Nature, prevalence and clinical significance. Barcelona, Spain

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1 Nature, prevalence and clinical significance Jaime Kulisevsky Barcelona, Spain 1

2 Non motor (neuropsychiatric) symptoms are an integral part of Parkinson s s disease (PD) Affective disorders And are associated with Anxiety Depression Cognitive impairment Frontal executive Excess disability Worse quality of life Poorer outcomes Caregiver distress 23 impairment Main contributors to quality of life 4 Dementia Predictors of deterioration in health-related quality of life in Parkinson's disease: results Psychosis from the DATATOP t i l 5 Are particularly common 1 Neuropsychiatry Psychiatry Mood Affect Thought Behaviour Attention Alertness Perception Memory Language/speech Intelligence Cognition Motivation/apathy Neurology Motor Sensory (tactile, pain, temperature, two-point discrimination) 1 Aarsland et al. Arch Neurol 1999;56: ; 2 Goetz & Stebbins. Neurology 1993;43:2227 9; 3 Marsh et al. Neurology 2004;63: ; 4 Schrag et al. J Meurol Neurosurg Psychiatr 2000;69:308 12; ; 5 Marras et al. Mov Disord 2008;23:

3 Wide range of behavioural and personality changes in patients with PD according to the Neuropsychiatric Inventory (NPI) n=1,351 PD patients without dementia At least one psychiatric symptom reported in 68% of the sample Psychiatric symptoms, executive impairment i and excessive daytime somnolence (EDS) were significantly more common in patients with PD >7 years duration and Hoehn & Yahr stage IV-V disease Executive impairment (phonemic verbal fluency (PF)< 10, semantic verbal fluency (SF) < 15 and alternating verbal fluency (AF) < 8 words per minute) seen in 41% of patients EDS seen in 26% of patients t Anxiety seen in 21% (Hospital Anxiety and Depression Scale) Kulisevsky et al. Mov Disord 2008;23: To view abstract, click Abstracts link above 3

4 Incidence of neuropsychiatric symptoms in PD Patients with (PDD) 1 and without 2 dementia 80 PD with dementia PD without dementia (%) Patients NPI item 1 Aarsland et al. J Neurol Neurosurg Psychiatry 2007;78:36 42; 2 Kulisevsky et al. Mov Disord 2008;23: To view abstract, click Abstracts link above 4

5 Spectrum of PD cognitive impairment Predominantly subcortical items 1. Sustained attention 2. Working memory 3. Verbal memory Free and delayed recall 4. Verbal fluencies AF and action verbal fluency Predominantly cortical items: 1. Confrontation naming 2. Clock drawing (copy) 5

6 Cognitive impairment in PD Although precise identification of the impaired processes and their explanations in terms of cognitive models are debatable Impaired cognitive tasks in PD are very reminiscent of tasks impaired in processes affecting the frontal lobes 6

7 Types of cognitive impairment vary between newly diagnosed PD patients As a whole, lower cognitive performance in all tests vs control group Cortical and subcortical changes may occur simultaneously in some patients Patie ents (%) sh howing impa airment Memory and language g are more cortical than attention and visuospatial functions Muslimovic D. Neurology 2005;65: To view abstract, click Abstracts link above 7

8 The most important clinical predictors of global cognitive decline in PD (corrected for age) Neurological tasks with (a more posterior) cortical basis Semantic fluency Ability to copy Intersecting pentagons figure As well as a non-tremor dominant motor phenotype at the baseline assessment Profile of cognitive dysfunction amongst PD patients at baseline and at 3.5 (+/ 0.7) years from diagnosisi Pentagons: pentagon copying; PF: phonemic fluency; PRM: pattern recognition memory; SF: semantic fluency; SRM: spatial recognition memory; TOL: Tower of London Williams-Gray et al. Brain 2007;130: To view notes, click notes tab 8

9 Comparative progression of impairment of subcortical-type type (A,B) and cortical-type type (C,D) items Estimated Mar rginal Means Estimated Marg ginal Means selective decrease in cortical-type items scores in PDD TOTAL SCORES independently discriminated controls from PD without dementia as well as PD without t dementia from PDD (P<0.001) A. Alternating verbal fluency B. Working memory CG Cognitively intact MCI Dementia CORTICAL SCORES independently discriminated PDD from PD without dementia (P<0.01) Estimated Marg ginal Means CG Cognitively intact MCI Dementia C. Clock drawing task Copy part D. Confrontation naming CG Cognitively intact MCI Dementia PDD is characterised by the addition i of cortical dysfunction upon a predominant and progressive fronto- subcortical impairment rginal Means Estimated Mar CG Cognitively intact MCI Dementia Click for further details. Pagonabarraga et al. Mov Disord 2008;23: To view abstract, click Abstracts link above 9

10 Cognitive impairment in PD Cognitive impairment Normal Cognitive dysfunction Dementia Diagnosis of PD MCI * Time Age Phenotype Cortical deficits * Mild cognitive impairment Naming Pagonabarraga et al. Mov Disord 2008;23:

11 PD cognition: the boundaries between these 'systems' are not well defined Acetylcholine impairments in memory, attention, and frontal dysfunction Noradrenaline Contributing to impaired attention Glutamate? Serotonin Depressive mood Dopamine Partly responsible for dysexecutive syndrome 11

12 Heterogeneity of cognitive impairment in newly diagnosed PD PD patients had lower cognitive performance in all tests vs healthy controls Overall, the PD population suffered only mild cognitive impairment Dopamine agonist (DA) Cholinergic denervation? Muslimovic D. Neurology 2005;65:

13 Clinical features may reflect the extent of pathological burden Relatively subtle cognitive impairment i in PD (R-SCI) From visuo-perceptual and attentional-executive dysfunction PD with concurrent dementia PDD To visuo-perceptual and attentional-executive dementia Mainly dopaminergic deficits Crucial contribution of non-da systems How many legs? Hilker et al. Neurology 2005;65: To view abstract, click Abstracts link above. To view notes, click notes tab 13

14 DA medication appears to have little if any influence on the epidemiology of non-motor phenomena PD patients without dementia (n=1351) Current therapeutic combinations for PD Lev+DAs Lev+DAs 16% 3% Lev+DAs+ICOMT Lev+DAs+Anticholinergics 27% Lev+DAs+Other 44% 17% 64% 3% 0% 8% 16% 2% Monotherapy DAs* Lev alone Pramipexole Lev+ICOMT 4% Cabergoline Lev+(selegiline/amantadine/other AP) 22% Ropinirole DAs+ICOMTs Pergolide Monotherapy others 51% Monotherapy DAs 23% Lev+DAs No clear relationship between pharmacological data and: NPI items (including hallucinations) Executive dysfunction EDS (Epworth questionnaire) Levodopa (Lev) used by 74.2% of the patients, either alone (27%) or mainly in combination with dopamine agonists (DAs) Kulisevsky et al. Mov Disord 2008;23: To view abstract, click Abstracts link above 14

15 Evolving pharmacological response to Lev: three types of PD patients without dementia in whom DA cognitive response should be examined (1) Executive task perfor rmance Proper prefrontal cortex function De Stable responders Wearingoff PD novo PD Optimum patients (for PD) Too little DA receptor stimulation Too much Kulisevsky J. Drugs Aging 2000;16: To view abstract, click pause then click Abstracts link above 15

16 Evolving pharmacological response to Lev: three types of PD patients without dementia in whom DA cognitive response should be examined (2) De-novo 1 Incomplete (below normal range) cognitive improvement Working memory various frontal tasks Declines at 18 months, lost significance at 24 months Advanced PD patients (acute challenge of Lev) Stable responders to oral Lev 2 Little, if any, modification in tasks covering a wide range of cognitive domains Wearing-off 3 Acute (reversible) worsening performance in highly demanding frontal tasks Wisconsin Card Sorting Test (WCST), Sternberg paradigm, or associative conditional learning 1 Kulisevsky et al. Mov Disord 2000;15: Kulisevsky J. Drugs Aging 2000;16: Kulisevsky et al. Brain 1996;119: To view abstract, click Abstracts link above. To view notes, click notes tab 16

17 Cognitive effects of pharmacological manipulation of the DA system Chronic DA replacement Acute DA challenge may have contrasting Improves motor and cognitive effects 1. Same task different motor response functions but is not enough to (e.g. WCST) compensate for Fuctuating patients worsening performance in On vs Off All motor deficits Returns to previous level of All cognitive deficits performance when plasma levels of LD decays Proper prefrontal cortex function 2. Same patients different tasks Executive ta ask performan nce De novo PD Too little Stable responders Wearing -off PD Optimum patients (for PD) DA receptor stimulation Kulisevsky J. Drugs Aging 2000;16: Too much Depending on frontal cortical regions with different DA depletion in PD 3. Same task - different polymorphisms Genes regulating g dopaminergic transmission COMT 4. Same patients rapid vs slower plasma increase in LD level Standard transient negative effects vs retard protecting effects 17

18 Cortical cholinergic activity is reduced in PD and PDD Mean Cortex Amygdata Hippocampus Inferior Temporal Superior Temporal Parietal Patients With Alzheimer Disease Patients With Parkinson Disease Without Dementia Patients With Parkinsonian Dementia Cerebral AChE activity correlates with neurological deficits in PDD Verbal memory Stroop colour word tests Trail-making test Digit it span Benton s Judgement of Line Orientation Frontal % Reduction in AChE Activity Hilker et al. Neurology 2005;65: ; Bohnen. J Neurol 2005;253: To view abstract, click Abstracts link above. To view notes, click notes tab 18

19 Rivastigmine versus placebo: changes from baseline on the Alzheimer s Disease Assessment Scale cognition (ADAS-cog) Change from baselin ne, ADAS-co og Rivastigmine (n=329) Placebo (n=161) * ** Improvement Baseline 1.0 Deterioration Week: *P = 0.002; **P < 0.001, efficacy analysis Emre et al. N Engl J Med 2004;351: To view abstract, click Abstracts link above. To view notes, click notes tab 19

20 Question 1. In Kulisevsky's 2008 study, what proportion of patients without dementia had at least one psychiatric symptom? A) 38% B) 58% C) 68% D) 97% Correct - Click anywhere to continue Incorrect, please try again Incorrect, You must please answer try again the question before continuing Submit Clear 20

21 Question 2: Impaired cognitive tasks in PD are very reminiscent of tasks impaired in processes affecting: A) Temporal lobes B) Occipital lobes C) Frontal lobes Correct - Click anywhere to continue Incorrect, please try again Incorrect, You must please answer try again the question before continuing Submit Clear 21

22 Copyright statements Slide 8 Slide 9 Slide 13 Slide , reproduced with permission from Oxford University Press 2008, reproduced with permission from John Wiley & Sons, Inc 2005, reproduced with permission from Wolters Kluwer, Inc 2004, reproduced with permission from Massachusetts Medical Society. All rights reserved 22

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