Dementia Disorders of Brain Function PDF

Dementia SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Defi...

Dementia SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Define dementia 2. Differentiate between mild, moderate, and severe presentation of Alzheimer disease 3. Identify cardinal symptoms of Alzheimer disease 4. Describe postulated pathophysiologic processes for Alzheimer disease. Normal Cognitive Aging Short-term memory ○ Intact; Aging may require greater (slower) processing Long-term memory ○ Deficiencies noted by 50 years ○ Retrieval processes affected Connectivity of neuronal network impaired ○ Hippocampus  cortices ○ Neurotransmitters  Acetylcholine  Glutamate  Neuropeptide Y  Orexin A  Opioid peptides  Cholecystokinin  Ghrelin  Dementia Defined as a syndrome of deteriorating cognitive function significant enough to interfere with normal interactions and performance Cognition is refers to the perception and processing of all sensory input and the ability to learn and manipulate new information, recognize objects/ experiences, problem solve, think abstractly, and make judgements Dementia 10% of > 65 years of age 50% of > 85 years of age Causes ○ *Alzheimer disease (60-80% of dementia cases) ○ Vascular dementia (2nd most common cause)  Due to ischemic/hemorrhagic damage  Characterized by psychomotor deficits ○ Frontotemporal dementia  Disinhibited behavior/inappropriateness  Disturbance in understanding/expressing language  Memory loss is minimal ○ Creutzfeldt-Jakob disease  Rapid course of decline ○ Wernicke-Korsakoff syndrome  Associated with chronic alcohol abuse  Wernicke: Weakness/paralysis of EOM, nystagmus, diplopia, ataxia, confusion (Vit B1 deficiency)  Korsakoff: impairment of recent memory; confabulation (not responsive to treatment) ○ Huntington disease ○ Parkinson disease ○ Dementia with Lewy bodies Alzheimer Disease Pathophysiology Macro changes ○ Loss of neurons  cortical atrophy  Particularly in parietal and temporal lobes Micro changes ○ Amyloid (neuritic) plaques  Altered degradation of Amyloid Precursor Protein (APP) ○ α-secretase –degrades APP to non-toxic byproduct ○ ↑γ-secretase activity  neurotoxic byproducts  Accumulation of protein (amyloid β) in nerve terminals ○ Neurotoxic (directly and via ↑glutamate release) ○ ↑Proinflammatory cytokines ○ Neurofibrillary tangles  Accumulation of hyperphosphorylated Tau protein; wound in helical pattern  Altered Tau protein diminished cell’s microtubule (cell transportation system) support  neuronal cell death  Alzheimer Disease Pathophysiology ○ Choline acetyltransferase in cortex & hippocampus  ↓Acetylcholine production (important for memory) due to loss of cholinergic receptors and nicotinic receptors ○ Nicotinic receptors also governs glutamate, serotonin, norepinephrine release ○ APO-E (*4 isoform)  ↑Amyloid β protein deposition  ↓Amyloid β protein clearance ○ Vascular disease (i.e. secondary to HTN, diabetes, hyperlipidemia) may compound AD development  ↑ amyloid protein deposition and ↓ clearance Alzheimer Disease Clinical Presentation Insidious in onset and progressive ○ 8-10 year survival following diagnosis Cardinal (hallmark) symptoms 1. Short-term memory loss 2. Language difficulty 3. Behavioral changes Short-term memory Often associated with denial Randomly forgetfulness Lost objects, missed appointments, directions/getting lost (spatial disorientation) Language Initial Unable to name familiar objects/persons (anomia) (mild) Behavior Social withdrawal Loss of normal personality/spontaneity Difficulty problem solving Spatial relationships impaired Lost in familiar environmentswandering behavior Language Difficulty remembering and retrieving words (aphasia) Behavior Moderate Neglected personal hygiene Awareness of deficits  depression Restless, hostile, aggressive, abusive toward family Paranoia, delusions Sleep disturbances Loss of connection/response to surroundings Severe Require 24h care/bedridden  Treatment Cholinesterase inhibitors ○ Donepezil ○ Rivastigmine ○ Galantamine NMDA antagonists ○ Memantine Amyloid β protein target ○ Lecanumab ○ Aducanumab