Lecture 8 PAD - Dementia Treatment

LEC TU RE 8 – DEMENTIA TREATMENT Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Date Lectur Details Theme e 1 Introduction to Ageing and Dementia 2 Biologic...

LEC TU RE 8 – DEMENTIA TREATMENT Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Date Lectur Details Theme e 1 Introduction to Ageing and Dementia 2 Biological Ageing “HEALTHY 3 Cognitive Ageing AGEING AND THE BRAIN” 4 Neurophysiological and Psychosocial Ageing “Talking about Healthy Ageing” discussion 5 MCI – Diagnosis / Research “AGE-RELATED 6 MCI – Treatment DISEASES AND PATHOLOGY” 7 Dementia – Diagnosis / Research 8 Dementia – Treatment “Talking about Dementia” discussion 9 Living with Dementia “THE INTRA- 10 Dementia friendly INDIVIDUAL PERSEPCTIVE” 11 Revision – Feedback and Reflection OVERVIEW OF TODAY’S LECTURE PART ONE: Dementia Treatment Pharmacologic Interventions: Cholinesterase Memantine Non-pharmacologic interventions PART TWO: Treatment considerations Links between Depression and Dementia Future Directions  PA R T ON E : DEMENTIA TR E ATM E NT O N -P HA R M AC OL O G IC DN PHARMACOLOGIC AN F A C TION A N D M O D ES O INTERVENTIONS  A) DRUG- BASED TREATMENT FOR ALZHEIMER’S DISEASE  ACETYLCHOLINE (AChE) INHIBITORS Acetylcholine (ACh) is a highly abundant neurotransmitter in the brain. It is a chemical messenger that is released from the synapse of one neuron across a synaptic gap to the receptors of receiving neuron, to generate an action potential (chemical message). Cholinergic neurons are lost in AD reducing ACh in the system. Acetylcholine inhibitors aka cholinesterase inhibitors stop the breakdown of ACh via the Acetylcholinesterase (AChE), allowing Ach to remain active for longer and increase concentrations  POSSIBLE PHARMACEUTICAL INTERVENTIONS. Three possible pharmaceutical interventions for AD: TAU – neurofib 1) Target TAU protein rillary production/disruption tangles (Brion & Delacourte, Deficien 1985). Amyloid cy in 2) Target Amyloid beta Beta Acetylch mutation. and Aβ Plaques Neural oline plaque formation death (Glenner, 1984). and failure 3) Increase production of in ACh to improve Alzheime neurotransmitter r ’s signalling (Davies, 1976). Disease  CHOLINERGIC HYPOTHESIS IN AD (PETER DAVIS, 1976) In Alzheimer’s disease there is a loss in memory function. ACh is the prominent neurotransmitter in attention, memory and learning and is essential for plasticity in the brain. This “Cholinergic hypothesis in AD” identifies a deficit in ACh in AD, either by reduction in production, or too much Hence the creation of drugs Acetylcholinesterase (AChE) at that inhibit acetylcholine the synapse breaking it down. break down (Acetylcholinesterase, AChE) back into Acetyl and Choline. Singh et al. (2013). Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection, European Journal of Medicinal Chemistry, Volume 70: 165-188.  CHOLINESTERAS E THERAPY FOR TheAD 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity. The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials. However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these https:// consultqd.clevelandclinic agents..org/alzheimer-dementia- starting-stopping-drug- therapy/ COMMO N SIDE EFFEC TS https:// consultqd.clevelandclinic.org/alzheimer-dementia- starting-stopping-drug- therapy/ Memantine is another sub- family of drugs used for MEMANTINE treating dementia symptoms. The main mechanisms is via the blockage of the NMDA (N- Methyl-D-Aspartate) receptor stopping glutamate from exciting the neuron i.e. it is a NMDA antagonist. The main reason is to reduce the effects of glutamate in the brain that leads to SIDE EFFECTS: Dizziness, Headache, Confusion, Excitability/emotional lability, Constipation. hyperexcitability in AD and CONTRAINDICATIONS: Memantine should not be used in patients with renal/hepatic excess noise. disease Parsons et al.,(2007). Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacol. Neuropharmacology. 53. 699-723. 10.1016/j.neuropharm.2007.07.013.  NEW TREATMENT (2023) – LECANEMAB (FDA APPROVED) Video interlude https://youtu.be/ BFE8nOyKwhQ  There are limited treatment options: Due to the nature of vascular dementia then life expectancy from diagnosis is ~ 5 years. Cause of TREATME death is often stroke or heart attack in patients rather than from NT FOR Dementia per se. VASCULA Daily Aspirin/Clopidogrel helps reduces the risk of blood clots and R anticoagulant medicine (Warfarin) DEMENTIA may also help reduce further strokes. Medicines to treat high blood pressure and diabetes's may also be given. Please note that there is no cure and no way of reversing damage in the brain already done.  There are limited treatment options and again it is about treating the symptoms: TREATME FTD affects individuals in terms of NT FOR mood, and behaviour. Due to the lack of inhibition, FRONTO- overeating and the compulsive types TEMPORA behaviours SSRIs (Selective Serotonin Reuptake Inhibitors) are L prescribed aka anti-depressants. DEMENTI In addition, some individuals can A experience hallucinations with FTD and severely challenging behavior, and therefore anti-psychotic drugs may also be prescribed. Examples include olanzapine (Zyprexa) or quetiapine (Seroquel).  TREATMENT FOR DEMENTIA WITH LEWY BODIES (DLB) Due to the similar nature of Dementia with Lewy Bodies and Alzheimer's Disease the drug options are the same as with AD. These include Acetylcholine Inhibitors (Ach) and memantine (NMDA blockers).  Acetylcholi Levodopa ne – Inhibitors replaces dopamin : Galantamine, FURTHER e Moveme nt Neurotr ansmitt Donepezil, Rivastigmine TREATMEN Problem s er issues , Memantine TS FOR (GLUTAMATE ) DLB Depress REM Sleep ion Disorder Anti- Clonazepa depressan m: ts: SSRIs sleeping increases and serotonin anxiety For sever behavioural problem that are life threatening anti-psychotics maybe used such as haloperidol.  Interactive Task – IN “ CONSIDER THE PRO’S groups AND CON’S OF PHARMACOLOGIC INTERVENTIONS SIDE EFFECTS, COSTS, EFFECTIVENESS, QUALITY OF LIFE, ADHERENCE ”  REVIEW OF PHARMACOLOGIC INTERVENTIONS FOR There are DEMENTIA. modest improvement with drugs in standardized mini mental state examination (SMMSE) or the Bristol Activities of Daily Living (BADLS) for Schwarz, S. , Froelich, L. & Burns, A. (2012). dementia Pharmacological treatment of dementia. Current patients. Opinion in Psychiatry, 25 (6), 542-550. doi: 10.1097/YCO.0b013e328358e4f2. “ ANTI-DEMENTIA MEDICATION IS MINIMAL IN ITS EFFECTIVENESS IN SIGNIFICANTLY ALTERING THE TIME-COURSE IN DISEASE PROGRESSION. MORE RATIONALE IS NEEDED FOR USING DRUGS IN THESE PATIENTS. ” B) NON-DRUG BASED TREATMENT FOR ALZHEIMER’S DISEASE.  NICE GUIDELINES FOR NON- PHARMACOLOGIC INTERVENTIONS Cognitive Stimulation may offer some support for Dementia. Physical exercise has the most supporting evidence for early-stage Dementia. There is a significant lack of high-quality studies and Randomized Control Trails (RCT) investigating the effects of non-pharmacologic interventions in Dementia. Some areas not reflected in the report are assistive https://www.nice.org.uk/guidance/ng97/ technologies which needs further validation and evidence/appendix-o-yhec-report-pdf-174697045530 investigation.  Behav COGNITIVE iour THERAPY - Cognitive stimulation CBT - Cognitive Thoug Feeli rehabilitation hts ngs - Cognitive training Cognitive Behavioural Therapy (CBT) or Cognitive Restructuring Focus on symptoms of depression and anxiety in individuals with dementia and despite some misconceptions, some PLWD can really benefit from CBT. More about how they are linked next !!  BEHAVIOUR THOUGHTS AND FEELINGS QUESTIONNAIRE – Question DEMENTIA VERSION (BTFQ-D) Response Correct response The list of 1) Sad F 2) Angry F words on the 3) Working B left is read to 4) This is hard T 5) Answering the phone B the participant. 6) Happy F 7) Making a cup of tea B 8) I’m good at things T For each word, 9) Worried F use the key 10) I don’t know what to do for the best T 11) Gardening B below to list 12) I hope this works out T 13) Having a bath B the response of 14) Frightened F the participant: 15) I’ve achieved something T 16) Frustrated F 17) Washing up B B = Something 18) I’m a good person T 19) Playing darts B you do 20) Upset F F = Something 21) I’m looking forward to my holiday T 22) Miserable F you Feel T = Something youdementia: Stott J, (2020). Thought-feeling discrimination in people with think adaptation and preliminary validation of the first dementia-specific measure. Int Psychogeriatr. 2020 Jan;32(1):87-96  COMPARISON OF BFT QUESTIONNAIRE RESULTS SUMMARY OF TREATMENT OPTIONS Pharmacologica Non- l Pharmacologi cal Acetylcholine Inhibitors, e.g. Memantine Aspirin, blood pressure drugs. Levodopa, SSRIs, Chlonazepam , Mem/Ach inhibit. SSRIs, Anti- psychotic drugs BRAIN BREAK  P A R T T W O : DEM E N T IA A N D DEPR E S S IO N A N D FURTHER IN S IG H T S. LINK S B E T WE E N DE ME NT I A AN D DEP R E S S I ON  COVID HAS AFFECTED WORLD MENTAL HEALTH PREVALENCE Additional 1% of cases translates into millions of people worldwide. Prevalence has increased in all age groups, but especially those between 18-25 years old. Females are hardest hit. Click here to see source of info A WORRYING TREND IN MENTAL HEALTH  WHY IS Depression has often been linked with Dementia in DEPRESSION extensive research. WORTH Depression is also one of the CONSIDERIN early indicators of cognitive G FOR decline and Mild Cognitive Impairment (MCI). DEMENTIA Depression can develop at 3 TREATMENT possible stages of dementia … Precli Prodro Dement nical mal ia Predisposing risk Early Clear cognitive factor neurodegeneration deficits But HOW are depression and dementia linked ????  Hypothalamus-Pituitary-Adrenal Axis Increase in stress hormone cortisol Glucocorticoids Receptor Amyloid Precursor Protein (gene) Neurofibrillary tangles Brain Derived Neurotropic Factor HPA AXIS LINK BETWEEN DEPRESSION AND DEMENTIA Dafsari, F.S., Jessen, F. Transl Psychiatry 10, 160 (2020).  NEURO-INFLAMMATION AFFECTS OF DEPRESSION ON AD PATHOLOGY Dafsari, F.S., Jessen, F. Transl Psychiatry 10, 160 (2020). 5 – hydroxytryptaminergic neurons aka serotonin NEUROTRANSMITTER AFFECTS OF DEPRESSION ON AD PATHOLOGY Dafsari, F.S., Jessen, F. Transl Psychiatry 10, 160 (2020). SUMMARY OF DEPRESSION AFFECTS ON ALZHEIMER’S DISEASE. Dafsari, F.S., Jessen, F. Transl Psychiatry 10, 160 (2020). Neuromodula tor/Excitatory Inhibitory – [ B/C ] reduces over- excitation. Excitat Neuromodul ory ator [C/M] Inhibitory [S/H/P] Yang, Zou and Wang, 2023  AGE AT DEPRESSION ONSET RELATED TO DEMENTIA RISK … A review from Byers and Yaffe (2011) suggest that early onset depression is related to a higher incident of dementia in later life (2-4 fold increase). Some studies actually suggest it is more related to the number of depressive episodes rather than onset date. However this was only based on 5 studies and they defined early onset as < 60 years !! Much more research needed in this area to decipher causal direction i.e. does preclinical Dementia pre- disposition to depression or vica versa (chicken and egg issue). Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011 May 3;7(6):323-31. doi: 10.1038/nrneurol.2011.60. PMID: 21537355; PMCID: PMC3327554.  CAN ANTI-DEPRESSANTS AFFECT DEMENTIA RISK ? +’ve anti-depressant -’ve antidepressant effects In theory Anti-depressants effects Anticholinergic drugs can alleviate some of the stress mechanisms the body engages in during a depressive episode. It can reduce used for bladder Conflict the circulating stress hormone (cortisol), reduce neuroinflammation, increase neurogenesis and neurotropic effects, symptoms (i.e. stops to production of Ach) can increase dementia risk by Tau. ing increase BNDF = all counteracting AB and Some studies show SSRIs actually improve up to 20%. Some studies report a evidence cognitive function in daily life in MCI and clear and associated risk Dementia. of taking anti-depressants Other studies suggest anti-depressants may and increasing the risk of infact delay/stop the progression from MCI to = still Alzheimer's Disease. development of dementia Dafsari, F.S., Jessen, F. Depression—an underrecognized target unresolv for prevention of dementia in Alzheimer’s disease. Transl Psychiatry 10, 160 (2020). TIME TO VEVOX PAD - Dementia Treatment https://vevox.app/#/m/143375945 Session ID: 143-375-945 WATCH THIS … “THE 3 D’S OF GERIATRIC PSYCHIATRY” This is a nice simple lecture on: DELIRIUM, DEPRESSION and Why not try the DEMENTIA SAQs for lectures 5-8 in MINERVA https://www.youtube.com/ watch?v=2ikIlSgJ90w READING LIST FOR TODAYS LECTURE: Cummings, Jeffrey L., Tong, Gary, and Ballard, Clive. ‘Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options’. 1 Jan. 2019 : 779 – 794. Schwarz, S. , Froelich, L. & Burns, A. (2012). Pharmacological treatment of dementia. Current Opinion in Psychiatry, 25 (6), 542-550. doi: 10.1097/YCO.0b013e328358e4f2. Dafsari, F.S., Jessen, F. Depression—an underrecognized target for prevention of dementia in Alzheimer’s disease. Transl Psychiatry 10, 160 (2020). https://doi.org/10.1038/s41398-020-0839-1. Further reading: Parsons et al (2007). Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacol. Neuropharmacology. 53. 699-723.