases that go undetected.
Parkinsons Disease Foundation, Inc. 2007

Parkinsons Disease Costs

Combined direct and indirect cost of Parkinsons, including treatment, social security payments and lost income from inability to work, is estimated to be more than $5.6 billion per year in the U.S. alone

Parkinsons Disease Foundation, Inc. 2007

Pathogenesis of Parkinson Disease

ACTUAL CAUSE UNKNOWN FACTORS IMPLICATED INCLUDE:

GENETIC, ENVIRONMENTAL TOXINS, AND ENDOGENOUS TOXINS, FROM CELLULAR OXIDATIVE REACTIONS. TWO MAJOR PATHOGENETIC HYPOTHESES: MISFOLDING OF PROTEINS, etc. MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

Etiology of Parkinsons Disease

Environmental agents

+
Parkinsons disease/parkinsonism

Genes

The Problem: Loss of Dopaminergic and Non-Dopaminergic Neurons

A Lang, Neurology 2007;68;948-952.

Parkinsons Disease
General Considerations

The second most common progressive neurodegenerative disorder The most common neurodegenerative movement disorder It is a complex disease with variable symptoms Symptoms and neuropathology are well characterized Pathogenesis of PD is not clear May be multifactorial and heterogeneous in etiology Misdiagnosis rate of PD is about 10-25%

Parkinsons Disease
Classical Clinical Features

Tremor, resting
Rigidity, cogwheel Akinesia, bradykinesia

Postural Instability

Parkinsons Disease
Associated Clinical Features

Micrographia Hypophonia Hypomimia Shuffling gait / festination Drooling Dysphagia Autonomic dysfunction Depression Dementia

Parkinsons Disease
Features supporting diagnosis

Unilateral symptom onset Characteristic resting tremor Narrow-based gait with flexed/ stooped posture Reduced arm swing with tremor

Sustained and significant levodopa effect

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

PARADIGM SHIFT OF PD: The BRAAK Hypothesis

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)

Braak Model for Pathologic Staging of Parkinsons Disease

Based on Lewy body localization Suggests that Lewy body pathology does not begin in substantia nigra

Braak stage 1-2 3-4 5-6

Clinical symptoms Premotor Motor Cognitive decline

Begins in dorsal motor nucleus of glossopharyngeal and vagus nerves, anterior olfactory nucleus, and enteric nerve cell plexus Proceeds in rostral direction toward neocortex

Progression of Parkinsons Disease may not always comply with this model

Clinical correlates of Braak PD staging

Braak stage Site of Lewy neurite formation Clinical Features

Dorsal motor nucleus Vagus VIP Neurons Aucherbach pl. Locus Ceruleus, RF, Raphe Nucleus SNpc, amygdala, basolateral nuclei, basal forebrain, hypothalamus Temporal mesocortex

GI dysfunction, i.e., constipation

II

Sleep-wake disorders (RBD)

III

Dysosmia, motor dysfunction, subtle cognitive change Apparent dysautonomia, neurocognitive change Mild dementia, hallucinations, motor impairment Marked motor impairment, dementia

IV

Depigmentation of SN, prefrontal/sensory assoc Cx Entire neocortex

VI

Parkinson Disease Pathology

Proteinacious inclusion bodies: Lewy bodies & Lewy neurits

Lewy bodies are: Fibrillar deposits of alpha synuclein

Neuropathology of Parkinsons Disease Substantia nigra pathology

Neuronal loss

Lewy body inclusions

Pathology in Parkinsons Disease

Pathology in Parkinsons Disease

Nigrostriatal denervation is only the tip of the PD iceberg (Langston, 2006)

PD = a Centrosympathomyenteric neuronopathy

Tracers
Characterization of presynaptic degeneration
L-[11C]-DOPA (dopamine synthesis) [11C]-CIT-FE (dopamine re-uptake)

Characterization of postsynaptic degeneration

[11C]-RAC (dopamine receptors) [18F]-FDG (glucose transport)

Neurodegeneration
Substantia nigra
Presynaptic neuron

Putamen
Dopamin

RAC

FDG

DOPA/ CIT

D2-r Normal

Parkinsons disease without treatment

Neurodegeneration
Substantia nigra
Presynaptic neuron

Putamen
Dopamin

RAC

FDG

DOPA/ CIT

D2-r Normal

Parkinsons disease without treatment

Parkinsons disease after treatment

Neurodegeneration
Substantia nigra
Presynaptic neuron

Putamen
Dopamin

RAC

FDG

DOPA/ CIT

D2-r Normal

Parkinsons disease without treatment

Parkinsons disease after treatment

Striato-Nigral degeneration

Improved Detection of Lewy Body Pathology

Alpha-synuclein mutations in familial PD Alpha-synuclein immunoreactivity in all Lewy bodies

Classic brainstem Lewy bodies Cortical Lewy bodies Lewy neurites

Lewy Body Inclusions

Characteristic inclusions in substantia nigra neurons of patients with Parkinsons disease Immunoreactive for neurofilaments, ubiquitin and alpha-synuclein, but not tau (NFT are tau and ubiquitin positive) In substantia nigra it is cytoplasmic, round, eosinophilic with clear halo In cortex less distinct appearance, best visualized with alphasynuclein immunohistochemistry

Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex

Substantia nigra Cerebral cortex

a-Synuclein

a-Synuclein is a tubular-filamentous nonsoluble protein, with important role in the maintenance of synaptic pool misfolded a-synuclein is part of the abnormal protein aggregate found in Lewy bodies

Tau & Taupathies

Tau is a neuronal Microtubule stabilizing protein, It contribute to axonal transport, growth & morphology. Tau misregulation and deposition correlates with neuronal cell death in: Frontotemporal dementia & Parkinsonism associated with Chr.17(FTDP-17) Alzheimers neurofibrillary tangles are composed of phosphrylated Tau. Its role however in pathogenesis is controversial

Synucleinopathies

NDD characterized by intracellular aggregation of alphasynuclein:

Parkinsons Disease Dementia with Lewy Bodies Lewy Body Variant of AD Multiple System Atrophies OPCA & SND & Shy-Drager Syndrome Neurodegeneration with brain iron accumulation type 1 ( Hallervorden-Sp.)

Role of Tau and a-synuclein in neurodegenerative diseases

Relevant Brain Structures

Motor Circuit

Imaging Biomarkers for Parkinsons Disease (PD)

Method
fMRI SPECT

Tracer
NA

Assessment
Indirect marker of neuronal activity

Expected results with PD

activation in specific brain areas levels

[123I]b-CIT DA transporter levels [99mTc]TRODAT [11C]MP [18F]DOPA [11C]DTBZ Estimate number of DA terminals and nigral neurons VMAT2 as estimate of number of DA terminals and nigral neurons Striatal DA receptor availability Estimate synaptic DA concentration Metabolic activity of basal ganglia network

PET PET

levels levels Early PD: in putamen Advanced PD or after chronic DRT: in caudate PDRP and PDCP

PET

[11C]RAC

PET

FDG

NIGROSTRIATAL DOPAMINERGIC DENERVATION IS CONSIDERED A KEY PATHOBIOLOGICAL EVENT IN PD

NC

PD

PET or SPECT imaging can demonstrate presynaptic dopaminergic denervation in

PD. Striatal reductions are asymmetrically more prominent in the posterior and dorsal putamen.

Parkinsons Disease

Progressive cognitive decline Specific to basal ganglia Slowing of emotional and voluntary movement Muscular rigidity Tremor Dopamine deficiency

Uniform reduction of metabolism but may have parietal and temporal hypometabolism similar to AD
[18F]fluorodopa PET shows decreased uptake in the putamen

FDG PET Findings in Dementia With Lewy Bodies (DLB)

Patients with DLB (Dementia with Lewy Bodies) may have hypometabolism of visual association cortex and occipital cortex, in addition to temporal and parietal hypometabolism

Cognitive ageing

Cognitive, or thinking ability is the product of fixed intelligence , the result of previous thinking , which often increases with age i.e wisdom fluid intelligence i.e. real time information processing which declines modestly in old age Intellectual function is maintained until at least 80 years of age, but processing is slower. Non critical impairments include: forgetfulness, reduced vocabulary, slower learning

Cognitive impairment in PD

In PD, selective cognitive deficits, esp. executive dysfunction with difficulties planning, innovating, and sequencing 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 However, more pure measures of executive functioning do not show significant benefit with dopaminergic treatment . 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 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).

A Transition in Grouping PD Patients by Cognitive Impairment

Trster 2009

Correlation Coefficients Between Individual Cognitive Tests and Cortical AChE Activities in Combined PDD and PD Groups
Correlation coefficient (significance) Rs = 0.13 ns Rs = 0.20 ns Rs = 0.43 (p < 0.05)

Cognitive test California Verbal Learning Test-STM California Verbal Learning Test-LTM Judgment of Line Orientation Test

Stroop Color Word Test

Trail Making Test B-A WAIS-III Digit Span

Rs = 0.46 (p < 0.05)

Rs = 0.44 (p < 0.05) Rs = 0.57 (p < 0.005)

Bohnen NI, et al. J Neurol. 2006;253:242-247.

Neurochemistry of PDD and AD

Cholinergic System

Cholinergic basal forebrain Neuronal loss and Lewy body pathology in PD and PDD Neuronal loss and neurofibrillary tangles in AD Pedunculopontine (PPT) nucleus Neuronal loss and Lewy body pathology in PD and PDD Neuronal loss and neurofibrillary tangles in AD
Jellinger K. J Neurol Neurosurg Psychiatry. 1988;51:540-543.

Two Distinct Disorders With a Common Cholinergic Deficit

PDD
Lewy body pathology in cholinergic basal forebrain and brainstem PPT

AD
Neurofibrillary tangles in cholinergic basal forebrain and brainstem PPT

Cholinergic deficit

Neuropsychological Comparison of DLB/PDD vs. AD

AD involves greater impairment of memory, especially verbal , probably related to greater temporal lobe pathology AD hallmarks: rapid rates of forgetting and intrusions DLB involves greater visuoperceptual and constructional deficits which may be linked to posterior cortical hypometabolism and vissal hallucinations

Trster 2009

Neuropsychological Comparison of DLB/PDD vs. AD

DLB/PDD perform worse than AD on complex attention tasks (Stroop, Trailmaking) (Calderon et al. 2001) but not on simple tasks (e.g., digit span) DLB/PDD perform worse on executive function tasks (e.g., card sorting) than AD (Simard et al. 2000). Executive dysfunction linked to basal forebrain cholinergic deficits Language data more equivocal: same naming and fluency deficits in AD and DLB, worse naming in AD, worse letter fluency in DLB

Trster 2009

Dementia and Parkinsonism

DEMENTIA WITH LEWY BODIES PARKINSONS DISEASE WITH DEMENTIA

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.

Dementia with Lewy bodies

Cognitive and behavioural problems precede motor symptoms Gradual progression, insidious onset Fluctuations in cognitive function and alertness Prominent auditory and visual hallucinations, paranoia, dellusions Levodopa or dopa agonists may worsen the confusion

Dementia with Lewy Bodies

Most common dementia after Alzheimer's Tiny protein deposits in nerve cells interrupt neurotransmissions Daily fluxuation of problems Spatial disorientation often falls, shuffling Visual hallucinations (of animals) Nightmares Symptoms similar to Parkinson's and Alzheimer's Treated very differently than other FT lobe dementias

Consensus Criteria for Dementia with Lewy Bodies

Progressive cognitive decline with loss of normal social and occupational function: loss of memory, attention, frontal subcortical skills, visuospatial ability Two of the following: a. fluctuating cognition, attention, alertness b. visual hallucinations c. motor features of parkinsonism Supportive features: falls, syncope, LOC, neuroleptic sensitivity, delusions, non-visual hallucinations

Consensus Criteria for Dementia with Lewy Bodies

It is suggested that if dementia occurs within 12 months of the onset of extrapyramidal motor symptoms, the patient should be assigned a primary diagnosis of possible DLB If the clinical history of parkinsonism is longer than 12 months, PD with dementia will usually be a more appropriate diagnostic label

Consensus Criteria for Dementia with Lewy Bodies

Criteria good predictor of Lewy body pathology
(with or without concomitant AD pathology) - high positive predictive value

Criteria poor predictor of the absence of Lewy

body pathology - low negative predictive value

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.)

Depression and 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 (Trster 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.

PD & DBS Surgery

Neurobiology

Brain areas targeted in DBS: 1. 2. 3.

Vim = ventralis intermedius nucleus of the thalamus GPi = posteroventral portion of the internal segment of the globus pallidus STN = subthalamic nucleus

Intervention
Patient Selection

Goal: Find ideal patients, where individual benefit > risk of surgery Advanced idiopathic PD with motor complications is main indication for DBS in PD Multidisciplinary approach: 1. Neurosurgeon 2. Neurologist 3. Neuropsychologist

Intervention
Patient Selection

Response to levodopa = best prognostic indicator for DBS suitability Neuropsychological evaluation
- Depression - Psychosis

Age Full medical assessment Discussion of long-term and short-term effects of DBS Education regarding environmental concerns with implantable devices

Intervention
Surgical Procedure

Precise implantation of stimulation electrode in targeted brain area. Connecting electrode to internal programmable pulse generator

Intervention
Pre-Operative Stage:

Stereotactic Surgery
- Locate targeted brain areas - Stereotactic frame - MRI, CT, or ventriculography - Stereotactic atlas

Intervention
Pre-Operative Stage:

Functional Stereotactic Surgery

- Electrophysiological exploration of targeted regions via test electrodes - Involves: 1. Microrecording
2. Test-stimulation

- Increases accuracy of localization (i.e. finding optimum target in GPi or STN) - Under local anesthesia

Intervention

Optimal Stimulation Sites:

- Dorsolateral STN border
- Posteroventral GPi

Implantation of Electrode:

DBS electrode stereotactically inserted with special rigid guide tube Patient is awake and in the medication-off state after 12-hour withdrawal

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.

STN Connections

(Temel et al., 2005)

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

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

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)

DBS:Non Motor Side Effects

Cognitive deficits post DBS: verbal memory; verbal fluency; attention and executive functions; working memory; mental speeds and response inhibition Mood changes: depression, incl. suicide, mania, anxiety 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 No major behavioral changes from Vim thalamic and GPi target stimulation.

Patient Enrollment and Randomization Assignment DBS

278 screened for eligibility

23 excluded

255 randomized 121 assigned to receive DBS GPi 61 and STN 60 111 patients assessed 7 withdrew due to medical or psychological problem 2 withdrew consent 1 died

134 assigned to receive BMT

3 month assessment

119 patients assessed 7 withdrew consent 2 withdrew because randomized to BMT 6 withdrew when BMT group closed

6 month assessment

116 assessed 3 no follow-up data

108 assessed at 3 no follow-up data

134 included in primary analysis

121 included in primary analysis

Patient Baseline Characteristics by Treatment Group

BMT (n=134) Mean (std) or % DBS (n=121) Mean (std) or % p-value

Beck depression inventory

Mattis Dementia rating scale Processing speed index WAIS-III Working memory index Phonemic Fluency (FAS) Category Fluency (Animal) HVLT total (learning/memory) HVLT delayed recall Finger tapping Boston Naming Test (language)

11.7(8.1)
136.6(5.8) 89.4(14.1) 97.3(13.6) 44.7(12.1) 49.5(11.6) 39.9(11.5) 38.1(13.4) 37.6(12.9) 55.9(4.3)

11.3(8.7)
136.7(4.8) 91.0(13.9) 101.2(13.3) 45.7(12.1) 50.9(11.3) 38.9(11.3) 37.3(13.3) 37.1(11.4) 55.5(4.5)

0.680
0.842 0.366 0.023 0.520 0.336 0.499 0.619 0.746 0.444

Neuropsychological Outcomes at Baseline and Six Months by Treatment Group

BMT (n =134) DBS (n = 121) 6 Months
56.2 (3.8)

BMT - DBS Diff (95% CIs)

-0.4 (-0.8, 0.1) 1.3 (-1.2, 3.8) 1.6 (-0.4, 3.5) 3.2 (0.4, 6.0) -1.0 (-2.7, 0.6)

Outcome
Boston Naming Test

Baseline

6 Months

Baseline
55.5 (4.5)

P-value

55.9 (4.3) Finger Tapping 37.6 (12.9) Stroop Interference 51.0 (7.6) BVMT Delayed Recall 42.4 (13.3)

56.2 (4.0)

0.127

38.7 (13.2)

37.1 (11.4)

36.9 (11.3)

0.319

51.8 (8.4)

50.7 (7.4)

49.8 (7.1)

0.111

44.6 (13.7)

42.1 (13.3) 11.3 (8.7)

41.1 (13.6)

0.026

Beck Depression Inventory

11.7 (8.1) 10.2 (6.9)

10.9 (8.6)

0.224

Causal Genes
Analysis of large nuclear families with many affected individuals have revealed several single gene mutations/locus replications that cause PD

-synuclein Parkin DJ-1 PINK LRRK2

Genes Associated with Sporadic Late Onset Parkinsons Disease

Tau

H1 haplotype -synuclein promoter variant (SNCA gene) Vesicular monoamine transporter-2 (VMAT2) UCHL1 variant LRRK2

Parkinson's disease Summary of genes

Gene Mode Chromosome Gene product Park 1 AD Park 2 AR Park 3 AD Park 4 AD 4q21-23 6q25.2-27 2p13 4p14-16 .3 a- synuclein Parkin Unknown Unknown

Summary

PDD is a clinical disease with a unique progression

Begins with Parkinsons disease Motor signs present for years before onset of dementia Dementia syndrome characterized by memory, executive, attentional, and functional deficits Prominent neuropsychiatric symptoms with psychotic features

PDD can be identified and diagnosed in usual settings of care Need for effective treatments

There are no currently approved treatment options

Summary

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.
Clinical PDD is highly predictive of specific neuropathologic and neurochemical characteristics Neuropathology Lewy body pathology Limited AD pathologic change

Summary

Because PD is a progressive disorder, early diagnosis and treatment intervention with neuroprotective therapies to slow or prevent further degeneration and to promote neuronal repair are current goals in the management of PD The development and validation of diagnostic markers in symptom recognition and neuroimaging will aid in early diagnosis of PD Advances in neuroimaging and development of quantitative diagnostic biomarkers will also improve evaluation of potential neuroprotective therapies