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ETIOPATHOGENESIS MANAGEMENT AND RECENT ADVANCES IN ALZHEIMERS

DISEASE

Presented by Dr. Karrar HusainModerator – Dr. M. Amir Usmani

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INTRODUCTION AND HISTORY EPIDEMIOLOGY ETIOPATHOGENESIS ASSESMENT DIAGNOSIS AND D/D MANAGEMENT PREVENTION

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INTRODUCTION HISTORY

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INTRODUCTION

Alzheimer’s disease (AD) is the commonest progressive,

dementing neurodegenerative disease in elderly, which

affects innumerable people each year, and these numbers are

likely to further increase as the population ages.

In addition to the financial burden of AD on health care

system, the disease has powerful emotional impact on

caregivers and families of those afflicted.

BRIEF HISTORY Alois Alzheimer, a German physician,

is credited with being the first to describe AD.

In 1906, Dr. Alzheimer observed a patient, Auguste Deter, in a local asylum who exhibited strange behaviors. He followed her care and noted her memory loss, language difficulty and confusion. Alois Alzheimer

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After her death at the age of 51, he examined her brain tissue. The slides showed what are now known as plaques and tangles.

In 1911, Doctors were using Dr. Alzheimer’s research to base diagnosis.

In the 1960’s British pathologists determined that AD was not a rare disease of the young but rather what had been termed “senility.”

In the 1990’s researchers identified that the beta amyloid protein was a factor in AD.

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EPIDEMIOLOGYRISK FACTORSPROTECTIVE FACTORS

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MC cause of dementia, > 65yr.

Starting with 0.5% prevalence at 55 yrs., it goes on doubling every five years (60yrs-1%; 65yrs. – 2%; 70 yrs. -4%; 75yrs.-8% and so on)

Risk at the age of 80 years is around 15 to 20%

About 7.7 million new cases of dementia each year. A new case detected in every 4 seconds somewhere in world.

EPIDEMIOLOGY

WHO

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The incidence rates per 1000 person-years for AD was 11.67 for ≥55 years 15.54 for aged ≥65 years.

Neurol India. 2012 Nov-Dec;60(6):625-30. doi: 10.4103/0028-3886.105198.

COMMON TYPES OF DEMENTIAS

Type of Dementia % in total Cases

Alzheimer’s Dementia 50-55

Vascular Dementia 30-35

Lewy body Dementia 5-7

Pick’s Dementia 3-5

Other Dementias 10-15

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12Ziegler-Graham K et al. Alzheimer’s & Dememtia 2007;3(Suppl):S168–9

New Estimate of Dementia Worldwide

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ALZHEIMER’S PREVALENCE

Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128.

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RISK FACTORS

Age : every 5 yr beyond 65, the % of people with AD doubles

Family history : strong genetic component1. Early onset – fully penetrant2. Late onset – reduced penetrant

Gender – women, ? Estrogen

Tobacco

Head injury

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Obesity

Hypertension , diabetes

Elevated serum cholesterol

Elevated serum homocysteine

Depression

Lack of intellectual stimulation/education

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PROTECTIVE FACTORS

Physical activity

Caffeine consumption

Antioxidants – VITAMIN C, E, B6 and B12

Folate

N -3 fatty acid intake

Speaking > 2 language

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PATHO PHYSIOLOGYGENETICS

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AD is characterized by generalized cerebral cortical atrophy, neuronal loss, widespread cortical neuritic plaques and neurofibrillary tangles.

Following mechanisms have been attributed for the development of Alzheimer’s dementia Amyloid cascade theory Neuronal loss Cholinergic hypothesis Excitotoxicity Genetic factors

PATHOGENESIS AND PATHOPHYSIOLOGY

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Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in the brain from APP(amyloid precursor protein).

APP normally found in the cell membranes of neurons and normally metabolised by a protease enzyme α–secretase.

In AD, the metabolism of APP is altered by two other enzymes β and γ secretase and is called β amyloid (Aβ).

AMYLOID CASCADE THEORY

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Amyloid-β is originated by the alternative cleavage of the amyloid precursor protein (APP) into smaller peptides (Aβ1-40 and Aβ1-42) by two other enzymes β and γ secretase

Aβ1-42 is more prone to form insoluble aggregates (and therefore more toxic) than Aβ1-40.

Once Aβ is formed, it accumulates into insoluble sheets (called β-pleated sheets).

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The interaction between genetic and environmental factors, along with the homeostatic changes that pertain to the ageing, seems to affect the balance between production and clearance of toxic Aβ peptides.

These deposits are neurotoxic and activate inflammatory reaction resulting in the formation of senile or neuritic plaque.

This is accompanied by hyperphosphorylation of tau protein, supporting the microtubules.

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Hyperphosphorylated Tau aggregates into oligomers to form NFTs.

Several protein kinases are involved in this process, namely glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase-5 (CDK5), and extracellular signal-related kinase-2 (ERK2).

GSK-3β, the most important Tau kinase in neurons, is overactive in AD

Journal of Alzheimer’s Disease 33 (2013) S185 -S194DOI 10.3233/JAD-2012-129028

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The classic gross neuro-anatomical observation is Diffuse atrophy with

widening cortical sulci Enlarged cerebral

ventricles. There is a progressive

loss of neurons and their supportive glial cells.

The loss is more marked in the entorhinal cortex, hippocampus and basal forebrain.

NEURONAL LOSS

27Source: Image from the Alzheimer’s Society of Saskatchewan with permission from Alzheimer’s Broken Brain.

Alzheimer’s Brain Normal Brain

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Levels of acetylcholine, noradrenaline, serotonin, γ-aminobutyric acid (GABA), glutamate, somatostatin, neuropeptide Y, and substance P have all been documented to be reduced in the brains of AD patients.

Reductions in acetylcholine and choline acetyltransferase are the most profound.

Neuronal loss in the basal forebrain, which is the major region from which cholinergic projections originate.

CHOLINERGIC HYPOTHESIS

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Excessive release of glutamate into the synapses.

Excessive influx of calcium into the cells leading to cell death called excitotoxicity.

Also lead to excessive production of Aβ and tau phosphorylation.

EXCITOTOXICITY

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Growing evidence for the role of additional factors such as

oxidative stress, neuroinflammation, and mitochondrial

dysfunction in the pathogenesis of AD.

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GENETICS

Four genes1. Presenelin 1- chr 142. Presenelin 2- chr 13. Amyloid beta protein precursor- chr 214. Apolipoprotien E gene – chr 19

Typically divided into – early onset and late onset

Arch. Neurol. 1998;55:294-296

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GENETICS OF EARLY ONSET

APP gene Increase the production of amyloid.

Age of onset range from – 39 to 68 yrs

6 different mutation – all are fully penetrant.

APOE-4 mutation further decrease the age of onset.

Arch. Neurol. 1998;55:294-296

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THE PRESENELIN GENES Half of the early onset AD patient

Increase the production of amyloid and promote apoptosis.

It increase the production of Aß 1 -42,which is more hydrophobic more prone to agreggation, hence more toxic

All PS1 mutation are fully penetrant and autosomal dominant

Age of onset in PS1 mutation range from 32 to 56 yrs

Age of onset in PS2 mutation range from 40 – 85 yrsArch. Neurol. 1998;55:294-296

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GENETICS OF LATE ONSET AD

APOE GENE Has 3 alleles – 2,3 and 4…. 4 is associated with pathology

Normal gene promote proteolysis and clearence of amyloid, and mutant gene promote aggregation and deposition of amyloid.

Increase the risk of disease.

Age of onset 60s

It decrease the age of onset with APP mutation.Arch. Neurol. 1998;55:294-296

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SIGN AND SYMPTOMSASSESMENTLABORATORYIMAGING

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SIGN AND SYMPTOMS OF AD

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Who should be evaluated for AD

Age more than 60yr

People with risk factors – head injury, CV risks

People with memory or cognitive complaints, with or without change in functioning.

Memory difficulty noted by friends, relatives or spouse.

Patient with depression or anxiety without memory complaints

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ASSESMENT

History 1. Patient 2. Relatives Comprehensive physical and neurological examination

Cognitive evaluation

Functioning status

Lab work

Imaging

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HISTORY

Memory impairment – trouble remembering recent conversation, events, appointments, frequently misplaces objects.

Executive impairment – deterioration of complex task performance, decreased ability to solve problems, impaired driving.

DRUGS

Focal motor or sensory symptoms

Behavior personality and mood changes

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TOOLS

Screening Mini Mental State Examination (MMSE) (Folstein et al. 1975)

Hindi Mental State Examination (HMSE) (Ganguli et al. 1995)

Hindi Cognitive Screening Test (Tiwari and Tripathi, 2011)

St. Louis University Mental State (SLUMS) Exm. (JE Morley, 2000)

Clock Drawing Test (CDT) (Shulman et al. 1993)

Bender Gestalt Test (BGT) (Lauretta Bender, 1938)

Hachinski Ischemic Scale (1975)

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Detailed Assessment

Survey Psychiatric Assessment Schedule (Bond et al. 1980)

CAMDEX-R (Roth et al. 1986, 1998-R)

Alzheimer's Disease Assessment Scale (Rosen et al. 1984)

Schedule for Clinical Assessment in Neuropsychiatry (SCAN) (WHO, 1996)

Clinical Dementia Rating (Morris, 1993)

Blessed Dementia Scale (Blessed, 1968)

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Scoring:0- 4: Severe, 5-14: Mod. 15-19: Mild Dementia; 20-24: MCI, 25-28 :Age related Cog Impairment, 29-30:Normal

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Features Score

1. Abrupt 2

2. Stepwise deterioration 1

3. Fluctuating course 2

4. Nocturnal confusion 1

5. Relative preservation of personality

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6. Depression 1

7. Somatic Complaints 1

8. Emotional incontinence 1

Features Score

9. History or presence of hypertension

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10. History of strokes 2

11. Evidence of associated atherosclerosis

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12. Focal neurologic symptoms 2

13. Focal neurologic sign 2

Total Score 18

Hachinski Ischemic Scale (1975)

Scoring 0-4: Alzheimer's Dementia; 5-6: diagnosis unclear; 7 or more : Vascular Dementia

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Score Error(s)1 No error2 Minor visuospatial

error3 Inaccurate

representation of “10 past 11”

4 Moderate visuospatial disorganization of times

5 Several disorganization

6 No reasonable representation of a clock

Score≥ 3: Cognitive deficit

CLOCK DRAWING TEST

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FUNCTIONAL STATUS

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LABORATORY EAVALUATION

CBC, full chemistry, TSH.

Serum B12 and folic acid

No value of genetic testing at present

CSF markers – used only for research purpose not recommended for clinical diagnosis

• Amyloid beta 42 - low• Total tau - elevated• Phosphorylated tau - elevated

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CSF marker may assist in differentiating from other dementia.

A study in 2014 recommended the ratio of tau to A beta 42 with a cut of point of > 0.52 for differentiating AD from other dementia…its more sensitive than individual marker.

Its also important in predicting progression of MCI and dementia.

F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11

53 F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11

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IMAGING

STRUCTURAL IMAGING – CT, MRI

May reveal atrophy, white matter changes

Not sensitive/specific to AD.

In AD – diffuse cerebral atrophy, enlarged sulci, increased size of ventricles, loss of hippocampal volume.

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CEREBRAL ATROPHY

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FDG - PET Functional imaging of brain metabolism.

It measures synaptic activity in different part of brain

In AD – temporal and parietal glucose hypometabolism.

Can differentiate AD from FTD.

IOFLUPANE SPECT for evaluation of presynaptic dopamine transporters,

useful in differentiating AD from lewy body dementia

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AMYLOID IMAGING

11C – labelled pittsburgh compound B First PET ligand to visualise beta amyloid in living patient It have short half life.

Flourine 18 agents have longer half life and FDA approved. Sensitivity – 80 to 93% Specificity – 91 to 96%

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PET TAU IMAGING

In vivo marker of abnormally phosphorylated TAU protein. Tangles correlate best with cognitive impairment Amyloid may be present for years in the absence of

impairment

Combined amyloid and TAU imaging my help in early diagnosis and intervention.

61Alzheimer’s & Dementia 7 (2011) 257–262

62Alzheimer’s & Dementia 7 (2011) 257–262

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THANK YOU

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ETIOPATHOGENESIS MANAGEMENT AND RECENT ADVANCES IN ALZHEIMERS

DISEASE

Presented by Dr. Karrar HusainModerator – Dr. M. Amir Usmani

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INTRODUCTION AND HISTORY EPIDEMIOLOGY ETIOPATHOGENESIS ASSESMENT DIAGNOSIS AND D/D MANAGEMENT PREVENTION

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DIAGNOSTIC CRITERIADIFFERENTIAL DIAGNOSIS

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DSM 5

NEUROCOGNITIVE DIORDERS

DELIRIUM

MAJOR NEUROCOGNITIVE DISORDERS

MILD NEUROCOGNITIVE DISORDERS

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Mild NCD

A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains based on:

1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and

2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

B. The cognitive deficits do not interfere with capacity for independence in everyday activities

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C. The cognitive deficits do not occur exclusively in the context of delirium.

D. The cognitive deficits are not better explained by another mental disorder.

Specify: Without behavioral disturbance With behavioral disturbance

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Specify whether due to Alzheimer’s disease FTD LBD Vascular TBI Substance/medication use ……… Unspecified

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Major NCD

A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains based on:

1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and

2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

B. The cognitive deficits interfere with independence in everyday activities.

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C. The cognitive deficits do not occur exclusively in the context of delirium.

D. The cognitive deficits are not better explained by another mental disorder.

Specify: Without behavioral disturbance With behavioral disturbance

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Specify whether due to Alzheimer’s disease FTD LBD Vascular TBI Substance/medication use ……… Unspecified

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Specify current severity

Mild

Moderate

Severe

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Major or Mild NCD Due to Alzheimer’s

A. The criteria are met for major or mild neurocognitive disorder.

B. There is insidious onset and gradual progression of impairment in one or more cognitive domains.

C. Criteria are met for either probable or possible Alzheimer’s disease as follows:

For major neurocognitive disorder For mild neurocognitive disorder

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For major neurocognitive disorder Probable alzheimer’s disease is diagnosed if either of the

following is present; otherwise, possible Alzheimer’s disease should be diagnosed.

1. Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.

2. All 3 of the following are present:A. Clear evidence of decline in memory and learning and

at least one other cognitive domain.B. Steadily progressive, gradual decline in cognition,

without extended plateaus.C. No evidence of mixed etiology

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For mild neurocognitive disorder

Probable alzheimer’s disease is diagnosed if Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.

Possible alzheimer’s disease is diagnosed if there is no Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.

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DIAGNOSIS(ALZHEIMERS ASSOCIATION 2011)

3 stages of AD Preclinical AD requires measureable changes in

biomarkers and/or poor performance on challenging cognitive tests.

MCI - mild changes in memory and other cognitive abilities; these changes can be detected through careful evaluation, but do not interfere with day-to-day activities.

Dementia - changes in two or more aspects of cognition and behaviour that interfere with function in everyday life.

Alzheimer’s & Dementia 7 (2011) 257–262

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DIFFERENTIAL DIAGNOSIS

Dementias of other types

Delirium

Depression

Schizophrenia

Normal ageing

Mental retardation

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S.N Pseudodementia Dementia

1 Informant aware of memory disturbance and can date the onset accurately

Onset is insidious and informant usually can not date onset.

2 Patient complains enthusiastically about the memory loss

Unlikely

3 Questions about cognitive functions lead to DON’T KNOW RESPONSE accompanied by irritation

Try their best but are incorrect

4 History is usually short and often there is a previous history of depressive episode

History is long and depressive episode may or may not be present

5 Depressed patients perform better on memory tests.

Don’t perform well.

6 Memory complains are accompanied by insomnia, diurnal variation etc.

May or may not be present

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Feature Dementia Delirium

Onset Insidious Sudden

Duration Months to years Hours to week

Attention Preserved Fluctuates

Memory Impaired Impaired recent and immediate

Speech Word finding difficulty Incoherent

Sleep & wake cycle Fragmented sleep Disrupted sleep, day night reversal

Thoughts Impoverished Disorganized

Awareness Unchanged Reduced

Alertness Usually normal Hypervigilant or reduced vigilance

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Characteristics Alzheimer’s Disease Vascular Dementia

Sex Women Men

Age Generally over age 75 years Generally over age 60 years

Onset & progression Gradually progressive Episodic with stepwise deterioration

History of hypertension Less common Common

History of stroke(s),transient ischemic attack(s),or other

focal neurological symptoms

Less common Common

Hypertension Less common Common

Focal neurological signs Uncommon Common

Emotional lability Less common More common

Cognitive deficits Uniform patchy

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Features Pick’s disease AD

Personality change Early Late

Amnesia Late Early

Language disturbances Early Late

Stereotypes Early Mid or late

Apraxia, agnosia, alexia Late Variable

Kluver-Bucy syndrome Early Late

Visuospatial disorientation Rare Common

Age of risk Mean 50, up to 80yrs Risk increases with age

CT Scan Fronto-Temporal atrophy Widespread atrophy

Gross Pathology Anterior hemi. Atrophy, Posterior hemispheric atrophy,

Histopathology pick’s body Neurofibrillary tangle

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MANAGEMENT

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MANAGMENT

Treatment of AD Treatment of secondary symptoms Experimental therapy Preventive measures

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Treatment of AD

Cholineesterase inhibitors - mild-moderate AD Donepezil

Rivastigmine

Galantamine

NMDA antagonists – severe AD Memantine

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Characteristic DONEPAZIL RIVASTIGMINE GALANTAMINE MEMANTINE

Chemical class Piperidine Carbamate Phenanthrene alkaloid

Similar to amantadine

Primary mechanism

AchE inh AchE inh AchE inh NMDA antagonist

Other mechanism

None BuchE IN Nicotine modulator

HT3 receptor antagonist

Half life 70 h 90 min 7 h 70 h

Metabolism Hepatic Renal Hepatic Hepatic

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Current status of AChE Inhibitors

Treatment over 6 month produce improvement in cognitive function.

Benefits were also noted on ADL and behaviour.

Direct comparison – equivocal result.

Delay institutionalization

Decrease troublesome behaviours

Combining memantine with AChE inhibitors - slowed cognitive and functional decline.

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Combined clinical trial data for the three licensed acetylcholinesterase inhibitors: rivastigmine (♦), donepezil ( ) and galantamine (•) versus placebo (▪). ▴

BULLOCK R BJP 2002;180:135-139

©2002 by The Royal College of Psychiatrists

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TREATMENT OF SECONDARY SYMPTOMS

Neuroleptic agents FDA in 2005 black box warning for atypical neuroleptics

2008 - haloperidol, chlorpromazine and thioridazine included

Typical antipsychotics – cardiac arrythmia and EPS

Atypical – thromboembolism and aspirational pnemonia.

Cognitive decline with both

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Antidepressants Sertaline & fluvoxetine – no benefits (wintraub & petrecca

et al study)

Mirtazipine has no benefial effect ( Banerjee et al)

Recommendation – not effective – not recommended.

Anticonvulsants Very limited evidence to support use

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EXPERIMENTAL THERAPY

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To date there is no effective approach in terms of cure or prevention of dementia.

The available pharmacological therapy is largely symptomatic, with temporary clinical benefits on cognitive, functional and behavioural manifestations of the disease.

There is an urgent need to develop new drugs with disease-modifying properties for AD.

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A disease-modifying drug is a agent intended to slow the progression of the neurodegenerative process by inhibiting critical events in the pathophysiology of the disease.

Patients treated with such agents would be expected to have a more benign course of the disease when compared to placebo-treated individuals

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Many drugs have been proposed and tested in neurobiological models of AD.

However, the promising effects of these compounds in animal models failed to prove beneficial to humans.

In addition, other drugs that underwent clinical experimentation delivered negative results, either due to limited efficacy or toxicity.

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Therapeutic targets for disease modification in AD

More than 200 pharmaceutical compounds are currently undergoing phase 2 and 3 trials.

Grossly divided into : Anti amyloid Drug that target other pathways

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Anti-amyloid compound

1. Block/inhibit the overproduction or aggregation Gamma secretase inhibitors Beta secretase inhibitors

2. Favour its clearance from the brain Active immunisation Passive immunisation

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ACTIVE IMMUNIZATION

Induces an IgM response to generate antibodies against pathogenic Aβ, which further mobilize microglia to clean plaques through phagocytosis

AN 1792 – PHASE 2 The trial was interrupted due to the occurrence of

meningoencephalitis in 6% of subjects.

CAD106 - PHASE 1 Able to reduce Aβ accumulation in cortical and subcortical

brain regions

Bioorg Med Chem Lett 2011; 21 : 2655-8.S, Jacobson LH, et al.. J Neurosci 2011; 31 : 9323-31.

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PASSIVE IMMUNISATION

Intravenous administration of full monoclonal antibodies or antibody fragments which directly target Aβ.

BAPINEUZUMAB Undergoing phase 3 studies. Researchers reported that it failed to protect against

cognitive and functional decline of AD patients undergoing a phase 3 trial.

Neurology 2009; 73 : 2061-70.

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SOLANEZUMAB Phase 3 trials failed to demonstrate clinical benefits. But In a study conducted in Japan with AD patients

associated with increased clearance of Aβ from the brain.

PONEZUMAB Targets the amino-terminal portion of Aβ1-40 Phase 2 studies did not confirm clinical efficacy.

The European Federation of Neurological Societies annual 23. meeting, in Stokholm, Sweden; 2012.Clin Neuropharmacol 2013; 36 : 14-23.

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Inhibitor of production and accumulation of Aβ

γ-secretase inhibitors Semagacestat –

Phase III trials found no efficacy. Even it was associated with increasing cognitive

impairment and worsening daily living activities, as well with increasing risk for skin cancer.

Avagacestat – Inhibitor of Ab 40 and Ab 42 formation Phase 2 study

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Tau-oriented strategies

LITHIUM AND VALPROATE - Inhibit GSK – prevent Tau phosphorylation in animal models Valproate was not associated with reduction of cognitive or

functional decline.

Long-term lithium treatment was associated with stabilization of cognitive and functional parameters, in addition to a reduction in CSF concentrations of phosphorylated Tau.

Phase 2 study in patients with mild AD treated with lithium for a shorter (10 wk) period, no significant differences were observed in biological or clinical outcomes. Neurology 2011; 77 : 1263-71.

J Clin Psychiatry 2009; 70 : 922-31Br J Psychiatry 2011; 198 : 351-6.

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Others

Ginkgo biloba

Previously - effective in mild to moderate Alzheimer’s disease with an advantage over placebo.

Recent cochrane review – no evidence of efficacy

Several reports of bleeding.

Pharmacopsychiatry 2003; 36:297–303. Cochrane Database Syst Rev 2009; 1:CD003120

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Antibiotics

Higher than normal titres of Chlamydia in people with AD

Multicentre Canadian double blind placebo controlled RCT

101 patients with mild to moderate AD (MMSE 11-25)

Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months

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Standardized ADAS Cog significant @ 6 but not 12 months

Standardized MMSE score higher @12 (but not 3 or 6) months

Intriguing results!

Larger study in planning stages

Loeb M, Molloy DW et al JAGS 2004;52:381

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vitamin E

High dose Vit E (2000U/day) for 2 yr slowed progression of AD ( large double blind placebo trial ,Sano et al 1997)

Alzheimer Disease Cooperative Study ( 769 pts) showed no benefit vs placebo (Peterson et al 2005)

Cause cardiovascular side effects

Not recommended currently

Cochrane Database Syst Rev 2008; 3:CD002854.

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Estrogen replacement therapy RCT with 351 pts for 2 weeks showed no beneficial effects

Cholesterol lowering agents RCT, double blinded study with 748 pts for 6 months failed

to prove efficacy

McGuinness B et al. Statins for the treatment of dementia. Cochrane Database Syst Rev 2010; 8:CD007514.

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Anti inflammatory agents NSAIDs delay onset of AD

Breitner et al showed NSAIDs don’t protect against AD in very old

A double blind,placebo controlled trial ( Grundman et al 2003) showed rofecoxib & naproxen don’t delay AD progression.

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Omega-3 supplementation

174 patients in a placebo-controlled RCT

No significant overall effects on neuropsychiatric symptoms, on ADL or on caregiver’s burden

Positive effects were seen on depressive symptoms

Freund-Levi Y et al. Int J Geriatr Psychiatry 2008; 23:161–169.

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Dimebon (latrepirdine) Non-selective antihistamine previously approved in Russia

Weak inhibitor of BuchE and AchE , weakly blocks the NMDA receptor signalling pathway.

A company sponsored study completed in Russia included 183 patients - significant benefits compared with placebo.

In the recent CONNECTION study, dimebon was not more effective than placebo.

Doody RS et al. Lancet 2008; 372:207–215.

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Huperzine A Alkaloid isolated from the Chinese herb Huperzia serrata

AChE inhibitor used since 1994 in China.

A recent meta-analysis found that huperzine A 300–500 g daily for 8–24 weeks in Alzheimer’s disease led to significant improvements in MMSE and ADL.

Wang BS et al. J Neural Transm 2009; 116:457–465.

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Cerebrolysin Porcine brain-derived peptide

Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability in several RCTs of up to 28 weeks.

A large RCT comparing cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline.

Plosker GL et al. Spotlight on cerebrolysin in dementia. CNS Drugs 2010; 24:263–266.

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STEM CELL THERAPY

South Florida university

Mouse model study in 2009

Several infusions of stem cells from umblical cord

Myeloid protein reduced by 62%

Cerebral amyloid angiopathy reduced by 82%

Hope to begin human trials.

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Conclusions

Most phase 3 trials with candidate drugs for AD in the last decade failed to present unequivocal clinical benefits, or were suspended due to severe adverse events.

To date, treatment of AD relies on the symptomatic effects of cholinesterase inhibitors and NMDA-receptor antagonists.

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Preventive measures

Exercise regularly

Eat a healthy diet rich in fruits and vegetables

Engage in social and intellectually stimulating activities

Control type 2 diabetes

Lower high blood pressure levels

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Lower high blood cholesterol levels

Maintain a healthy weight

Stop smoking

Get treatment for depression

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THANK YOU