Treatment of dementia

TREATMENT

OF

DEMENTIA

OUTLINE

Definition and Criteria

Classification of Dementia

Staging of Dementia

Classification Types and causes

of dementiaPathophysiology

Management of dementiaPHARMACOLOGIC

MANAGEMENT OF DEMENTIA Symptomatic Disease-modifying

treatments treatment of behavioral

disturbance

NON PHARMACOLOGIC MANAGEMENT OF DEMENTIA

Dementia

Term dementia in Latin means “devoid of the mind.”

It is defined as an acquired deterioration in cognitive abilities from a previ ously higher level of functioning that impairs the successful performance of activities of daily living.

In 2010, there are 3.7 million Indians with dementia and the total societal costs is about 14,700 crore(ALZHEIMER'S & RELATED DISORDERS SOCIETY OF INDIA ARDSI 2010)

DSM – IV Criteria for Dementia DSM-IV CriteriaMemory Impairment plus at least one of the following

APHASIA (Deterioration of Language function)

APRAXIA (inability to Execute Motor function)

AGNOSIA (inability to Recognise or Naming of Object)

Disturbance in executive functioning

with

• Impairment in occupational or social functioning• Represent a decline from a previous higher level of functioning

Mild cognitive impairment (MCI)Original Criteria

Memory complaint preferably qualified by an informant

Memory impairment for age

Preserved general cognitive function

Intact activities of daily living

Not dementedBy Peterson R, Negash S. CNS Spectr. vol 13 2008

Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term MCI is applied.

approximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years.

10% of persons >70 and 20–40% of individuals >85 have clinically identifiable memory loss. Harrison's 18 ed > Chapter 371. Dementia 

ROAD TO DEMENTIA

Staging of Dementias

MILD: difficulties with checkbook maintenance, complex meal preparations, complicated medication schedules

MODERATE: difficulties with simple food preparation, household or yard work. May need some assistance with self-care

SEVERE: Need considerable assistance with feeding, grooming and toileting

PROFOUND: Largely oblivious to surroundings, totally dependent

TERMINAL: Bed bound; require constant care

Mini Mental State Examiation :Staging of Disease by MMSENormal 27-30Mild 25-26Mild- Moderate 10-24Moderate- Severe 6-9Very Severe <6

MMSE

MMSE ‘norms’ by Age and Educational Level

Educational level

0-4y 5-8y 9-12y >12yAGE

18-24 23 28 29 30

35-39 23 27 29 30

50-54 22 27 29 30

70-74 21 26 28 29

80-84 19 25 26 28

Classification of Dementias

Primary versus secondary based on the pathophysiology leading to damaged brain tissue

Cortical versus sub-cortical depending on the cerebral location of the primary deficits

Reversible versus irreversible depending on treatment expectations

Early (before age 65) versus late onset

Causes of DementiaParkinsons diseaseHuntington’s disease

Primary Degenerative Dementia:•Alzheimer’s Disease

•Fronto temporal dementia

•Dementia with Lewy Body•Parkinsons disease•Huntington’s disease•Progressive supranuclear palsy•Corticobasal degeneration• ALS Parkinson's dementia complex of Guam•Multisystem atrophy

Secondary Dementia:

VITAMIN Deficiency

ENDOCRINE Chronic Infections

Vit B12/Folic acid

Hypothyroidism HIV

Thiamine B1 hyperthyroidism Neurosyphilis

 Nicotinic acid (pellagra)

Cushing Syndrome PML,   Prion Tuberculosis, fungal, and protozoal

Hypoparathyroidism

 Whipple's disease

Secondary DementiaTOXIC Head

Trauma/diffuse brain damage

Neoplastic

DIALYSIS DEMENTIAAluminum

Chronic Subdural Hematoma/Dementia pugilistica

Primary Brain Tumor

Drug PoisoningAlcoholism

Postencephalitis/  Postanoxia

Metastatic brain tumors

Heavy metal PoisoningMercury,lead

Normal Pressure Hydrocephalus

 Paraneoplastic limbic encephalitis

MiscellaneousAdditional conditions in children or adolescents

SarcoidosisVasculitisCADASILAcute intermittent

porphyriaRecurrent

nonconvulsive seizures

Pantothenate kinase-associated neurodegeneration

Subacute sclerosing panencephalitis

Metabolic disorders (e.g., Wilson's and Leigh's diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations)

Secondary Dementia

70% of dementia is Alzheimer’s

10-15% is Vascular dementia

10-15% Lewy Body dementias

5-10% Others

Overall Situation:

USA DATA

Alzheimer’s disease

70 %

Vascular Dementia

15-20%

Lewy Body Dementia

10-15 %

Others 5 %

Year : 2012  |  Volume : 60  |  Issue : 6  |  Page : 618-624

Types

CORTICAL SUBCORTICAL MIXED

Alzheimer’s Parkinson’s Vascular Dementia

Frontotemporal Dementia

Huntington’s disease

Lewy body dementia

CJD Normal pressure hydrocaphalus

Neurosyphilis

(REVERSIBLE DEMENTIA[10-20%]

IRREVERSIBLE DEMENTIA[80-90%]

D= Drugs Alzheimer

E= Endocrine disorders Lewy Body dementia

M= Metabolic Frontotemporal Dementia (Picks disease)

E= Emotional Parkinson disease

N= Nutritional Huntington’s disease

T = Toxic, Tumor, Trauma Creutzfeldt-Jakob disease

A= Alcohol others

BASELINE TESTS:

Baseline investigations for Dementia:CBC, ESR S. Electrolytes

Calcium, Phosphate Syphilis

Chest X ray HIV

CT, MRI Thyroid Function test

B12, Folate Liver function tests

EEG, ECG Renal Function Tests

Cholinergic deficit– progressive loss of

cholinergic neurones

– progressive decrease in available ACh

– impairment in ADL, behaviour and cognition

Hippocampus

Cortex

N. basalis Meynert

Pathophysiology of AD (Biochemical)

Alzeimer’s Disease

Loss of cholinergic

neurons

Senile plaques & neurofibrillary

tangels

Glutamate transmission dysfunctiion

30% symptoms

70% Symptoms

Alzheimer’s Staging:

Management :Dementia

Reduce Cognitive Symptoms

Reduce Behaviour Symptoms

Slow disease progression

Delay the Onset of Disease

PHARMACOLOGIC MANAGEMENT OF DEMENTIA

Three broad categories of dementia pharmacotherapy:Symptomatic treatment of memory

disturbanceDisease-modifying treatmentsSymptomatic treatment of behavioral

disturbance

Symptomatic Treatment of AD

. The mainstay of symptomatic treatment of AD, so far, is the cholinergic treatment strategies and most widely used, till now, are the Cholinesterase (ChE) inhibitors.

. These agents •Reduce the metabolism of acetylcholine

•Prolonging its action at cholinergic synapses.

Cholinesterase inhibitors: two classes exist for the treatment of Dementia

Class Inhibit

Dual ChE inhibitors

– Rivastigmine Both AChE

– Tacrine and BuChE

Single ChE inhibitors

– Donepezil AChE

– Galantamine

Weinstock, 1999

FDA-approved drugs

Drug Target dose Approved for

year

Tacrine 40 mg/day Mild to moderate

1993

Donepezil 10 mg daily All stages 1996

Rivastigmine 6 mg twice daily or 9.5-

mg patch daily

All stages 2000

Galantamine target dose 24 mg daily, extended-

release

Mild to moderate

2001

Memantine 10 mg twice daily

Moderate to severe

2003

TACRINE

In 1993 first Drug approved for the treatment of Alzheimer's disease

marketed under the trade name Cognex. Tacrine was first synthesised by Adrie

Albert at the University of Sydney.Tacrine is a centrally

acting anticholinesterase and indirect cholinergic agonist (parasympathomimetic).

Tacrine Pharmacokinetis

Bioavailability 2.4–36% (oral)Protein binding 55%Metabolism Hepatic (CYP1A2)Half-life 2–4 hoursExcretion Renal

Initiation of Treatment Dose Titration

Cognex® is supplied as capsules of tacrine hydrochloride containing 10, 20, 30, and 40 mg of tacrine.

Cognex® brand of tacrine hydrochloride is 40 mg/day (10 mg QID).

This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment.

Following 4 weeks dose to be increased to 80 mg/day (20 mg QID), providing there LFT is normal

Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a QID schedule) at 4-week intervals on the basis of tolerance.

Tacrine dose

Very Common >10%Common 1-10% incidence

Increased LFTsHepatitisNauseaVomitingDiarrheaHeadacheDizziness

Indigestion,Belching Abdominal pain Myalgia Confusion Ataxia Insomnia Weight loss Constipation Somnolence Tremor Anxiety

Tacrine Adverse Effects

Tacrine Overdose

nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse,convulsions. Atropine is a popular treatment for overdose.

Studies found that it may have a small beneficial effect on cognition and other clinical measures

though study data was limited and the clinical relevance of these findings was unclear.

Tacrine has been discontinued due to hepatotoxicity

DONEPEZIL

In 1996, donepezil, a selective cholinesterase inhibitor, was approved for use in Alzheimer disease.

marketed under the trade name Aricept by its is a centrally acting reversible  acetylcholinesterase inhibitor

devoid of peripheral cholinomimetic adverse effects.

Pharmacokinetics

Bioavailability 100 (%) not affected by the time of day or food intake

Protein binding 96%Half-life 70 hourspeak plasma concentration is reached in 3 to 5

hours. It is extensively metabolized by the hepatic

isoenzymes CYP2D6 and CYP3A4. minimally affected by hepatic or renal disease

and no dose adjustment is necessary for these conditions.

In mild to moderate A D Moderate to severe AD

Disease, a starting dose of 5 mg given once daily should be used.

a minimum of four to six weeks, an increase to 10 mg is recommended.

The usual dose is 5 to 10 mg once daily.

indicates the same regimen, but in a minimum of three months, a patient may receive a dose of 23 mg once daily.

The maximum daily dose is 23 mg once daily. 

In the UK, the maximum licensed dose is 10 mg

Dosage

CONTRAINDICATIONS

ADVERSE EFFECTS

cardiac disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome.

gastrointestinal disorders should use caution because nausea or vomiting may occur.

predisposition to seizures should be treated with caution.

Common side effects include bradycardia

cardiac conduction disturbances

nausea, diarrhea, anorexiaabdominal pain

vivid dreams and Several cases of mania induced by Donepezil have been reported

DONEPEZIL

Clinical Trials of Donepezil

Study (Rogers et al 1996).

Double-blind, placebo-controlled, 30-week, parallel study involving 450 patients with Alzheimer disease

ResultsSignificant

improvement on cognitive and clinical global assessments.

Study (Rogers and Friedhoff 1996).

Dose-ranging study on 161 patients with mild to moderate Alzheimerdisease who received donepezil 1, 3, or 5 mg, or placebo, daily for 12 weeks

ResultsPatients who received

donepezil 5 mg showed significant improvement in the Alzheimer Disease Assessment Scale Cognitive Subscale.

Clinical Trials of Donepezil

Study (Doody et al 2009)A 48-week, randomized,

placebo-controlled trial of donepezil for treatment of patients with mild cognitive impairment 

ResultsDonepezil produced small

but significant improvement on the primary measure of cognition, but there was no change on the primary measure of global function

Study (Farlow et al 2011). A pivotal phase 3 study of

the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d

ResultsGood safety and

tolerability profile of donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe Alzheimer disease.

Mechanism of Action PHARMACOKINETICS

Reversible acetylcholinesterase inhibitor that causes an increase in concentrations of acetylcholine, which in turn enhances cholinergic neurotransmission

Absorption Bioavailability: 36% (PO) Duration: 10 hr (PO); 24 hr (patch) Peak plasma time: 1 hr (PO); 8 hr

(patch)Distribution Protein bound: 40% Vd: 1.8-2.7 L/kgMetabolism Metabolized by cholinesteraseElimination Half-life: 1.5 hr (PO), 3 hr (patch) Total body clearance: 1.2-2.4 L/min Excretion: Urine (97%)

Rivastigmine (Rx) - Exelon

common UNCOMMON

Nausea (PO 47%; patch 21%) Vomiting (PO 31%; patch 6-

19%) Dizziness (PO 21%; patch 2-

7%) Diarrhea (PO 19%; patch 6-

10%) Headache (PO 17%; patch 3-

4%) Anorexia (PO 17%; patch 3-

9%) Abdominal pain (PO 13%;

patch 2-4%)

Decreased weight (3-8%)

Insomnia (PO 9%; patch 1-4%)

Anxiety (PO 5%; patch 3%)

Asthenia (PO 6%; patch 2-3%)

Vertigo (2%)Fatigue (2%)

Rivastigmine - Adverse effects

Rivastigmine Cautions

Renal impairmentHepatic impairmentSick sinus syndromeConduction abnormalities.H/O Asthma or COPDPregnancy .

Transdermal Patch Technology: Reservoir versus Matrix

Nitti VW, et al Urology. 2006;67:657–64

Drug contained in adhesive layer along with polymer

Smaller and thinner than reservoir patches

Reservoir

Matrix

Drug contained in separate layer, with a rate-controlling membrane

Matrix DiffusionControlled Patch

Release Liner

Drug + Polymer + Adhesive

Backing

Rate-ControlledReservoir/Membrane Patch

Dermal Layer

Backing

DrugReservoir

Release Liner Adhesive Layer

Exelon Transdermal 9.5 mg/24 h Patch

Where to Apply Exelon Patch

Apply to:Upper and lower backUpper armChest

The skin should be clean, dry and hairless before the patch is applied

Normal daily activities, such as bathing, are permitted

1Lefèvre G, et al. J Clin Pharmacol 2007;47:471–8.

Exelon Transdermal Patch: Smooth Continuous Delivery Through the Skin

Exelon 6 mg BID capsule

Exelon 9.5 mg/24 h patch

Pla

sma

conc

entr

atio

n (n

g/m

L)

Exelon 9.5 mg/24 h patch delivered comparable average concentrations (AUC) to those provided by an oral dose of 6 mg BID (12 mg/day)*

* Model-predicted analysis based on actual patient data corrected for body weight.

0

5

10

15

20

25

0 6 12 18 24

Time (hours)

Starting transdermal ChEI therapy

Rivastigmine 4.6 mg/24 h

patch

Rivastigmine 9.5 mg/24 h

patch

Starting dose Target dose

4 weeks

One-step dose increase

Clinical trials Rivastigmine

Study (Burns et al 2004)

A retrospective analysis of pooled data from 3 randomized, placebo-controlled, double-blind, 6-month trials involving 2126 patients with Alzheimer disease suggests that rivastigmine 6 to 12 mg/day may benefit subjects with more severe disease as well as subjects with mild to moderate impairment

In an open-label, comparative study of rivastigmine with donepezil and galantamine, there were no statistically significant differences between the 3 drugs at 3 months (Aguglia et al 2004).

In a placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson disease but also with higher rates of nausea, vomiting, and tremor (Emre et al 2004).

Clinical trials Rivastigmine

Results of a 6-month, double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer disease shows that the patch provides efficacy similar to the highest doses of capsules with a superior tolerability profile and may offer convenience important to many caregivers and patients (Winblad et al 2007).

A retrospective analysis of a large randomized, placebo-controlled trial of Alzheimer disease patients treated with transdermal rivastigmine or rivastigmine capsule compared to placebo showed greatest treatment effects in patients with more advanced dementia who received rivastigmine, and these were considered to be most likely due to greater decline in the patients treated with placebo (Farlow et al 2011).

Galantamine (Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine)

It is an alkaloid that is obtained synthetically or from the bulbs and flowers of Galanthus caucasicus 

(Caucasian snowdrop)Galantamine

hydrobromide was approved in 2001 by the FDA Indicated for the treatment of mild to moderate dementia  IN Alzheimer's.

Galantamine-MOA

weak competitive and reversible cholinesterase inhibitor in all areas of the body. 

It increases the concentration and thereby action of acetylcholine in certain parts of the brain.

It has shown activity in modulating the nicotinic cholinergic receptors on cholinergic neurons to increase acetylcholine release.

Pharmacokinetics DOSAGE

Bioavailability - 80 to 100%

Protein binding- 18%Metabolism-HepaticHalf-life-7 hoursExcretion -

Renal (95%, of which 32% unchanged), fecal (5%)

in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution.

The tablets come in 4 mg, 8 mg, and 12 mg forms.

The capsules come in 8 mg, 16 mg, and 24 mg forms.

Galantamine

Clinical Trials with Galantamine  

Study (Raskind et al 2004). Patients with mild-to-

moderate Alzheimer disease who had been randomized to galantamine therapy in previous trials received open-label continuous galantamine therapy for up to 36 months(Raskind et al 2004).

Results Cognitive decline over 36

months with continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients.

Study (Suh et al 2004) Prospective, randomized

multicenter, double-blind study of patients with mild-to-moderate Alzheimer disease: dose 8 mg/day, 16 mg/day, or 24 mg/day ).

Results All dose schedules were

well tolerated with significant improvements in all 3 treatment groups.

common Rare

Nausea, vomiting,Diarrhea, abdominal pain, upper abdominal pain, dyspepsia, stomach discomfort, abdominal discomfort

Bradycardia,First degree atrioventricular block, palpitations, sinus bradycardia, supraventricular extrasystoles, flushing, hypotension

Dizziness, headache, tremor, syncope, lethargy, somnolence

Blurred vision confusion decreased urination dizziness, faintness, or

lightheadedness dry mouth fainting fast, irregular, pounding, or

racing heartbeat or pulse feeling of warmth rapid breathing redness of the face, neck, arms,

and occasionally, upper chest sunken eyes,sweating, thirst

Galantamine-Adverse effects

Memantine 

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA receptor. 

Memantine is approved by the U.S. F.D.A and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease

Pharmacokinetic MOA

Bioavailability~100%

Metabolism-Hepatic (<10%)

Half-life- 60–100 hours

Excretion - Renal

Memantine is a low-affinity voltage dependent uncompetitive antagonist at glutamatergic NMDA receptors

non-competitive antagonist at the 5-HT3 receptor, this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Memantine 

 Common Less common

confusion, dizziness, drowsiness,

headache, insomnia, agitation

hallucinations.

vomiting, anxiety, hypertonia cystitis, increased libidorareextrapyramidal side

effects(such as dystonic reactions etc.) may occur, in particular, in the younger population

Memantine -Adverse effects

Clinical trials Memantine The M-Best Study

The M-Best Study (Benefit and Efficacy in Severely demented patients during treatment with memantine) was a double-blind, placebo-controlled, phase III trial of memantine conducted in Sweden on care-dependent patients with severe dementia (Winblad and Poritis 1999).

The trial population consisted of 161 patients, 51% with vascular dementia and 49% with Alzheimer disease. Treated patients were given 10 mg memantine per day for 12 weeks, and evaluation was done using

Clinical Global Impression of Change by the physician and Behavioral Rating Scale for Geriatric Patients by the nursing staff.

The results supported the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.

The DOMINO-AD clinical trial

This study looked at 295 people with moderate to severe Alzheimer's disease

All of the study participants had been prescribed donepezil for at least three months, and had been taking a dose of 10mg for at least the six weeks prior to the trial. The trial lasted for 52 weeks.

Participants were divided into four different groups and were each given two drugs. These groups were:

donepezil and memantine donepezil and placebo

memantine placebo donepezil and

memantine placebo donepezil and placebo

memantine

Standardised Mini-Mental State Exam (SMMSE) and their abilities in daily life using the Bristol Activities of Daily Living Scale (BADLS).

All of these measures were taken at the start of the study, after six weeks, at 18 weeks, at 30 weeks and finally after 52 weeks.

The DOMINO-AD clinical trialRESULTS

There were benefits to cognitive function of taking donepezil (about 32% less cognitive decline than those on placebo).

Memantine also showed these benefits, although smaller (about 20% less decline than those on placebo).

Compared to placebo, memantine led to fewer behavioural symptoms developing, showing about 83% fewer symptoms.

The functional benefits of continuing donepezil showed about 23% less deterioration than those on placebo.

The functional benefits of memantine were about 11% less deterioration than those on placebo.

There were also small reductions in caregivers' psychological symptoms with either of the drugs, although these were not large enough to be measured reliably with statistics.

Combined treatment with both donepezil and memantine was not better than treatment with donepezil alone for any of the measures.

RCT of donepezil &/or memantine &/or placebo in patients with moderately severe/severe AD (MMSE 5-13) who have been on donepezil for at least 12 months

Howard et al 2012

RESULTS

DELAY OF PROGRESSION:

Duration

Memantine alone 2-3 yearsMemantine + Ch E inhibitors

5-6 years

Ch E Inhibitors alone 1.5 years

TREATMENT OPTIONS IN DEMENTIA

AD VaD FTD LBD

DONEPEZIL ChE Inhibitors

No ChE inhibitors

ChE inhibitors

RIVASTIGMIE HMG CoA SSRI SSRI

GALANTAMINE Stroke Prevent

Antipsychotics

Memantine

MEMANTINE Memantine Memantine Levodopa

SSRI Antipsychotic AvoidAntipsycho

tics

Disease-Modifying Agents

Proposed or unregulated drugs which require further studies

Selegeline

Vit-E

Oestrogen

Prednisolone

NSAIDs

Ginkgo biloba

Statins

IVIg

Glycogen syntehtase kinase 3 (GSK 3)

β-secretase inhibitors

γ-secretase inhibitors

α-secretase enhancers

Immunotherapy

Disease-Modifying Agents

Vitamin E Limits free-radical formation, oxidative stress and lipid

peroxidation Promotes survival of cultured neurons exposed to

beta amyloid Clinical trials have not be overwhelmingly convincing

Selegiline MAO-B inhibitor, increases brain catecholamines Also has antioxidant properties Clinical trials – alone and in combination with Vit.

E not effective

Disease-Modifying Agents

Anti-Inflammatory drugs Pathophysiological studies demonstrate a marked

inflammatory reaction induced by amyloid with microglial activation and cytokine release

Case-control studies of subjects taking NSAIDs regularly for arthritis demonstrate a reduced odds-ratio for developing AD

Recently developed NSAIDS currently in clinical trials of AD

Estrogen Body of preclinical evidence that estrogen enhances

cerebral blood flow, prevents atrophy of cholinergic neurons, reduces oxidative stress, and modulates the effects of nerve growth factors

Disease-Modifying Agents

Statins Direct association between amyloid processing and

cholesterol in the brain An indirect effect via decreasing the risk of stroke, since

even small vascular lesions worsen the severity of Alzheimer's disease

Ginkgo Biloba A single placebo-controlled trial with an extract of ginkgo

biloba showed a very modest improvement on cognitive testing

Only 50 percent of the treatment group completed the trial Use of ginkgo not recommended due to limited efficacy and

lack of regulation, including variability in the dosing and contents of herbal extracts

Disease-Modifying Agents

Idebenone Synthetic analogue to Co-Q10, known to have anti-

oxidant properties Controlled clinical trials have shown modest improvement

in cognitive function with highest doses Side effects including liver enzyme abnormalities (non-

serious) along with predominant G-I upsetNegative trials

Propentofylline (stimulates synthesis and release of NGF) Acetyl-L-carnitine (promotes ACh release, increases

acetyltransferase activity, has antioxidant properties)

The amyloid cascade hypothesis & drugs in clinical trials

Adapted from Biochem. Soc. Trans. (2005) 33, 553-558

Statins - promotes alpha secretase

Flurizan - modulates gamma secretase

Lilly - inhibits gamma secretase

Alzhemed - anti-fibrillar

Active and passive immunisation

?

Active and passive beta amyloid immunisation against AD

Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation.

In human trials, this approach led to life-threatening complications, including meningoencephalitis

modifications of the vaccine approach using passive immunization with monoclonal antibodies are currently being evaluated in phase 3 trials.

Bapineuzumab (anti-amyloid antibody)

Bapineuzumab (anti-amyloid antibody)

“I think the data are pretty clear from this trial that bapineuzumab is not effective for mild to moderate dementia, and the company was wise to stop the ongoing trials in that population,” said Salloway, who leads one of the trial sites.

Another antibody (solanezumab) also showed cognitive & functional benefit in mild AD.results awaited

Behavioral Problems in ADBehavioral Problems in AD depression (occurs in 20-40% - esp. AD

and VaD) psychosis (occurs in 30- 50%) - usually

see paranoid delusions (theft, infidelity) wandering/purposeless activity agitation/threatening behavior sleep disturbances delirium - minor insults can lead to major

decompensations

Depression and Alzheimer’s

Common early in the course of the illnessIncidence 40-50%Use SSRIs first; avoid anticholinergic

antidepressantsECT can be helpful but may temporarily

worsen cognitive symptoms

Treatment of Depression

Recognize that irritability and/or apathy /withdrawal may be indicative of depression

Allow patient choices and controlIdentify pleasurable activities (such as

singing old songs, pet therapy, etc.)Cognitive enhancers (e.g. Aricept) may help

Agitation

Non-aggressive verbal: complaining, constant requests for

attention, repetition of words, constant talk, screaming

physical: pacing, disrobing, stereotypies, trying to get to a different place

Aggressive Verbal: threats, name calling, obscenities Non-verbal: biting, scratching, spitting,

kicking, pushing, swinging fists

Medications for Agitation

Buspirone – Takes a while to workAntidepressants (SSRIs, Trazodone)Anticonvulsants (esp. valproate)Atypical Antipsychotics (stroke risk

concerning)Low dose narcotics?Estrogen?

Treatment of PsychosisTraditional antipsychotics

Low potency (chlorpromazine)– orthostasis, sedation, anticholinergic

High potency (haloperidol)– EPS/TD but otherwise well tolerated

New generations drugs (e.g. olanzapine, quetiapine, risperidone)- less EPS/TD but still see anticholinergic, BP and sedative effects

Treatment of Insomnia

Sleep hygiene (avoid caffeine, etc.)Treat causative psychiatric or medical

disordersPhsysiological remedies - melatonin, warm

milk, lavendar oilMedications - Benadryl, benzos, sedating

antidepressants or antipsychotics (all these drugs can make memory and confusion worse)

Light Therapy - to reset natural circadian rhythms for sleep

Use of Atypical Antipsychotics

Older, “typical” agents such as haloperidol and thioridazine (mellaril) associated with significant extrapyramidal symptoms

Theoretically combination of dopamine and serotonin effects of atypical agents allow treatment of positive and negative psychotic symptoms with less EPS

Risperidone

Evidence demonstrates efficacy in treatment of psychotic and behavior symptoms in patients with dementia

Exacerbates movement disorder in patients with Parkinson’s

Start .25/day, average daily dose 1-1.5mg/dayEPS in dose dependent manner (6mg/day)Insomnia, hypotension, weight gainElevation of prolactin levels

Olanzapine

Evidence that it is effective in AD patientsIncreases motor symptoms in PD patientsRecommended not to use with PDStart: 1.25-2.5/day, increase to 5/day (dosages of

10-15/day are not more effective!)More sedating than others (more anticholinergic

effects)Sedation, weight gain, orthostatic hypotension,

seizures, glucose intolerance

Quetiapine

Showing promise in patients with AD and PDDoes not exacerbate movement disorder of PD May be first line for PD patients with psychosis12.5 QHS, titrate every 3-5 daysSedation, HA, orthostatic hypotension?Cataract formation

Ziprasidone

New, clinical data lackingNon dose-dependent QT prolongation

Clozapine

Very effective in treating psychosis in PD patients

The most effective agent in treatment of drug induced psychosis in PD

Some efficacy with AD patientsStart: 6.5mg/dayAgranulocytosis, frequent monitoring limits

use

Caregiver Burden

Alzheimer’s caregivers spend an average of 69 to 100 hours per week providing care

Caregivers of patients suffering from dementia(compared to control subjects) reported: 46% more physician visits Over 70% more prescribed drugs More likely to be hospitalized

More than 50% of caregivers are at risk for clinical depression

Behavioral Strategy

Scheduled toileting, prompted voiding for incontinence.

Graded assistance, & positive reinforcement to increase functional independence

Music, esp. during meals, bathing

Walking , Light Exercise

Other Drugs in the Pipeline

Tau protein modulators (to prevent abnormal phosphorylated ‘tau’ protein

Bryostatin – drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning.

New generation NSAIDS (flubiprofen) – testing in humans looks promising

Immune enhancers (immunoglobulin)New vaccines and new anticholinesterases

(huperzine A)LADOSTIGIL-multimodal drug

Dementia and clinical trialsWhere next?

Disease modifying drugs need to start early Much of the damage been done by the time the patient presents with

dementiaWe need to consider new targets

Is amyloid the cause, or just a byproduct? What about tau? What about inflammation?

We need to have better outcome measures Current assessments do not always reflect outcomes that matter to

patients and families. We need more patients to enter clinical trials

Recruitment into dementia clinical trials is a fraction of the number entering cancer trials

Take Home Points

Cholinesterase Inhibitors are MODESTLY effective in treatment of mild to moderate AD

Cholinesterase Inhibitors are probably effective in more severe AD

No large difference in efficacy between agents, but Donepezil more easily titrated and tolerated

Evidence to support use of cholinesterase inhibitors for vascular and vascular/AD dementia

Memantine looks to be effective for more severe AD and vascular dementia, will likely be used in combination with cholinesterase inhibitors