Parkinson s Disease COGS 172

Transcription

1 Parkinson s Disease COGS 172

2 Background: Neuroanatomy of the motor system

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6 Black: inhibitory Grey: excitatory

7 Parkinson's Disease (PD) urodegenera<ve disorder ally age ~50 Incidence rises with age Affects 1-2% of popula<on > age 65 her incidence in men (~60%) compare men. Reasons unclear (hormones vs lifestyl

8 Parkinson's Disease (PD) erved since ancient <mes Sanskrit Ayurvedic texts ~10 th century BC refer tremors, rigidity, drooling (Kampavata) Egyp<an papyri and Bible references to tremor and drooling due to age Galen wrote an essay on shaking palsy that is thought to be a clear reference to PD (~150 AD es Parkinson: An essay on the shaking alsy (~1897, London) di<on named by French neurologist Jeanar<n Charcot (~1865)

9 Parkinson's Disease (PD) ptoms Rigidity Tremor Akinesia/Bradykinesia Posture/Balance disturbances Cogni<ve deficits (esp. execu<ve func<on Psychiatric/Mood symptoms

10 iad of motor symptoms remor ost common first symptom, usually asymmetric and most evident in one and with the arm at rest. igidity uscle tone increased in both flexor and extensor muscles providing a co esistance to passive movements of the joints; stooped posture, anteroflex ead, and flexed knees and elbows. radykinesia (slow movements) ifficulty with daily activities such as writing, shaving, using a knife and nd opening buttons; decreased blinking, masked facies, slowed chewing wallowing. ptoms worsen as disease progresses.

11 PD Symptoms

12 e<c Basis: en<cal twins tend to develop around same age veral genes iden<fied ironmental Factors: lso known to affect PD but not all iden<fied posure to: Pes<cides Metals Certain solvents auma<c brain injury ot geographically uniform (diet? toxin exposure?

13 Tremors Usually first symptom occurs in the hands or arms can occur in head, face, jaw, & leg disappears during purposeful movement such as picking up an object

14 Tremors Con<nued Usually unilateral Can become bilateral Can worsen with stress

15 ostural manifesta6ons Postural instability Rigidity Stooping Postural changes can cause balance instability

16 Stage Symptoms One Two Unilateral Bilateral No balance impairment Three Balance impairment Mild to moderate disease Four Five Physically independent Severe disability Still able to walk & stand unassisted Wheelchair-bound or bedriddened unless assisted

17 ctory changes ysfunc<on p disturbances ression: Mild to moderate depression ~50 % pa<ents. ni<ve impairment: Mild cogni<ve decline including impaired visual-spa<al percep<on a ajen<on, slowness in execu<on of motor tas and impaired concentra<on in most pa<ents least 1/3 become demented during the cours

18 e studies report changes in neural oscilla<o, theta and beta bands) y body protein deposits may be found (Lew body demen<a can be confused with Alzheimers and Parkinsons)

19 Neuropathology Cells degenerate in substan<a nigra (Sn)

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21 Dopamine Black: inhibitory Grey: excitatory Reduced dopami

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23 Parkinson s Disease Parkinson s and Depression Parkinson s Disease Parkinson s Disease Genetic factors: twins affected by PD Symptoms: almost always develop symptoms together Rigidity been identified Tremor - 13 genes have factors : exposure to Cognitive deficits Environmental toxins - manganese, carbon monoxide, Other MPTP-->MPP+, pesticides Possibly oxidative stress (free radicals)

24 Cognitive Impairment in PD Parkinson s Disease Working memory deficits - Symptoms: verbal, visuo-spatial Rigidity Executive function - Wisconsin Card Sort Task, Tremor Tower of London Sometimes Cognitive difficult deficits to separate from dementia Other Possibly due to cortical dopamine deficiency

25 (Leh, 2010) peaks within the retrieval with vs the retrieval without condi<on of the Montreal Card Sor<ng Task trols during fmri. Coronal sec<ons are shown. The images display significant ac<va<on in the VLPFC and e control group, whereas none is observed in the Parkinson's disease group. They also show larger ac<va<o p than in the pa<ent group in the posterior cingulate cortex and the posterior parietal cortex bilaterally. (b) sis. Images display significantly greater ac<vity in the control group vs the pa<ent group in the le@ dorsolater

26 Treatment not give dopamine? Not quite pamine itself, does not pass the blood-brain barr odopa (L-dopa) can be given to pass into the bra the nerve cells then use it to make dopamine acy tends to decrease as the disease progresses. nic treatment associated with adverse events (m ctua<ons, dyskinesias and neuropsychiatric blems). Cf schizophrenia lecture

27 Treatment not give dopamine? Not quite pamine itself, does not pass the blood-brain barr odopa (L-dopa) can be given to pass into the bra the nerve cells then use it to make dopamine cacy tends to decrease as the ease progresses. ronic treatment associated h adverse events (motor ctua<ons, dyskinesias and uropsychiatric problems). Cf izophrenia lecture Side-effects Dyskinesia

28 Side-effects Dyskinesia

29 not give dopamine? Not quite pamine itself, does not pass the blood-brain barr odopa (L-dopa) can be given to pass into the bra the nerve cells then use it to make dopamine cacy tends to decrease as the ease progresses. ronic treatment associated with verse events (motor fluctua<ons, skinesias and neuropsychiatric blems). Cf schizophrenia lecture Side-effec Dyskinesia r medica<ons pamine-agonists: act on dopamine receptors, mi tural dopamine, not as effec<ve as L-dopa

30 (Lozano, 19 Microelectrode ablation of unilateral GPi for the treatment of ideopathic PD.

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33 Neuroanatomy Deep Brain the Stimulation motor syste Look Neuroanatomy away if you are of the squeamish motor system

34 DBS surgery

35 Localization of the subthalamic nucleus (STN)

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37 Effects of STN DBS Improved motor function (generally) Improved motor function (generally) Effects on cognition and mood are not well Effects on cognition and mood are not well understood: understood: - impaired attention, executive function, and impaired attention, executive function, and memory memory - improved mental flexibility, executive improved mental flexibility, executive function, function, working memory, and conceptual working memory, and conceptual reasoning reasoning increased apathy, depression, hypomania, increased apathy*, depression, hypomania, and emotional reactivity and emotional reactivity -

38 STN DBS

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41 STN DBS: How does it work?

42 STN DBS: How does it work? TP monkey model of PD with STN stimulation resulted in

43 STN DBS: How does it work? Does not simply modulate the rate of cell firing STN DBS may reset the patterns of firing throughout the basal ganglia Operates at the level of network dynamics rather than serving as a targeted reversible lesion

44 Conclusions PD may have multiple etiologies (genetic and environmental) Motor symptoms are attributed to dopaminergic cell loss in the substantia nigra pars compacta Motor symptoms: rigidity, tremor, akinesia/ bradykinesia Not only a motor disorder (cognitive and psychiatric symptoms as well) Treatment: L-dopa, surgery, cell transplant, deep brain stimulation DBS may provide insights into overall network dynamics in the BG for the treatment of motor an