The Neuropsychiatry of Movement Disorders Eileen Joyce

1. The Neuropsychiatry of Movement Disorders Eileen Joyce

2. Neuropsychiatric symptoms of Parkinson’s disease • Early : • Cognitive impairment • Apathy, depression and anxiety • Sleep disturbance • Late: • Dementia • Psychosis • Drug induced: • Addictive/compulsive – gambling, sex, shopping • Psychosis

3. Neuropsychiatric symptoms of Parkinson’s disease • Early : Pathology • Cognitive impairment Lewy body – subcortical nuclei • Apathy, depression and anxiety • Sleep disturbance • Late: • Dementia Lewy body - cortex • Psychosis • Drug induced: • Addictive/compulsive – gambling, sex, shopping • Psychosis

4. Neuropsychiatric symptoms of Parkinson’s disease • Early : PathologyNeurochemistry • Cognitive impairment Lewy body Dopamine • Apathy, Depression and anxiety (subcortical nuclei) Noradrenaline • Sleep disturbance Serotonin • Late: • Dementia Lewy body Acetylcholine • Psychosis (cortex) • Drug induced: • Addictive/compulsive – gambling, sex, shopping Dopamine • Psychosis

5. Neuropsychiatric symptoms of Movement Disorders • Early : NeuropathologyNeurochemistryMechanism • Cognitive impairment Lewy body Dopamine frontostriatal • Depression and anxiety (subcortical nuclei) Noradrenaline • Sleep disturbance Serotonin • Late: • Dementia Lewy body Acetylcholine cortical • Psychosis (cortex) • Drug induced: • Addictive/compulsive Dopamine frontostriatal • Psychosis

6. Parkinson’s disease • The incidence of the disease rises steeply with age • 17·4 in 100 000 person years between 50 and 59 years • 93·1 in 100 000 person years between 70 and 79 years, • Lifetime risk of developing the disease = 1·5% • Median age of onset is 60 years • Mean duration of the disease from diagnosis to death is 15 years

7. Parkinson’s disease • Hallmark motor symptoms: • Bradykinesia • reduced frequency and amplitude of spontaneous • movement =poverty of movement • Tremor • ‘pill rolling’ resting tremor • Rigidity • increased muscle tone Lees at al 2009

8. Parkinson’s disease Hallmark neuropathology: A region-specific selective loss of dopaminergic, melanin-containing neurons from the pars compacta of the substantia nigra

9. Lees 2009 Parkinson’s disease • Neuropathological lesions: • nerve-cell loss is accompanied by three distinctive intraneuronal inclusions: • the Lewy body = α-synuclein • the pale body – predecessor of Lewy body • the Lewy neurite – α-synuclein in the axons or dendrites

10. Parkinson’s disease • Alpha synuclein: • normally an unstructured soluble protein • expressed in the limbic and neocortex, substantia nigra, brainstem nuclei • aggregates to form insoluble fibrils in pathological conditions • these form Lewy bodies and result in neuronal degeneration • occur in Parkinson disease, dementia with Lewy bodies and • the multiple system atrophies • these disorders are known as synucleinopathies

11. Dopamine Projections Dense dopamine projections to striatum = caudate, putamen and n accumbens [n.accumbens=ventral striatum] Diffuse dopamine projections to frontal cortex Nigrostriatal pathway: Substantia nigra Dorsal striatum Mesolimbic and mesocortical system: Ventral striatum Ventral tegmental area Frontal cortex

12. FluoroDOPA PET scans Health Parkinson’s onset Parkinson’s after 12 years Rodriguez-Oraz 2009 NB DaT scan: SPECT scan of labelled dopamine transportor = index of number of dopamine terminals

13. Functional neuroanatomy of basal ganglia: frontostriatal feedback loops cortex striatum thalamus pallidum Direct pathway loop facilitates action

14. Functional neuroanatomy of basal ganglia: frontostriatal feedback loops cortex striatum thalamus pallidum subthalamic nucleus Indirect pathway inhibits action

15. Functional neuroanatomy of basal ganglia: frontostriatal feedback loops Normal Dopamine facilitates the direct pathway Parkinson’s disease Reduced dopamine facilitates the indirect pathway Difficulty initiating movement

16. Rodriguez – Oraz et al 2009 Motor symptoms of PD correlate with dopamine loss in putamen = motor region of striatum

17. Functional neuroanatomy of basal ganglia: frontostriatal feedback loops movement cognition: emotion: executive function motivation social responsivity empathy mood Rodriguez –Oraz 2009 motor cortices dorsolateral prefrontal cortex orbitofrontal + anterior cingulate cortex

18. Neuropsychiatric symptoms of Parkinson’s disease - cognition • Early cognitive impairment: • Executive function: • prefrontal cortex and associative circuit • the optimisation of behaviour on novel situation (i.e. non-routine) • Five situations are thought to be particularly governed by executive functions • (Norman & Shallice 1980): • Those that involve planning or decision making • Those that involve error correction • Situations where responses are not well learned or contain novel sequences of actions • Dangerous or technically difficult situations • Situations requiring the overcoming of a strong habitual response/resisting temptation • Executive dysfunction in early PD • Secondary to dopamine reduction in associative circuit • Can be improved by dopamine enhancement treatment

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23. Accuracy Speed Owen et al 1992 bradyphrenia

24. Neuropsychiatric symptoms of Parkinson’s disease - cognition Development of cognitive impairment with disease progression: the pattern of cognitive impairment in PD emerges and subsequently progresses according to a defined sequence that evolves in parallel with the motor deficits that characterize the disorder parallel depletion of dopamine innervation of dorsal striatum that also receives inputs from motor cortex and dorsolateral prefrontal cortex controlling action (motor circuit) and executive function (associative circuit) respectively

25. Parkinson’s disease dementia Early: executive dysfunction Late: widespread cognitive impairment Neuropsychiatric symptoms of Parkinson’s disease - cognition

26. Parkinson’s disease dementia The rate of cognitive deterioration in patients with PD is faster than in normal controls The greatest risk factor for dementia is the age of the patient and not the duration of the disease Frontostriatal mediated executive impairment does not predict dementia Predictive cognitive impairment are impaired semantic fluency and copying intersecting pentagons - reflecting temporal and parietal impairment A recent meta-analysis of 25 longitudinal studies reported strong evidence that significant cognitive changes occur, particularly in memory function and visuoconstructive abilities Dementia is probably due to Lewy body neurodegeneration in cortex and degeneration of subcortical acetylcholine neurones

27. Neuropsychiatric symptoms of Parkinson’s disease - cognition Nucleus basalis of Meynert (ACh) involved in Lewy body neurodegeneration Acetylcholine – nucleus basalis of Meynert - basal forebrain – memory and attention Consider using rivastigmine for cognitive impairments especially later in disease when cortical cholinergic involvement is widespread

28. Neuropsychiatric symptoms of Parkinson’s disease: emotion Schapira 2009 Depression, anxiety, and apathy are the most prevalent symptoms in untreated patients with early PD and often precede motor symptoms depression (37%), anxiety (17%) apathy (27%)

30. Neuropsychiatric symptoms of Parkinson’s disease - emotion PD with depression versus Major Depression: less guilt and self-blame greater rates of anxiety, irritability and suicidal ideation When patients experience fluctuating drug effects (on/off) acute lowering of mood can suddenly emerge during ‘off’ periods Treatment with dopamine enhancing drugs can improve in mood Apathy Reduction in affective responsivity and motivation Can be dissociated from depressed mood – sadness and distress Can be improved by dopamine agonist therapy Why do some patients develop apathy and others depression?

31. Non dopamine inputs to frontostriatal loops and emotional symptoms Raphe nuclei (5HT) Locus coeruleus (NA) Can be involved in Lewy body neurodegeneration

32. Non dopamine inputs to frontostriatal loops and emotion Lewy body degeneration of other neurotransmitter systems known to be involved in emotion and cognition: Serotonin (5HT) – raphe nuclei – brainstem – emotion processing/limbic loop Noradrenalin – locus coeruleus – pons – emotion processing/limbic loop Rule of thumb for management: Optimise dopaminergic medication first Consider boosting serotonin with SSRI Consider boosting serotonin and noradrenaline with SNRI

33. Neuropsychiatric symptoms of Parkinson’s disease Sleep disturbance (18%) Disturbed sleep—including shouting out, flailing movements of arms and legs, and falling off the bed during dreaming Rapid eye movement (REM) sleep disorder In patients without signs of parkinsonism: 5-year risk of neurodegenerative disease to be 17·7% 10-year risk to be 40·6% after RBD associated with degeneration of lower brainstem nuclei, such as the pedunculopontine and peri-coeruleal nucleus

34. Neuropsychiatric symptoms of Parkinson’s disease • Early : PathologyNeurochemistry • Cognitive impairment Lewy body Dopamine • Depression and anxiety (subcortical nuclei) Noradrenaline • Sleep disturbance Serotonin • Late: • Dementia Lewy body Acetylcholine • Psychosis (cortex) • Drug induced: • Addictive/compulsive – gambling, sex, shopping Dopamine • Psychosis

37. Impulsive/compulsive behaviour and dopamine dysregulation syndrome The lifetime prevalence of ICD in patients with Parkinson’s disease is 6% to 9%, and almost 14% in patients treated with receptor agonists Hypersexuality 4-7% Pathological gambling 6-7% impulsive/compulsive Excessive spending 1.5% - 7% Compulsive eating ~6% Punding ~ 14% (~30% of patients receiving high DRT dose) An intense fascination with excessive, repetitive, non-goal directed behaviours – analogue of amphetamine induce stereotypy Dopamine medication dependence i.e. pathological use, <1% to 4% = dopamine dysregulation syndrome despite destructive compulsive behaviours and dyskinesias

38. Psychosis in Parkinson’s disease Psychotic symptoms rarely occur in untreated PD patients Common > 10 years after the initial diagnosis Estimates of the prevalence of illusions or hallucinations in treated PD patients vary from 15 to 52%. Delusions occur in 7–16% of patients who have PD, usually in addition to hallucinations Unlike hallucinations in schizophrenia, hallucinations in PD are predominantly visual and less often auditory, gustatory, olfactory or tactile

39. Psychosis in Parkinson’s disease PD patients with psychotic symptoms can be divided into two phenomenological groups: Group 1 mild, primarily visual hallucinations (animal or human figures) insight into the hallucinations retained not troubling (‘‘benign hallucinosis’’) Usually a consequence of medication: limbic dopamine less depleted than motor striatal dopamine resulting in relative over activation Increased dopamine transmission in limbic circuitry Why do some patient become psychotic and others impulsive/compulsive behaviours?

40. Psychosis in Parkinson’s disease Group 2 Typically PD patients with dementia, suffering complex psychotic symptoms, including both hallucinations and delusions. No insight into their psychosis, and often find their hallucinations frightening Probably due to Lewy body deposition in limbic areas and/or depletion of cortical acetylcholine – cholinergic enhances can improve hallucinations Persistent psychosis in PD results in significant anxiety, increases the risk of long-term nursing home placement, has a strong impact on caretaker burden, and is strongly associated with social and functional impairment The only antipsychotic with proven efficacy is clozapine which can be effective at low doses - 50mg

41. Understanding the neuropsychiatry of movement disorders Parkinson’s disease Lewy Body dementia Multisystem atrophies Alpha synuclein: Substantia nigra Pons Cerebellum Basal forebrain limbic and neocortex Parkinsonism Cerebellar ataxia Autonomic dysfunction executive dysfunction dementia apathy depression psychosis

42. Understanding the neuropsychiatry of movement disorders Progressive supranuclear palsy Tau: Substantia nigra Nucleus basalis Locus coeruleus Raphe nuclei Subthalamic nucleus Striatum and pallidum Oculomotor complex Parkinsonism Opthalmoplegia Dysarthria Pseudobulbar palsy Executive dysfunction Apathy Lability of mood Disinhibition Compulsive behaviour

43. Understanding the neuropsychiatry of movement disorders Wilson’s disease Copper deposition: basal ganglia thalamus cerebellum Rigidity Dystonia Choreoathetosis Cognitive impairment Mood disorder Personality change

44. Understanding the neuropsychiatry of movement disorders Huntington’s disease Huntingtin in GABA neurones Caudate Frontal cortex Chorea Depression Irritability and aggression Psychosis Cognitive impairment

45. Understanding the neuropsychiatry of movement disorders Tourette’s syndrome Neurodevelopmental abnormality of GABA/DA synaptic function in striatum Impaired inhibition of movement and thought Tics ADHD OCD

46. Don’t forget to take a history for Psychosocial factors Premorbid factors