Cholinesterase inhibitors and memantine use for Alzheimer s disease TOPIC REVIEW

Transcription

1 Cholinesterase inhibitors and memantine use for Alzheimer s disease TOPIC REVIEW

2 Diagnosis of Dementia : DSM-IV criteria Loss of memory and one or more other cognitive abilities Aphasia Apraxia Agnosia Disturbance in executive functioning Substantial impairment in social or occupational functioning Deficits that do not occur exclusively during the course of delirium

3 Subtypes of Dementia Alzheimer s Disease Vascular Dementia Parkinson s Disease Dementia with Lewy Bodies Frontotemporal Dementias : e.g. Pick s disease Substance induced persistent Dementia Dementia due to HIV Disease

4 Alzheimer s disease

5 Alzheimer s Disease : Clinical The most common form of dementia, accounting for 50 to 56% of cases Slow onset Short-term memory impairment Relative preservation of remote memory Gradual deterioration of cognitive capacities

6 Alzheimer s Disease: Risk Factors Advanced Age Family History of AD Parkinson s Disease Down s Syndrome Genetic Factors History of Head Injury

7 Alzheimer s disease Pathogenesis

8 Pathogenesis : Alzheimer's disease caused by accumulation of abnormally folded beta amyloid and tau proteins in the brain triggering neuron degeneration. Cerebral plaques laden with β-amyloid peptide (Aβ) and dystrophic neurites in neocortical terminal fields as well as prominent neurofibrillary tangles in medial temporal-lobe structures are important pathological features of Alzheimer's disease. NEJM ; Volume 362: January 28, 2010

9 Beta-amyloid is a fragment of amyloid precursor protein (APP), a transmembrane protein In AD, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques Amyloid fibrils from the viewpoint of protein folding. Cell. Mol. Life Sci. 61 (5):

10 Tau protein stabilizes the microtubules when phosphorylated, and therefore called a microtubule-associated protein In AD, tau becoming hyperphosphorylated then begins to pair with other threads, creating neurofibrillary tangles Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739 (2-3):

11 N Engl J Med 2004;351:56-67.

12 Neurotransmitter in AD : Acetylcholine Deficiency of cholinergic projections has been linked to the build-up of Aβ and tau. Aβ binds to nicotinic acetylcholine receptors, impairing the release of acetylcholine and maintenance of long-term potentiation. The level of muscarinic acetylcholine receptors is reduced in the brains of patients with Alzheimer's disease. Glutamate Chronic state of excitatory amino acid (glutaminergic) receptor activation is thought to aggravate neuronal damage in late-stage Alzheimer's disease NEJM ; Volume 362: January 28, 2010

13 Acetylcholine Pathways : Two major cholinergic projections within CNS 1. Ascending reticular activating system - Sleep-wake cycles 2. Cortical structures: neocortex, hippocampus and amygdala - Learning and memory function

14 Cholinergic deficit in AD : Progressive decrease in avaliable Ach Impairment in ADL, behavior and cognition

15 Glutamate pathways : Glutamate is the fast excitatory neurotransmitter in regions associated with cognition and memory. Cortical and subcortical structures that contained glutaminergic receptors are structurally damage in AD. Glutamate acts as an excitotoxin causing neuronal death when excessive levels are chronically released.

16 Excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 330: , 1994 Pathways for excitotoxicity in AD : Energy deficiency Decrease in membrane potential Decrease glutamate uptake Increase glutamate release Increase glutamate levels NMDA receptor activation Increased Ca2+ influx Excitotoxicity

17 N-Methyl-D-Aspartate Receptors : Excessive activation of NMDA receptors can lead to massive Ca2+ influx and trigger irreversible process leading to cell death.

18 Cholinesterase inhibitors and memantine use for Alzheimer s disease Effectiveness and adverse events

19 Disease Modifying Agents use in dementia N Engl J Med 2004;351:56-67.

20 Alzheimer Disease Assessment Scale Cognitive Subscale (ADAS-cog) 11-Item Score range Memory and new learning 0-35 Word recall (mean number of words not recalled) 0-10 Orientation 0-8 (one point for each incorrect response) Word recognition 0-12 (mean number of incorrect responses) Remembering test instructions 0-5 Language 0-25 Commands 0-5 Spoken language ability 0-5 Naming objects/fingers 0-5 Word-finding difficulty 0-5 Comprehension 0-5 Praxis 0-10 Constructional praxis 0-5 Ideational praxis 0-5 Total 0-70 Increasing scores indicate worsening cognitive function. Rosen WG, et al. Am J Psychiatry. 1984;141:

21 Clinician s Interview Based Impression of Change plus Caregiver Input CIBIC- PLUS Global ratings of patient s clinical condition Rated by the clinician, by interviewing both patients & informant Clinical Impression of Change : Total 7 points 1 = Very Much Improved 2 = Much Improved 3 = Minimally Improved 4 = No change 5 = Minimal worsening 6 = Much worsening 7 = Very much worsening

22 Cholinesterase inhibitors Cholinesterase inhibitors are approved by FDA for the treatment of mild to moderate Alzheimers disease. Clinical trials have shown changes on ADAS-Cog of 2.5 to 3.5 points (range of scores, 0 to 70) and differences on the CIBIC-Plus of 0.3 to 0.5 (range of scores, 1 to 7) in patients receiving the drug as compared with patients receiving placebo. Optimal duration of treatment is uncertain => duration of most blinded trials has been 6 months N Engl J Med 2004;351:56-67.

23 Cholinesterase inhibitors Side effects reported in clinical trials included Nausea & vomiting Diarrhea Weight loss Insomnia Abnormal dreams Muscle cramps Bradycardia Syncope Fatigue N Engl J Med 2004;351:56-67.

24 Donepezil : Effectiveness & Adverse effects Ann Intern Med. 2008;148:

25 Donepezil : Adverse effects Rates of withdrawal due to adverse events ranged from 0%-57% in treatment groups and 0%-20% in placebo groups. However, no serious harms were attributed to donepezil in any study. Ann Intern Med. 2008;148:

26 Galantamine : Effectiveness & Adverse effects Ann Intern Med. 2008;148:

27 Galantamine : Adverse effect Rates of withdrawal due to adverse events ranged from 4% to 17% for placebo and 8% to 54% for active treatment. No important differences emerged in the rates of serious adverse events between the placebo and galantamine. Ann Intern Med. 2008;148:

28 Rivastigmine : Effectiveness & Adverse effects Ann Intern Med. 2008;148:

29 Rivastigmine : Adverse effects Rates of withdrawal due to adverse events ranged from 0% to 11% in the placebo groups and from 12% to 29% in the treatment groups. Frequency of severe adverse events did not differ between the treatment and placebo. Ann Intern Med. 2008;148:

30 Memantine : N-methyl-d-aspartate antagonist Approved by FDA for the treatment of moderate to severe Alzheimers disease In patients with moderate to severe Alzheimers disease showed the superiority of memantine over placebo as indicated by both the Activities of Daily Living Inventory and the Severe Impairment Battery No clinically differences between patients in the memantine and placebo groups in terms of adverse events N Engl J Med 2004;351:56-67.

31 Memantine : Effectiveness Ann Intern Med. 2008;148:

32 Memantine : Adverse events Adverse events included GI symptom, dizziness, headache No harms reported for memantine was statistically significant Patients withdrawing because of any adverse events varied from 5%to17% in the placebo groups and 8%to13% in the treatment groups Ann Intern Med. 2008;148:

33 Effect size of drug use in Alzheimer s disease (all severity) Drug Outcome of benefit Outcome of harm (Adverse events) ADAS-cog CIBIC-plus Significant AE Serious AE (WMD) (RR) Relative risk Donepezil Anorexia RR 3.21 Galantamine Anorexia RR 3.41 Rivastigmine Vomiting RR 6.06 Memantine NA 1.25 No statistically significant AE No No No No Ann Intern Med. 2008;148:

34 Conclusion For Alzheimer disease, cholinesterase inhibitors and memantine can improve symptoms, primarily in domains of cognition and global function. Clinically important differences were not consistently evaluated or demonstrated in these 2 domains for all drugs. Direct comparisons among these drugs are limited and do not suggest important differences. Adverse events of cholinesterase inhibitors are primarily associated with GI problems Ann Intern Med. 2008;148:

35 Thank you for your attention

36 Vascular dementia

37 Vascular Dementia : Vascular Dementia makes up 15-25% of all dementia cases. Risk factor - Advanced Age - Stroke - Smoking - Obesity - Alcoholism - Hypertension - Diabetes

38 Vascular Dementia : Diagnosis

39 Vascular Dementia : Disruption of cholinergic pathways contributes to the pathophysiology of vascular dementia has led to clinical trials of Cholinesterase inhibitors in treatment of vascular dementia. Clinical trials of memantine suggest benefits in vascular dementia possibly due to its effect in reducing glutamatergic neurotoxicity. In vascular dementia, Donepezil & Memantine showed statistically significant improvement in cognitive function. Lancet Neurol 2007; 6:

40 Donepezil : Ann Intern Med. 2008;148:

41 Memantine : Effectiveness Ann Intern Med. 2008;148: