Memory and Treatment of Cognitive Impairments

1. Memory and treatment of cognitive impairments MUDr. Tomáš Kašpárek Dep. of Psychiatry Masaryk University, Brno

2. Contents • Introduction • Physiology and classification • Memory assessment • Disturbances in memory • Treatment of cognitive impairment

3. Introduction • Definition: ability to register, store, and recall information (three stages of memory) • Memory: part of cognitive functions (involved in information processing;such as perception, thinking, attention) • Dimensions of behavior • cognition (reasoning) and emotionality

4. Stages of memory I: Registration • capacity to add new material (sensory, conceptual, perceptual) to memory • new information need to be properly processed(percepted) – disturbing factors • consciousness • attention • emotions • repetition

5. „Life cycle“ of a memory trace • Immediate memory • information stored for 15-20s • Short-term memory • consolidation of the memory trace – several minutes to 2 days • medial temporal structures • Long-term memory • formed trace • large cortical areas

6. Stages of memory II: Retention • ability to hold memories in a storage • large # of neurons (changes in connectivity) involved in the storage of specific memory • sensory specific fractions of complex perceptions in corresponding cortical areas

7. Stages of memory III: Recall • ability to return stored information • active reconstructions • adding together fractions of the exact recollection • in a specific situation (=influence) – possibility of the failure to represent of past events properly • awareness of the recollection, sureness, proper addressing of time and situation of recollection acquirement

8. Types of memory: Memory modules (Willingham 1997) • Explicit (declarative) memory – medial temporal cortex • Procedural memory – sensory-motor functional systems • Working memory – prefrontal cortex • Classical conditioning – cerebellum; relation between motor function and perception • Emotional conditioning – amygdala; relation between perception and emotion • Priming - parietal, temporal and frontal cortex

9. Memory assessment • Immediate recall • series of numbers (most adult recall 6 # forward and 3 in reverse) • Short-term memory • names of 3 inrelated objects after 5 min • Long-term memory • personal history (independent confirmation), general information (names of presidents...) • Scales – MiniMental State Examination • Specific tests – Wechsler Memory Scale III

10. Disturbances in memory

11. General notes • memory = set of functions based on different neuronal processes = various dysfunctions according to the pathological process

12. Disturbances in registration • pathological process • disturbed vigilance, attention • head trauma, seizures, delirium, intoxication (BZD, sedatives), psychosis, depression, anxiety • disturbed structures involved in memory consolidation • hippocampus, mammillary bodies, fornix – i.e. mediotemporal structures • short-term memory dysfunction, immediate recall may be spared

13. Disturbances in retention • pathological process • impairment of large cortical areas • posttraumatic amnesia • cognitive disorders

14. Disturbances in recall • may reflect damaged storage • may occur separately • failure to recall with later proper recollection • personality, situation • attention, fatigue...

15. „Quantitative“ dysfunctions • Amnesia: short/long-term memory impairment in a state of normal consciousness • anterograde: failure to form new information • head trauma, state of CNS dysbalance, drug effect • retrograde: failure to recall old information • head trauma • dissociative amnesia: patchy or selective • Hypermnesia: unusually vivid memory • mania, posttraumatic stress disorder (intrusive memories), obsessive or paranoid personality traits

16. „Qualitative“ dysfunctions • paramnesias – retrospective falsification of memories during its recollection (awareness of recalled memory, failure to proper class time and situation of memory acquirement) • confabulation – filling memory gaps with inaccurate information; frontal lobe and self-monitoring? • deja vu – sensation of previously experienced situation when experiencing the first time • false awareness of memory • common in normality, increased in fatigue, intoxication, complex partial seizures

17. Treatment of cognitive impairment

18. General notes • no specific way to treat memory deficit • treatment modalities focused on the whole spectrum of impairments in cognitive disorders • the most data available for Alzheimer's disease

19. Psychopharmacotherapy • Reinforcement of cholinergic mechanism • Cholinesterase inhibitors (ChEIs) • Prevention of excitotoxicity • Memantine - NMDA antagonists

20. Cholinesterase inhibitors I • cholinesterases: acetylcholinesterase (AChE), butyrylcholinexterase (BChe)– hydrolysis of acetylcholin, thus decrease its amount in synapses • molecular forms of AChe • G4 (tetramer) – presynaptic membrane – both hydrolysis and feedback inhibition; decrease in AD and aging • G1 (monomer) – postsynaptic membrane; no significant decrease

21. Cholinesterase inhibitors II • donepezil • long-acting, selective, reversible AChEI • metabolized by the liver microsome syst. • rivastigmin • pseudo-irreversible, both AChEI (G1) and BChEI • no liver microsome metabolism • galantamin • reversibilie, competitive (increases AC only in areas with low AC concentration – lower central cholinergic side effects than noncompetitive inhibitors) AChEI + allosteric modulation of nACR

22. Cholinesterase inhibitors III – adverse effects • significant cholinergic side effects in 15% of patients receiving higher doses • most common: • GIT: nausea, vomiting, diarrhea, anorexia, weight loss • CNS: headache, dizziness, insomnia, drowsiness, fatigue, agitation • CVS: bradycardia, syncope • generally mild in severity, short-lived, related to titration (slowly!) • caution in patients with asthma, CHOPD, cardiac conduction defects/clinically significant bradycardia

23. Memantine I - Rationale • excessive glutamate release in Alzheimer's disease (as well as vascular dementia - ischemic damage) • excitotoxic degradation of neurons • progression of cognitive decline, severity of other symptoms • neuronal degradation is linked with amyloid accumulation

24. Memantine II – Mechanism of action • non-competitive NMDA antagonist • voltage dependent, fast receptor kinetics – enable physiologic function (LTP, memory) decreased activity of glutamate system • hippocampus, neocortex decreased excitotoxicity - neuronal damage – amyloid accumulation i.e. slow down progression of the disease • 5HT3 blockade • facilitation of LTP • antiemetic effect and regulation of GIT motility (combination with ACEI)

25. Memantine III – Clinical efficacy • slower progression of vascular and Alzheimer dementia • fast onset of action – 2 weeks • improvement of cognitive functions, vigility, daily activities • reduction of the need for the help of caregivers • efficacy even in the moderate to severe disease stages x ACEI

26. Memantine IV • Adverse events • generally well tolerated • higher than placebo: insomnia, dizziness, headache, hallucinations (NMDA antagonist – PCP) • Pharmacokinetics • renal excretion • no extensive metabolization • no cytochrome P 450 inhibition • dosage • 20 mg pro die in 2 doses • start: 5 mg, titration: 5 mg per week

27. References : • Waldinger R.J.: Psychiatry for medical students, Washington, DC : American Psychiatric Press, 1997 • Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Sadock´s synopsis of psychiatry, Baltimore: Williams and Wilkins, 1997