Alzheimer’s DiseaseDiagnosis , Management and D/D

08/09/2008

Alois Alzheimer

Introduction

• Alzheimer's disease (AD) a progressive & fatal neurodegenerative disorder manifested by – Cognitive and memory deterioration – Progressive impairment of ADL– A variety of neuropsychiatric symptoms &

behavioral disturbances

• AD MC form of dementia in aging adults

• Incidence increases rapidly with age, so the number of affected individuals with AD is ballooning rapidly

• The diagnosis is still primarily made on basis of history & physical examinations

• Early recognition of AD allows time to plan for the future and to treat patients before marked deterioration occurs

Historical facts

• At a scientific meeting in Nov. 1906, German physician Alois Alzheimer presented case of “Frau Auguste D.,” a 51-year-old woman brought to see him in 1901 by her family

• Auguste had developed problems with memory, unfounded suspicions that her husband was unfaithful, and difficulty speaking and understanding what was said to her.

• Her symptoms rapidly grew worse, and within a few years she was bedridden.

• She died in Spring 1906, of overwhelming infections from bedsores and pneumonia

• Dr. Alzheimer had never before seen anyone like Auguste D., & gained the family’s permission to perform an autopsy

• In Auguste’s brain, he saw dramatic

shrinkage, especially of cortex, outer layer involved in memory, thinking, judgment and speech

• Under microscope, he also saw widespread fatty deposits in small blood vessels, dead & dying brain cells, & abnormal deposits in and around cells

• The condition entered the medical literature in 1907, when Alzheimer published his observations about Auguste D

• In 1910, Emil Kraepelin, a psychiatrist noted for his work in naming and classifying brain disorders, proposed that the disease be named after Alzheimer

• In the late 1960s , Blessed and colleagues in the UK demonstrated correlation between neuritic plaque no. and severity of cognitive impairment

Mild cognitive impairment

• MCI was initially described in the late 1980s by Reisberg and colleagues

• In the mid to late 1990s, MCI came to be characterized as a stage of memory impairment beyond aging but in which other cognitive domains were preserved & daily function remained largely intact

• AD is estimated to be by far MC (65% to 75%) form of dementia in US

• Currently afflicting as many as 4.5 million mainly elderly individuals

• The incidence doubles every 5 years after the age of 60

• The prevalence of dementia in the United States in individuals aged 65 years or older is about 8%,

Indian Data

• Two epidemiological studies of dementia conducted in residents aged 60 years and

over,

• City of Chennai (Madras) and another in a rural block of southern India

• Obtained prevalence rates of 27 per 1000 and 36 per 1000 respectively

Rajkumar & Kumar, 1996; Rajkumar et al, 1997

• A study rural community in Kerala yielded a prevalence of 34 per 1000 in people aged >60 yrs

• Chandra et al (1998) reported a prevalence rate of 8.4 per 1000 in a population aged >55 years

• Overall prevalence rate of 13.6 per 1000 in a population aged >65 years and above from a rural

community in northern India • Vas et al (2001) reported an overall prevalence of

18 per 1000 for those aged 65 years and above in an urban population in Mumbai

• AD was the most common type even in Indian studies

• Forming upto 80% of all dementia in age >80yrs (Ganguli et al)

• The major risk factor is aging• Although the illness has been reported to occur in

exceedingly rare pts in their 20s and 30s, • Onset of clinical symptoms in this illness is

uncommon until the 50s, • Prevalence rapidly increasing to age 65 years • By age 75 the prevalence is estimated at 15%• By age 85 estimated to be present in 35% to 50%

Risk Factors For AD

• Other demographic factors associated with differential risk for AD are – apo E4 allele, lower education level , family

history of AD, CAD, and significant prior head trauma.

• Women are at modestly greater risk for AD

Diagnostic Criterias

• Two sets of criteria for the clinical diagnosis of AD

• Dementia is commonly recognized with use of the criteria of DSM-IV

• Consensus criteria developed by (NINCDS-ADRDA) National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association

NINCDS-ADRDA Criteria

• Definite (clinical diagnosis with histologic confirmation),

• Probable (typical clinical syndrome without histologic confirmation), or

• Possible (atypical clinical features but no alternative diagnosis apparent; no histologic confirmation).

• Typical sensitivity and specificity 0.65 and 0.75, respectively

Clinical Evaluation

• History directly from pt may be unrewarding /unreliable

• Pt may offer none or a complaint of an unrelated minor physical problem

• A family member, close friend, or caregiver knowledgeable about pt's general level of cognitive

functioningc & ADLs present to give or corroborate hx

History

• Change in cognition & functioning relative to previous performance

• Mode of onset of impairment (insidious onset is characteristic of AD),

• Progression of illness (slow gradual decline is typical of AD)

• Duration of impairment - earlier signs that may have indicated a change

• In addition to inquiring about cognitive function, it is critical to inquire about the – use of prescription and over-the-counter

medications– alcohol, and illicit drugs and their temporal

relationship to any cognitive changes

Other Co-morbid Conditions

• Cardiovascular diseases

• Sensorial handicap

• Other neurological diseases apart from dementia

• It is essential to take details of these conditions in history

• The ideal history should document presence of cognitive deficits, impairment in function in ADLs, & any possible behavioral abnormalities

• The classic C/F of Alzheimer's disease are – An amnesic type of memory impairment – Deterioration of language– Visuospatial deficits – Executive dysfunction

• Behavioral and neuropsychiatric symptoms develop in mid –stage

• Motor ,sensory abnormalities, gait disturbances, & Sz are uncommon until late phases

• There are 10 classic warning signs of Alzheimer's disease: – Memory loss– Difficulty performing familiar tasks – Problems with language – Disorientation to time and place – Poor or decreased judgment

– Problems with abstract thinking – Misplacing things – Changes in mood or behavior – Changes in personality – Loss of initiative

• Individuals are typically repetitive in conversation and forget – Appointments – Material they have read in the newspaper – TV programs they have recently watched.

• Memory impairment becomes more severe, to include past longer-term memory, as the illness worsens

• History of language difficulties, including naming family or friends and inability to find words in conversation

• This progresses to decreased fluency in the severe stages, eventually leading to the individual's becoming mute

• Visuospatial impairment is common, with the individual getting lost trying to find a car in the parking lot or while driving

• Items around the house may be misplaced

• Difficulty with calculations frequently occurs, – such that a tip can no longer be calculated or the

checking account can no longer be balanced

• Pts have executive functioning difficulties, becoming unable to follow a recipe, plan a family trip, or manage their financial affairs

• There may be difficulty with dyspraxia, particularly for dressing &/or operating kitchen or other home appliances

• Pts progress from loss of higher-level ADL, such as check writing & use of public transportation

• Through abnormalities of basic ADL, such as eating, grooming & using toilet, as the disease enters advanced phases

Behavioral And Psychiatric Disturbances

• 4 groups

• Mood disturbances

• Psychosis

• Personality changes

• Behavior disorder

• Mood change & apathy commonly develop early & continue for duration of disease

Apathy

• Most pervasive neuropsychiatric symptom in AD – 42% of pts with mild– 80% of those with moderate– 92% of those with advanced AD

• Reflect fronto-subcortical dysfunction & disconnection of Ant. cingulate cortex from other cortical & subcortical areas

Apathy..

• It presents with loss of interest in previously enjoyed activities, including – Hobbies, social outings or spending time with

beloved relatives – Aloofness, diminished spontaneity– Emotional behavior, and reduced motivation

Anxiety

• Another early feature of AD• The prevalence of anxiety among cognitively

normal elderly persons is around 6% • In MCI frequency 10% to 25% & in AD is ~ 50% • Triggered by pt’s subjective awareness of his or

her cognitive decline– The increased dependency on others, & fear of the

disease & future

Agitation & Irritability

• Frequently co-occur

• They may begin in the MCI phase of AD

• Then progressively increase in freq. throughout the course

• More common in males, pts with later onset of dementia & pts of more advanced age

Depression

• Very common in AD– occurring in 10% of mild, – 40% to 60% of moderate– 60% or more of patients with severe AD

• Symptoms are rarely severe enough to merit diagnosis of major depressive disorder

• Represent less severe dysphoria or minor depression

• Depression may be direct result of neuronal damage in locus ceruleus with decrease in CA

• Risk factors - family or personal history of depressive disorder, female gender & younger age

• Depressive symptoms associate with decreased quality of life, functional dependency, increased institutionalization, caregiver burden, & caregiver depression

• New-onset depression in elderly persons may indicate the presence of dementia & predict cognitive decline

Psychosis

• Hallucinations, delusions, or delusional misidentifications syndrome

• Psychotic symptoms could be medication or delirium induced– Visual hallucinations, triggered by poor visual

acuity

• Psychotic symptoms occur more frequently in mod. & advanced stages of AD

Psychosis…

• 10% - 20% of patients with AD experience hallucinations, which are most frequently visual>auditory>olfactory

• Pts with hallucination experience a rapid cognitive decline• Delusions in 30% to 50% of pts , later stages of AD• The most common themes are infidelity, theft, &

paranoia , more in man• Female gender is a risk factor for psychosis in AD, while

living with a spouse seems to convey protection

• Neuropsychiatric symptoms, known to be very common among pts with AD, have been reported in > 80 % of subjects in most studies

• Other features include– Wandering & repetitive motor symptoms - pacing – Disinhibition

• inappropriate behaviors such as off-color jokes • rough play with children• aggressive or occasionally sexual advances toward family

members, including children or even strangers

Neurological Examination

Neurological Examination

• Two major components are important in examining the dementia pt: – (1) General physical & neurological exam

• to look causes of dementia• to document any findings that may relate directly to AD

– (2) mental status testing to document • presence of cognitive deficits supporting dementia diagnosis • to begin staging the illness • to determine whether more extensive neuropsychological

testing might be indicated to better characterize the illness

• General neurological exam may often be normal in demented pt with AD

• Presence of focal deficits, eg, visual field cuts, weakness or spasticity in an arm or leg, suggests a vascular cause for dementia

Other findings in AD

• Pathological reflexes in later stages (G/R/S)

• At end stage , pt is mute incontinent, & bedridden with flexion deformities of limbs and impaired swallowing

• Wt loss begins in mid-stage

• Parkinosian features may be present in later stage but early involvement (<1 year) -DLB

Mental Status Testing

• Anosognosia can be an early feature of AD• Assessment should include

– Level of alertness or attention, – Orientation (person, place, time), – Short-term & remote memory (3 words for 5 minutes

and knowledge of their birth date and high school) – Language – Visuospatial functioning (copying figures), – Calculation – Executive functioning or judgment

MMSE

• Most widely used to screen for cognitive dysfunction to support diagnosis of dementia and to stage dementia

• Does not assess executive function, a major feature of AD and other dementias

• Education, as well as ethnicity, & other factors may influence MMSE scores

• Clock drawing is a similarly useful very short screen for cognitive impairment or dementia

• It is easy for physicians to administer and score

Memory loss

• Memory impairment is a sine qua in the diagnosis of AD

• Working memory affected with complex attention tasks early then simple working task (digit span, word span)

• Recent episodic memory- Memories of personal experience (delayed recall)

• Long term memory (remote memory) is good but detail examination may reveal some impairment

Language Disturbance

• Semantic categories are more impaired than orthographically constrained tasks in AD

• Opposite is true for depression

Staging Of Functional Disability

• Functional Assessment Questionnaire given to the caregiver or family member

• Document the patient's deficits in performing ADLs that are secondary to cognitive impairment

Hx ,exam, mental status exam neuropsychological testing

Cognitive function is normal Compatible with dementia

Not normal & not demented (MCI)

• Amnestic MCI involves deficits in learning and memory, specifically, episodic memory

• If memory is the only domain impaired, diagnosis is amnestic MCI single domain

• If other domains (e.g., language, executive function, or visuospatial skills) are impaired, the designation is amnestic MCI –multiple domain

MCI etiology

– Degenerative (gradual onset, insidious progression),

– Vascular (abrupt onset, risk factors, history of strokes, TIAs)

– Psychiatric (h/o depression, depressed mood, or anxiety)

– Sec. to concomitant medical disorders (CHF, DM, systemic cancer)

Alzheimer's Disease Variants

• Frontal variant of AD is an AD subtype • In addition to symptoms outlined above, pt present

with prominent executive dysfunction • Frontal-type behaviors including impulsivity,

disinhibition, agitation, euphoria, and compulsive behaviors (ie, hoarding)

AD with posterior cortical atrophy

• Early progressive impairment in complex visual processing

• Elements of Balint syndrome• Apperceptive visual agnosia• Constructional and dressing apraxia• Gerstmann’s syndrome• Episodic memory and insight spared

relative to these features

Overlap Syndome (Mixed Dementia)

• Dementia due to vascular disease may coexist with that due to AD

• When CVA is superimposed on a clinical picture of AD

• A detailed history and temporal relationship b/n CVA & cognitive defect for diagnosis

Investigations

Laboratory Studies

• Though majority of dementia in elderly persons is caused by neurodegenerative or ischemic illnesses

• Focus of laboratory evaluations has been to 1st & primarily identify small minority of pts who have reversible causes for their dementia

• A potentially reversible factor may be identified in 25% to 40% of pts

• When lab abnormality is corrected or an offending drug is withdrawn

• Only transient mild improvement or stabilization in disease progression ensues

• Nonetheless, any improvement in cognitive functioning or function in ADLs, even if limited or transient, is greatly appreciated by pts & their caregivers

• Benefits fully justify doing an evaluation for reversible conditions

• A second purpose of lab evaluation is to aid D/D among the irreversible types of dementia

• AD, DLB, VaD, FTDs, PDD

• Correct diagnosis about type of dementia can assist counseling of pts & providing appropriate information for caregiver about cause & prognosis

• Particularly in regard to ultimate nursing home placement and mortality

• Accurate dementia classification will also be important in choosing appropriate therapy

Structural Imaging

• In screening for reversible causes of dementia, space-occupying masses or other structural abnormalities may be identified by brain imaging studies such as CT or MRI

• Common abnormalities identified would include – Strokes or ischemic changes,– NPH, SDH and hygromas, – Tumors such as large meningiomas, and gliomas or

brain metastases

MRI in AD

• 1st structural changes in medial temp lobe with early vol. loss of hippocampus & entorhinal cortex

• Posterior cingulate, precuneus & TP association neocortex, with concurrent expansion of ventricles

• There is a relative sparing of SM cortex, visual cortex, and cerebellum

• FTD - severe patterns of atrophy in frontal & ATL with little involvement of T-P association neocortex

• This ant-post gradient of atrophy in FTD can help distinguish them from those with AD, who show a more posterior bias

• Asymmetry is also a common feature that is relatively sp.c to FTD & can be diagnostically useful.

• Rates of regional atrophy may also be useful

• More complex registration methods - provide detailed information concerning exactly where in brain change has occurred over time

• Show widespread patterns of tissue loss over time in T-P lobes, with relative sparing of the SM cortices in patients with AD

• Used to track progression of the disease over multiple scans

Functional Nuclear Medicine

• Measure glucose uptake or cerebral blood flow

• Functional losses may precede structural changes & more sensitive markers of early disease progression

• Two main techniques. [18F] Fluorodeoxyglucose PET (FDG-PET) measures local cerebral metabolic rate

• SPECT measures blood flow alterations or perfusion

• Imaging using PET has a higher sensitivity and greater spatial resolution than SPECT

FDG-PET

• Pattern of abnormally low uptake in the posterior cingulate, precuneus, TP regions,& frontal cortex in AD

• Hypometabolism can also be observed in the medial temporal lobe

• Visual assessments of medial temp lobe can distinguish pts with MCI from controls at a sensitivity of 77% and specificity of 71%

• Medial templ lobes are difficult to image b/z of partial vol effects in FDG-PET

fMRI

• Reduced activation in hippocampus, entorhinal cortex & frontal lobe during memory tasks

• Reduced activation also in medial temp lobe & in post. cingulate in patients with MCI in response to memory tasks

fMRI …..

• Also to assess response to Tt with cholinesterase inhibitors in pts with MCI

• Tt shown to enhance activity in regions of brain that correlate with improvement in task performance

• Prolonged exposure resulting in decreases in activation in same set of regions

Magnetic Resonance Spectroscopy

• Decrease in NAA in posterior cingulate and T,P,&F lobes, compared with normal controls

• In contrast, the levels of MI/Cr increase in patients with AD

• The clinical specificity of the NAA decline is poor

• Patients with FTD also show reductions in NAA/Cr in temporal lobes but relative preservation of metabolites in parietal lobe

• The diff.in ratio of anterior to posterior metabolite changes b/n AD and FTD

Diffusion-weighted Imaging

• Patients with AD and MCI show elevated ADC in brain regions that are typically involved in AD

• In addition, hippocampal diffusivity is greater in patients with MCI who convert to dementia compared with those who remain stable

• May provide better prediction of conversion than hippocampal vol measured on MRI

Amyloid Imaging

• A major recent advance -technique to image amyloid in human brain

• The compound most extensively studied is Pittsburgh Compound B, referred to as PIB

• PIB binds to aggregated fibrillar A[beta] deposits with high affinity & detected by PET imaging

• The assessment of PIB imaging may prove to be most useful in D/D of dementia, especially in differentiating AD & FTD

• Very recent work suggests that no PIB binding is found in patients with FTD

Note increased uptake and retention of [18F]FDDNP (arrowheads) in temporal lobes of pt with AD, compared with those in control subject. The pt with AD still demonstrates typical findings of decreased temporal (arrows) and parietal (not shown) FDG uptake.

A second compound FDDNP, labels multiple neuritic elements including neuritic plaques & NFT

Biological Markers And Disease Progression

• A[beta]1-42 protein levels in CSF from pts with AD lower than in age-matched controls

• Tau protein levels and phospho-tau levels are significantly higher

• Unfortunately, abnormal A[beta] and tau levels occur in other neurodegenerative conditions

• Combining these two measures improves accuracy of diagnosis

• Remains unclear that CSF A[beta] and tau measurements improve specificity of clinical diagnosis enough to justify this procedure in the majority of pts

Progression of MCI to AD

• The typical rate at which pts progress to AD ~ 10 to 15% /yr

• Petersen et al reported conversion rate to AD of 12% per year in their MCI sample over 4 years

• Compared with 1% to 2% for normal controls • As research is progressing, several predictive

features are beginning to emerge

California verbal learning test

• CVLT delayed recall performance was found to be one of the best predictors of conversion to AD

• Total words learned & immediate and delayed recall performance on CVLT best distinguishes which MCI or questionable AD subjects ultimately develop AD

• For amnestic MCI ApoE4 carrier status has been shown to be a risk factor

• Atrophy of the hippocampal formation predicts the rate of progression from MCI to AD

• Additional measure such as whole brain vol & ventricular vol. can be useful

• FDGPET & Amyloid PET may be a useful index as well in predicting progression toAD

• A recent large study indicated that low CSF Ab and high tau levels might predict which MCI subject are likely to progress to AD more rapidly than others

Treatment

Co-morbidities

• Metabolic abnormalities worsen cognitive deficits in patients with dementia

• Relatively minor deviations out of the normal range can exacerbate mental impairment

• Potentially reversible causes might include: – Hypernatremia and hyponatremia

– Hypokalemia and hyperkalemia

– Hypocalcemia and hypercalcemia

• Hypothyroidism

• DM-intermittent hyperglycemia or unrecognized hypoglycemia may contribute to cognitive impairment

Chronic Systemic Diseases

• These chronic diseases include pulmonary (acute and chronic disease), hepatic disease (hepatitis, cirrhosis), cardiac disease (CHF, arrhythmias)

• Chronic CNS infections including HIV, syphilis, tuberculosis, cryptococcus, and other fungal infections

Medications

• Particular offenders include anticholinergics, antihypertensives, antidepressants, anxiety drugs, antipsychotics, analgesics, and sedatives for sleep

• Should always be given lowest dosage necessary to achieve the therapeutic goal

• If they are not clearly indicated or are not helping, they should be eliminated from patient's regimen

Drugs For AD

Cholinesterase Inhibitors

• Cholinesterase inhibitors are approved for the treatment of mild-to-moderate AD

• Should be considered as a standard of care for pts with AD

• Four cholinesterase inhibitors are available: tacrine, donepezil, rivastigmine, and galantamine.

• Tacrine is now rarely used, since it has hepatotoxic effects in ~ 40%

• Second-generation cholinesterase inhibitors

seem less toxic

• Their duration of action permits more convenient dosage regimens

• The dose may be increased at intervals of 1-4 weeks– Fewer side effects (nausea, vomiting, and diarrhea)

emerge with longer periods between increases

– To achieve best dose to maximize benefits

• If adverse effects do occur, doses may be skipped or drug dosage reduced until -ve effects disappear ,& higher dosage may be again tried at a later date

• Finding most favorable balance b/n these drug effects in individual patient is the goal

• If patients do not tolerate one cholinesterase inhibitor, they may tolerate another

• Both the AD 2000 Collaborative Group study and the Alzheimer's Disease Cooperative Studies-Mild Cognitive Impairment Trial suggested that donepezil may be less effective after 18 to 24 months

• Substantial open-label follow-up data are available for all these drugs, suggesting continued effectiveness for 4 or 5 years or longer

• However, these data are uncontrolled and likely biased by selective dropouts

• Another topic of considerable interest to families and physicians is when to withdraw these drugs

• Drugs should be stopped when pt is no longer benefiting from their use, but this may be difficult to determine in late-stage individuals

• In severely affected pts, drugs should be withdrawn when pts are no longer able to meaningfully interact with family or caregivers

Memantine

• Antagonize glutamate at NMDA receptor, by preventing excess Ca2+ to rush into the neurons, thus providing neuroprotection

• In pts with mod. to severe stage disease, mildly improves cognitive deficits, function in ADLs, & behavior

• Currently not recommended for use in milder-stage AD

• Adverse effects with memantine are fewer than with the cholinesterase inhibitors

• Trial in pts previously taking donepezil suggested additive symptomatic benefits when memantine was added

Management of Neuropsychiatric

Symptoms and Behavioral Disturbances

• Nonpharmacological Tt approaches should be attempted 1st before pharmacological Tts

• Environmental manipulation or simple behavioral techniques may be helpful

• Creating a safe & consistent environment with moderate stimulation, contrasting colors, & pictures for directions/signs

• A structured routine & consistent environment as free from change as possible to eliminate confusion

• Provide familiar personal objects such as pictures & momentos, as well as cues for orientation like calendars and clocks

• Communication should be clear and simple

• Behavioral interventions such as validation and not correcting misstatements can ease anxiety

• Patients should be encouraged to be active participants in their care & in decision making

Pharmacological Treatment

• Atypical antipsychotic agents preferred medications for the management of psychosis or agitation

• Fewer side effects such as parkinsonism and tardive dyskinesia than do conventional

• Pts with inadequate responses may benefit from therapy with mood stabilizers or antidepressants alone or in combination with antipsychotic agents

• Mood-stabilizing agents may reduce behavioral disturbances in patients with Alzheimer's disease

• Agitation appeared to improve significantly in trials with carbamazepine

• Divalproex sodium has been studied for its effects on agitation, with mixed results

Depression

• Most clinicians choose selective serotonin-reuptake inhibitors when treating depression in patients with Alzheimer's disease

Treatment Of Insomnia In Ad

• Insomnia or sleep-wake cycle disturbance is common in AD – occurs in up to 20% to 40% of pts

• Significant distress to family caregivers who are awakened at night

• Vigilant to prevent wandering away from home or self-injury of the pt

• Treatment of insomnia and sleep-wake cycle disturbance is not well studied in AD

• Effective strategies include trazodone and zolpidem administered at bedtime

• Chloral hydrate and benzodiazepines should only be used for short-term treatment

Cholinesterase # tried

MCI Treatment

• What do you tell patients with mild cognitive impairment?

• This is a common question and deserves some attention.

• As noted above, there are no approved pharmacotherapies for mild cognitive impairment.

• If Pt is active, still employed, wants to remain in this capacity as long as possible, Tt with acetylcholinesterase # sooner rather than later might be warranted

• Alternatively, if pt is retired & not engaged in

many cognitively challenging activities on a daily basis– this person might opt for delaying Tt until functional

impairment becomes more prominent

Health Maintenance and General Medical Treatment

• As AD progresses, various conditions develop that may lead to death, such as septicemia, pneumonia and upper respiratory infections, nutritional disorders, pressure sores, fractures, and wounds

• Management of these conditions is critical

• Imp. to address basic requirements such as nutrition, hydration, and skin care

• Decisions abt use of methods of extending

life- gastrostomy, i/v hydration, antibiotics, should respect advance directives by pts & incorporate guidance from surrogate decision makers

Future Trends in Alzheimer's Disease Therapy

•Antiamyloid Therapies

Neuroprotective Approaches

• A protein seems to exert its neurotoxic effects through a variety of secondary mechanisms, – including oxidative injury and lipid peroxidation of cell

membranes, inflammation, hyperphosphorylation of tau protein, and increased glutamatergic excitotoxicity

• Neuroprotective strategies have targeted these mechanisms in an effort to reduce cell injury

Conclusions

• Current therapies for AD Pts may ease symptoms by providing temporary improvement & reducing

rate of cognitive decline • Given twide array of available molecular targets &

rapid progress toward identifying potential therapeutic compounds

• The development of interventions that substantially delay onset or modify progression of AD can be anticipated

References

• Neurology in Clinical Practice-Principles of Diagnosis and Management IVth Edition-Walter G. Bradley

• Roy Yaari, and Jody Corey-Bloom- Alzheimer’s Disease. Seminars In Neurology/Volume 27, Number 1 2007

• Bor Luen Tang,& Rajeev Kumar. Biomarkers of Mild Cognitive Impairment and Alzheimer’s Disease. Ann Acad Med Singapore 2008;37:406-10

• Stephanie S. Richards, Hugh C. Hendrie, Diagnosis, Management, and Treatment of Alzheimer Disease, Arch Intern Med/Vol 159, APR 26, 1999

• Ronald C. Petersen.Mild Cognitive Impairment: Current Research and Clinical Implications. Seminars In Neurology/Volume 27, Number 1 2007

• Jeffrey L. Cummings, Alastair J.J. Wood. Alzheimer’s Disease drug therapy. N Engl J Med 2004;351:56-67.

• Farlow, Martin R. ALZHEIMER'S DISEASE . Continuum:Volume 13(2), April 2007, pp 39-68

• Doody RS, Stevens JC, Beck C, et al. Practice parameter: Management of dementia. Neurology 2001;56:1154-1166

• Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525-1538

• Klafki H.W.et al.Therapeutic approaches to Alzheimer’s disease Brain (2006), 129, 2840–2855

• Greenaway et al. Patterns of Verbal Memory Performance in Mild Cognitive Impairment, Alzheimer Disease, and Normal Aging .Cognitive and Behavioral Neurology ;Volume 19(2), June 2006, pp 79-84

• Apostolova, Liana G.; Cummings, Jeffrey Psychiatric Manifestations In Dementia . Continuum: Volume 13(2), April 2007, pp 165-179

• Jiska Cohen-Mansfield. Nonpharmacologic Interventions for Inappropriate Behaviors in Dementia A Review, Summary, and Critique. Am J Geriatr Psychiatry 9:4, Fall 2001

• Jeffrey R. Petrella, R. Edward Coleman, P. Murali Doraiswamy.Neuroimaging and Early Diagnosis of AlzheimerDisease: A Look to the Future. Radiology 2003; 226:315–336

• Neuroimaging in Dementia. Continuum 2007• Review in Indian Neurology-2003

Q.1-Risk factors for AD all except

• A)- Age

• B)- Smoking

• C)- Education

• D)-apoE4

Q.1-Risk factors for AD all except

• A)- Age

• B)- Smoking

• C)- Education

• D)-apoE4

Q.2-Early feature for AD all except

• A)- Myoclonus

• B)- Episodic memory

• C)- Executive dysfuncion

• D)-Visuospatial dysorientation

Q.2-Early feature for AD all except

• A)- Myoclonus

• B)- Episodic memory

• C)- Executive dysfuncion

• D)-Visuospatial dysorientation

Q.3-True about AD

• A)- MRI shows charcterstic changes

• B)- MRS,DWI helpful for diagnosis of AD

• C)- Amyloid binding PET abnormal in AD but normal in FTD

• D)-All of the above

Q.3-True about AD

• A)- MRI shows charcterstic changes

• B)- MRS,DWI helpful for diagnosis of AD

• C)- Amyloid binding PET abnormal in AD but normal in FTD

• D)-All of the above

Q-4 Treatment of AD all true except

• A)- Cholinesterase inhibitors are approved for the treatment of mild-to-moderate AD

• B)- Tacrine is drug of choice

• C)- Memantine is indicated in mod-severe AD

• D)-Atypical antipsychotic drugs are Tt of choice for behavioral symptoms

Q-4 Treatment of AD all true except

• A)- Cholinesterase inhibitors are approved for the treatment of mild-to-moderate AD

• B)- Tacrine is drug of choice

• C)- Memantine is indicated in mod-severe AD

• D)-Atypical antipsychotic drugs are Tt of choice for behavioral symptoms

• Table 1 Common Clinical Features of AD by Stage

Early• Impairment of short-term memory• Relative preservation of remote memory• Mild difficulty with word-finding• Reduced ability to plan, judge, and organize• Relatively preserved social behaviorIntermediate• Deterioration of logical reasoning, planning, and

organizing• Worsening of remote memory• Greater word-finding difficulty, deterioration in language• Easy distractibility• Loss of insight into disease• Loss of skills such as using appliances and dressing• Deterioration of spatial orientation• Delusions• Visual hallucinations• Loss of emotional control, agitation• Decreased concern for appearance and hygiene• Sleep disturbances• Depression• WanderingLate• Severe deterioration of all cognitive modalities• Near-mutism• Urinary and bowel incontinence• Myoclonus and epileptic seizures• Assistance required for all activities of daily living

• Increased education has been associated with reduced risk for AD or later onset of dementia.

• An attractive hypothesis has been that better-educated individuals have a cognitive reserve, so biological disease progression must progress further before the reserve is overcome and clinical symptoms begin to develop.

• Interestingly, several studies have suggested that physical exercise may be protective or delay disease progression.

• It encompasses disruptive, aggressive, and/or resistive behaviors and is related to changes in frontal cortex on functional imaging studies and post-mortem examination (Cummings, 2003).

• Patients may have difficulties in understanding the actions or words of others.

• Widespread familiarity and use by physicians is a powerful force, and the MMSE is unlikely to be displaced in its assessment role anytime soon.

• It is, therefore, important that clinicians who use it remember its limitations.

• The topic of cognitive changes in aging has been studied for many years and gone by various terms, such as – Benign senescent forgetfulness – Age-associated memory impairment – Late-life forgetfulness – Aging associated cognitive decline

• MRI has a number of advantages in evaluating brain structures and is more appropriate for nonemergent evaluation.

• MRI also avoids the risks of ionizing radiation, and therefore, serial studies involving repeated measures over time are possible.

• Hence, MRI is one of the most widely used imaging techniques in the assessment of the degenerative dementias. The inclusion of MRI in the clinical workup can significantly improve the reliability of the differential diagnosis of dementia.

• Multiple large vessel or smaller subcortical strokes support diagnosis of vascular dementia

• Selective frontal and/or temporal atrophy on MRI or CT may indicate FTD

• Ability to reasonably discriminate FTD from AD in individual patients may be difficult on basis of clinical & standard CT or MRI

• In patients with AD, PIB binding is most prominent in cortical association areas, including the frontal lobes, temporal lobes, parietal lobes, parts of occipital lobe, and the striatum

• Particularly severe binding has been observed in the frontal lobes and precuneus (with low levels observed in the sensorimotor strip, the primary visual cortex, and medial temporal lobe

• Functional imaging measuring blood flow or metabolism by SPECT or PET may be better able to discriminate FTD from AD and/or other forms of dementia.

• Hypernatremia and hyponatremia: The former may be found in association with dehydration, which can occur in impaired elderly patients who are dependent on others for fluid intake.

• The latter may occur in association with a variety of chronic illnesses and/or medications.

• Hypocalcemia and hypercalcemia are found more rarely but also can affect cognitive functioning and should be screened for

Endocrine causes• for dementia include hypothyroidism, which is one of

the most commonly identified causes of cognitive impairment in older adults, and diabetes mellitus.

• Either intermittent hyperglycemia or unrecognized hypoglycemia may contribute to cognitive impairment.

• The long-term effects of diabetes mellitus may cause subcortical ischemic vascular disease and vascular dementia.

• Insulin resistance found in patients with pre-diabetes mellitus has recently been recognized as a risk factor for AD

• Most of these illnesses will have other historical symptoms or physical signs that will suggest their possibility and need for a lumbar puncture to allow CSF testing, a procedure which is no longer routinely indicated in the patient with dementia

• Emotion-oriented psychotherapy, supportive psychotherapy, interpersonal psychotherapy, and reminiscence therapy may be beneficial in individual cases.

• Stimulation-oriented therapy such as music, art, and pet therapy and exercise may be helpful for others.

• Such interventions have included music, videotapes of family members, audiotapes of the voices of caregivers, walking and light exercise, and sensory stimulation and relaxation.

• Little consideration has been given to nonpharmacologic interventions for patients living in the community, but attention has been given to interventions that may benefit the caregivers of these patients.

• A meta-analysis of controlled trials of neuroleptic

agents showed that approximately 20 percent more patients respond to active therapy than to placebo for the treatment of dementia.

• Greater treatment responses were observed with typical and atypical antipsychotic agents than with placebo.

Alliance with Caregivers

• An alliance between the clinician and the caregiver is essential in treating patients with Alzheimer's disease.

• Caregivers are responsible for supervising patients who live in the community and frequently continue to visit and provide assistance after a patient has been institutionalized

• The 3Rs - Repeat, Reassure, and Redirect - can help caregivers reduce troublesome behaviors and limit the use of medications

• Caregivers must make decisions regarding driving, advance directives, financial management,

removal of firearms, home safety, and programs such as Safe Return, a nationwide network created by the Alzheimer's Association.83

• Studies show that caregivers of patients with Alzheimer's disease rate their own health as relatively poor.

• Furthermore, they endure a greater number of illnesses, have more somatic symptoms, have more depression and anxiety, use more health care, and

engage in fewer preventive-health activities than people who are not caregivers

• Thus, it should come as no surprise that up to 50% of caregivers suffer from "caregiver burnout."

• This may take the form of depression, anxiety, isolation, substance abuse, or physical illness.

• Self-help groups, support groups, education, skills training, counseling, and psychotherapy may help caregivers

• Hormone-Replacement Therapy • randomized, placebo-controlled trials of estrogen-

replacement therapy in such women showed no benefit.47,48 The Women's Health Initiative study of estrogen plus medroxyprogesterone acetate showed an increased risk of dementia among postmenopausal women who lacked cognitive deficits at the time of randomization and were assigned to the active-treatment group.49 Thus, hormone-replacement therapy is not recommended for treatment or prevention of Alzheimer's disease.

• Ultimately, proteomic studies in plasma and CSF in large prospective longitudinal clinical studies, such as the Alzheimer's Disease Neuroimaging Initiative, may yield more sensitive and specific biological markers for AD.

• Herbal supplements and so-called nutraceuticals are commonly used by patients for the treatment of Alzheimer's disease and by family members as a putative preventive strategy.

• In some trials, but not all, ginkgo biloba had small but statistically significant effects as compared with placebo in patients with Alzheimer's disease.65

• A primary-prevention trial to determine

whether ginkgo biloba reduces the rate of development of Alzheimer's disease is currently in progress.

• Huperzine A is a cholinesterase inhibitor, and preliminary clinical trials have shown it to be of benefit in Alzheimer's disease

D/D

• Among the more important nondementing causes of dementia are delirium and depression.

• Delirium is common in elderly subjects, particularly in inpatient settings and in nursing homes.

• Unlike delirium in children, which is an acute disorder, delirium in the elderly can be subacute at onset, stretching over weeks or even months, char

• acterized by apathy rather than agitation, and vague paranoid symptoms rather than vivid hallucinations.

• Thus, delirium in the elderly can often be misdiagnosed. • Common causes of delirium include

– infection (particularly urinary tract infections),– hypoglycemia, – Electrolyte abnormalities (such as those accompanying

dehydration),– hepatic dysfunction,– renal insufficiency,– Endocrine dysfunction (particularly thyroid abnormalities

• Medications (especially anticholinergic agents, benzodiazepines, histamine2 antagonists, and narcotics),

• All of which are eminently treatable • Delirium and dementia can coexist• In fact, dementia predisposes to the

development of delirium with even modest metabolic insults.

• Severe depression in the elderly is often accompanied by complaints of memory loss and the presence of mild cognitive deficits on neuropsychological testing.

• In depression,the subjective complaintsof cognitive impairment often exceed the neuropsychological deficits, and the primary problem seems to be one of motivation or lack of effort.

• Depression and dementia can coexist, however

• Among the dementing disorders, vascular dementia follows AD as the second most common form.16

• The vascular dementias usually, but not always (eg, Binswanger disease),

• have a relatively acute onset temporally related to a vascular event such as transient ischemic attack or stroke and have a more fluctuating course than AD.

• Focal neurologic signs or symptoms usually accompany them.

• Cerebrovascular changes can also coexist with AD pathology,and this combination can adversely affect the dementingprocess.17

• Other neurodegenerative disorders that can cause dementia include Parkinson disease, Huntington disease, Pick disease, and dementia with Lewy bodies.

• Parkinson disease and Huntington disease are characterized by extrapyramidal signs, which usually predate the cognitive decline.

• Pick disease is one of the frontal lobe dementias and usually presents with behavioral disinhibition, poor insight, and language deficits early in the course of

• FTD tends to have an earlier onset.14

• FTD participants also had higher MMSE scores than the AD participants

• In contrast, persons diagnosed with FTD had more difficulty with tests of verbal ability and language than those with AD,

• Memory and constructional praxis are relatively spared early on.

• Frontal and temporal lobe atrophy is usually evident on computed tomography

• Petersen et al 3 reported an average conversion rate to AD of 12% per year in their MCI sample over 4 years, compared with 1% to 2% for normal controls.

• Conversion rates have been found to vary across studies, ranging from 3% to 37% over a period of 1 to 3 years,4

• which likely reflect differences in diagnostic and “conversion” criteria.

• In a study examining preclinical predictors of AD in a group of subjects with “questionable” AD (ie, Clinical Dementia Rating Scale=0.5),5

• California verbal learning test (CVLT)6 delayed recall performance was found to be one of the best predictors of conversion to AD,

• surpassing apolipoprotein E (APOE4) genotyping and a variety of neuroimaging variables.7

• Tests assessing new learning, delayed recall and attention/executive function seem to provide valuable information for screening and diagnosis of MCI and early AD if interpreted properly

• MCI patients had additional problems with response inhibition, switching and cognitive flexibility.

• Cortical extracellular amyloid plaques and intraneuronal NFTs are the basic features of AD, and stereotypic spread of the NFTs, as originally described by Braak and Braak (1991), provided a basis for staged neuropathologic criteria for AD that remain useful today.

• The first two stages involve NFTs in entorhinal cortex and adjacent portions of the hippocampus, typically without clinical symptoms.

• In stages III and IV, NFTs spread to limbic regions, and cognitive deficits develop.

• In stages V and VI, NFTs spread to other regions of the cortex, and the breadth and severity of cognitive deficits and the dementia progressively worsen.

• Considerable evidence indicates, however, that plaques and tangles can be found in substantial numbers in many elderly patients with normal cognitive functioning and that overlap exists in plaque and tangle pathology between the very elderly (over age 90) with normal cognition and those who are demented (Bennett et al, 2006), such that

• diagnosis on the basis of neuropathologic changes alone in the earlier stages may be difficult

• Current therapies for AD are primarily symptomatic, focused on treating either cognitive or behavioral symptoms

• None has been proven to delay biological progression of disease

• The currently available symptomatic therapies for AD mildly improve deficits in cognition and function in ADLs and global functioning

• As well as delay onset of or slightly improve behavioral symptoms

• Benefits may be subtle and may be difficult to judge against a background of disease progression

• Caregivers need to be advised to have realistic

expectations

• Any benefits need to be weighed against adverse effects that may occur in determining an appropriate dose or deciding whether to continue therapy with a particular drug

• Donepezil is an inhibitor more selective for acetylcholinesterase

• Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase; and

• Galantamine, in addition to inhibiting cholinesterase, apparently modulates stimulation at nicotinic receptors

• The clinical significance of these differences, if any, remains to be proven