Roger E. Kelley, M.D. Professor and Chairman Department of Neurology Tulane University School of Medicine New Orleans, Louisiana

Roger E. Kelley, M.D. Professor and Chairman Department of Neurology Tulane University School of Medicine New Orleans, Louisiana

FINANCIAL DISCLOSURE No potential conflict of interest to disclose.

OBJECTIVES AT THE CONCLUSION OF THIS ACTIVITY Define MCI and its subtypes State the diagnostic criteria for MCI including various cognitive screening tools available Ability to discuss the current management/treatment for MCI Ability to discuss the prognosis for MCI including the risk of dementia and the associated mortality risks

DEFINITION OF DEMENTIA This term represents a progressive cognitive disturbance which has a number of potential etiologies Can be listed as treatable or untreatable, but this is somewhat subject to interpretation For example, there are several potential treatments for Alzheimer s disease, but the value of such treatment is limited

MORE COMMON CAUSES OF DEMENTIA Alzheimer s disease is the most common in subjects in their 50 s and beyond; typically seen beyond age 65 and accounts for roughly 80% of all dementia in the elderly Prior to this age group, one can identify a number of alternative causes, depending upon the population at risk, and this can include: post traumatic dementia, HIVrelated dementia, inborn errors of metabolism, post infectious, etc

FRONTO TEMPORAL LOBE DEMENTIA (FTLD) A neurodegenerative form of dementia that tends to occur at an earlier age than Alzheimer s disease and is the third most common form of this type of dementia Characterized by personality change, behavioral disturbance, speech disturbance, inattentiveness and can have associated extrapyramidal features

FTLD Features Onset often in the 55 to 65 year range and can be younger Males more affected than females Clinical manifestations, reflective of the selective brain involvement, can include: (1) disinhibition (2) apathy (3) poor insight with impaired judgement (4) perseverative behavior (5) loss of social graces

FTLD Features (continued) Can include what has been known as Pick s lobar dementia with characteristic Pick s bodies seen pathologically Is associated with mutations of chromosome 17 with overlap between FTLD and parkinsonism as well as overlap between FTLD and amyotrophyic lateral sclerosis No specific treatment presently available

FTLD (continued) See more selective involvement of frontal and temporal lobes on brain imaging as opposed to the more generalized atrophy seen with Alzheimer s disease Cerebral PET scan can help in distinguishing the two entities with AD demonstrating bi parietal hypometabolism on 18 FDG scan versus fronto temporal hypometabolism

FTLD MRI Brain Scan

COMPARISON IMAGING WITH PET AND MRI BRAIN SCAN

ASSOCIATION OF DEMENTIA WITH MOVEMENT DISORDERS Parkinson s Disease is associated with dementia in up to 50% of subjects Dementia with Lewy Bodies Progressive Supranuclear Palsy Cortico basal ganglionic degeneration Huntington s disease FTLD in certain cases

DEMENTIA WITH LEWY BODIES Reported to be the second most common type of neurodegenerative dementia after AD Characterized by: (1) cognitive impairment (2) visual hallucinations (3) parkinsonism (4) gait instability with falling tendency (5) sensitivity to neuroleptic agents No specific form of treatment presently available

DEMONSTRATION OF LEWY BODIES

DEMENTIA ASSOCIATED WITH OTHER DISEASE PROCESSES Multiple sclerosis Leukodystrophies HIV disease Creutzfeldt Jakob Disease (a prion disorder) Neurosyphilis Cryptococcal meningitis Post traumatic Post viral encephalitis

ASSOCIATION WITH STROKE Often termed Vascular Dementia or Multi Infarct Dementia Related to either specific involvement of cognitive centers with resultant impairment of communication, memory, executive function, etc or cumulative tissue loss, sometimes reported to be 50 cc s or more, which can be either small vessel or large vessel ischemic or hemorrhagic

CUMULATIVE SMALL VESSEL ISCHEMIC TISSUE LOSS CAN LEAD TO DEMENTIA

ASSOCIATION WITH CANCER Paraneoplastic syndromes can include limbic encephalitis with cognitive impairment Post radiation encephalopathy is well recognized as a sequela of radiation therapy Chemotherapeutic agents can affect cognitive function

ASSOCIATION WITH ALCOHOL Alcohol related dementia is well recognized and can be a direct toxic effect on brain cells or multifactorial such as with associated head trauma related to falling episodes Wernicke Korsakoff s syndrome is not always fully reversible despite expected response of Wernicke s encephalopathy to thiamine

ASSOCIATION WITH TRAUMA

POTENTIALLY REVERSIBLE FORMS OF DEMENTIA Vitamin B12 deficiency Hypothyroidism Neurosyphilis Cryptococcal meningitis Removal of a chronic subdural hematoma or meningioma Normal pressure hydrocephalus Temporal lobe or Absence status epilepticus

RECURRENT SEIZURE ACTIVITY CAN MIMIC DEMENTIA

OTHER CONSIDERATIONS So called pseudo dementia in patients with severe depression who have difficulty registering information as part of their distraction and lack of focus Multiple sclerosis, over time, can affect cognitive areas and lead to dementia; there can be particularly malignant forms of demylinating disease such as Schilder s

MILD COGNITIVE IMPAIRMENT = MCI MCI identifies a symptomatic pre dementia stage of cognitive impairment Alternative designations have included: cognitive impairment not demented (CIND) and MCI due to Alzheimer s disease which identifies Alzheimer s disease changes as the underlying pathology Not all subjects progress to actual dementia

CRITERIA FOR MCI Cognitive complaint, decline or impairment Objective evidence of impairment in cognitive domains Essentially normal functional activities Not demented

POTENTIAL COGNITIVE SCREENING TOOLS FOR MCI The Mini Mental Status Exam (MMSE) is probably the most common screening tool for both MCI and dementia. The results are subject to interpretation with 30 as a perfect score and 24/30 or less compatible with dementia of a clinically significant degree However, missing 3/3 objects to remember over 3 to 5 minutes is a very important clinical clue and could identify clinically significant cognitive impairment Alternative testing: Minnesota Cognitive Acuity Screen (MCAS), Delayed Word Recall, Clock Drawing, Enhanced Mental Skills Test (EMST) and Mini Cog

LIMITATIONS TO SCREENING TESTS The patients must be engaged and cooperative In terms of short term memory with 3/3 object recall, it is important to ensure that the subject registers the information effectively prior to assessment of the ability to recall later Distracted or depressed patients don t tend to test as well and there can be significant variability

PRACTICAL ASPECTS OF COGNITIVE ASSESSMENT What the significant other or family tells you Can the patient effectively manage their affairs including finances? Is the patient safe to live alone? Is the patient safe to drive? These aspects sometimes require formal neuropsychological testing instead of a screening test

MCI SUBTYPES Amnestic MCI = clinical impairment reflective of memory impairment Non amnestic MCI is characterized by impairment in one or more non memory impairment cognitive domains including executive function/attention, language and visuospatial skills

MULTIPLE DOMAIN MCI This denotes a greater extent of disease with impairment found in more than one cognitive domain This will theoretically progress to dementia more readily than single domain MCI The progression of MCI to dementia reflects whether or not there is associated neurodegeneration i.e, atrophy of the hippocampus

MCI AS MORE OF A GENERIC TERM There is the potential for non amnestic MCI to progress to non Alzheimer s forms of dementia such as fronto temporal dementia which tends to be characterized by disinhibiton with personality change, with single domain involvement with neurodegeneration, while Dementia with Lewy bodies would be more likely seen with multiple domain involvement

MCI MAY REFLECT A REVERSIBLE PROCESS Cognitive impairment can be associated with sedative use, narcotic pain medication use, excessive ingestion of EtOH or use of illicit drugs such as heroin, meth or cocaine MCI can precede vascular dementia which may have a variable course depending upon the degree of involvement and the potential for recovery from an ischemic or hemorrhagic CNS insult

PREVALENCE OF MCI For subjects 60 years of age or older, the prevalence estimates range from 16 to 20% There is great variability reflective of comorbid factors including age, sex, level of education, ethnic background, presence of APO E4 allele as well as co morbid factors such as vascular disease, various medication needs as well as potential psychiatric factors

EVOLUTION OF MCI TO DEMENTIA The figure cited as 20 to 40% over time with 10 to 15% per year However, this is quite variable with vascular risk factors playing a potentially important role in the overlap of neurodegenerative dementia, such as AD, and vascular dementia Biomarkers such as structural brain atrophy, APO E4 status, PET, etc can presumably enhance predictive power

POTENTIAL RESOLUTION OF MCI It has been reported that up to 20% of subjects with MCI improve rather than progress over time and some return to normal cognitive status This underscores the potential contribution of EtOH consumption, illicit drug or prescribed drug use, medical condition and emotional status at the time of initial evaluation

OVERALL PROGNOSIS OF MCI Related to multiple factors including the age of the subject, co morbid medical factors including medications, level of social support, number of domains affected, emotional state including pre morbid personality MCI in and of itself should not affect life expectancy to a significant degree unless it translates into dangerous behavior

POTENTIAL DANGERS WITH MCI Forgetting to turn off the stove or other activities that could wreak havoc Getting lost while driving or impaired driving capacity Forgetting to takes one s medications Forgetting healthy lifestyle measures including keeping doctor visits and seeking medical help for new symptoms Potential impaired sense of smell

TREATMENT AND POSSIBLE PREVENTION OF MCI Promotion of a healthy lifestyle in terms of diet, exercise, control of risk factors for vascular disease, good diabetic control, compliance with medications, smoking cessation, avoidance of excess alcohol, abstinence from illicit drugs and avoidance of medications that blunt cognition such as benzodiazepines Avoiding concussions

Measures that May Preserve Cognition Active mental and physical exercise program Special diets such as the MIND diet or the Mediterranean diet Vitamin E 2000 IU a day Vitamin D3 1000 IU a day Recent reports of association with protein pump inhibitors Some reports of potential deleterious effect of statins

TREATMENT OF MCI Keep a notebook of what you need to remember Avoid sleep deprivation Cholinesterase inhibitors may provide some benefit The n methyl d aspartate (NMND) receptor blocker memantine may provide some benefit

ALZHEIMER S DISEASE REFLECTED BY PROGRESSIVE BRAIN ATROPHY

ALZHEIMER S DISEASE COMPARISON

Alzheimer s Disease Defined A neurodegenerative disorder characterized by progressive cognitive decline Related to the aging process and typically seen in patients in their 60 s and beyond although occasionally seen in younger patients Increasing recognition that there is a genetic predisposition for a number of patients

DIAGNOSIS OF ALZHEIMER S DISEASE A clinical diagnosis in which alternative explanations for the dementing illness are ruled out Based on the history provided, usually by the family or significant other, the lack of an alternative explanation, the clinical course, and routine diagnostic studies

DOCUMENTATION OF THE DEMENTIA The mini mental status exam is often used by clinicians with a score of 24/30 or below being compatible with dementia Formal neuropsychological evaluation with a battery of cognitive tests is potentially helpful for more accurately determining the cognitive realms involved and the patient s level of capability in terms of finances, driving capacity, etc.

ROUTINE DIAGNOSTIC STUDIES Standard lab tests include a CBC to assess for a significant hematological disorder that might be related to the presentation, an ESR to screen for an inflammatory, infectious or neoplastic process, metabolic studies including renal and liver function as well as potential effect of a low or high serum sodium, calcium, magnesium or phosphorus

ADDITIONAL DIAGNOSTIC STUDIES Serum B12 and folate level Thyroid profile Toxicology and possibly heavy metal screen Syphilis serology and HIV testing when appropriate MRI or CT brain scan to evaluate for a mass lesion, e.g. chronic SDH, hydrocephalus, cerebovascular disease

CEREBROSPINAL FLUID Can be useful for CSF VDRL, cryptococcal antigen, and to assess for other infectious or inflammatory disorders such as Lyme disease and neurosarcoidosis Measurement of CSF beta amyloid protein (decreased) and tau protein (increased) can be quite sensitive for the detection of Alzheimer s disease of the order of 95%

EEG Can be useful for patients with episodic confusion which could reflect an epileptic disturbance Can also be of value in the more rapid developing dementia seen with Creutzfeldt Jakob disease

EEG in Patient with Epilepsy

CJD EEG: Pseudo Periodic Triphasic and Biphasic Discharges

Brain Imaging in Dementia This is standard to rule out alternative explanations to AD Evaluate for possible cerebrovascular component, with MRI superior to CT brain scan for small vessel ischemic disease, hydrocephalus, late onset leukodystrophy or structural lesion such as a subdural hematoma or neoplasm

DIFFUSE ATROPHY ON CORONAL MRI IN AD

VOLUMETRIC ANALYSIS OF HIPPOCAMPAL ATROPHY IN AD

POSITRON EMISSION TOMOGRAPHY (PET) IMAGING Cerebral PET scan with either 18 FDG, Pittsburgh Compound B (PIB), a ligand that attaches to brain β amyloid plaques vs 18 F labeled amyloid PET tracers such as commercially available 18 F florbetapir Tau labeled tracers are now also available for detection of alternative pathology of Alzheimer s disease

18 FDG PET in Alzheimer s Disease: Normal vs AD

Pittsburgh Compound B PET

Florbetapir Amyloid PET scan in AD: A negative (gray contrast less intense) and B is positive

Beta Amyloid PET scan

TAU CEREBRAL PET SCAN IN NORMAL VS EARLY AD

APOLIPOPROTEIN E4 ALLELE TESTING Can provide some prognostic and potentially diagnostic information Normal subjects heterozygous for the APO E4 allele have a roughly 2 fold increased risk of developing AD while subjects who are homozygous have a 12 fold increased risk Heterozygous subjects with dementia have a roughly 85% chance of AD as an explanation and this with 95% for those homozygous

Role of APO E4 in the Pathogenesis of Alzheimer s APO E4 is the major known genetic risk factor for AD APO E4 carriers account for 65 to 80% of all AD cases Transgenic mouse models which express different apoe isoforms demonstrate potential neurotoxic contribution via apoe4 fragments as well as effect on beta amyloid and tau protein deposition in neurons and astrocytes

DEFINITIVE DIAGNOSTIC CRITERION FOR AD The diagnosis is only definitive when there are typical neuropathological findings of AD including: (1) beta amyloid plaques (2) neurofibrillary tangles (3) granulovacuolar degeneration (4) neuronal and synapse loss Lewy bodies are not uncommon in AD as well Clinical diagnostic accuracy now approaches 90%

Beta amyloid (Senile) Plaques

NEUROFIBRILLARY TANGLES FROM HYPERPHOSPHORYLATED TAU PROTEIN

ALZHEIMER S PATHOLOGY: AMYLOID PLAQUE AND NEUROFIBRILLARY TANGLE

LEWY BODY WHICH CAN BE SEEN IN AD AS WELL

Alzheimer s Disease Clinical Course Evolves over time and can be preceded by mild cognitive impairment (MCI) which can help identify those at risk for developing AD It is not unexpected to lose some memory function as part of the luxury of growing older as opposed to the alternative Just as our eyes, skin, bones, GI tract, etc age, so do our brains

Clinical Issues of Note AD manifestation is reflective of several factors such as baseline IQ, educational level, socio economic level and level of family support and protection Becomes clinically relevant when it begins to impact on functional independence and the quality of life

Compensatory Mechanisms Patients with AD are familiar, and comfortable, with their typical surroundings and can decompensate when taken out of a familiar setting; this can lead to serious consequences such as when an Alzheimer s patient needs to be hospitalized for another condition There is the potential for relatively minor issues to cause decompensation, e.g. a UTI

Concept of Break Point Patients with AD can chug along with various mechanisms to correct for their deficiencies such as writing things down, being overly defensive, becoming more socially withdrawn to avoid social challenges However, there can be an eventual point where they are no longer able to effectively compensate and the family has to step in and this can occur rather suddenly

Major Challenges for the Patient and Family Loss of driving privileges when it is no longer felt to be safe for the person with any form of dementia to be driving Financial issues as, believe it or not, people might take advantage of the cognitive impairment for their own benefit Safety issues in terms of associated loss of sense of smell; spoiled food may not be detected and cannot smell smoke

Manifestations Typically see progressive short term greater than longer term memory loss Progressive loss of ability to carry out task i.e. loss of executive function Can see loss of initiative, social withdrawal with personality change Can be selective in terms of aphasia (affecting dominant hemisphere) versus right hemispheric visuo spatial difficulty

Aggressive Behavior and Loss of Impulse Control This can be both embarrassing, for a former pillar of the community, as well as potentially dangerous Can strike out physically at their loved ones, wander off, engage in activity reflective of loss of appropriate judgment in terms of affairs, financial schemes, etc Cortex no longer as inhibitory as it once was

MANAGEMENT ISSUES Avoiding stressors Avoiding medications that can promote confusion such as benzodiazepines and certain sleeping aides; melatonin is a good first choice as a sleeping aide The so called enriched environment in which manageable mental challenges are promoted such as reading, mind games, etc

MEDICATIONS Cholinesterase inhibitors which include Aricept (now released at a 23 mg per day dose) versus the 10 mg a day dose, Razadyne and Exelon (available both orally and as a patch) Memantine (Namenda) which is an N methyl D aspartate receptor blocker Axona which is a food supplement designed to improve cerebral metabolism

Prognosis in Alzheimer s Disease Typically see progression to an advanced dependent stage over 5 years with some evidence that cholinesterase inhibitors promote some degree of delay of the progression as well as some potential benefit with memantine Most patients live for 8 to 10 years with women tending to survive longer than men

Prognosis II. Roughly 25% of women live for longer than 8 years from the time of diagnosis Some subjects live for up to 20 years Now the 8 th leading cause of death in the United States and the most common contributing factor is infection

Prognosis III. Factors which impact negatively on prognosis include: (1) age (2) co morbid conditions such as CHF (3) male sex (4) gait instability (5) wandering (5) incontinence (5) bedridden condition (6) pressure sores (7) dyspnea Roughly 50% of patients with advanced dementia who suffer either a hip fracture or pneumonia will be dead within the year

SUMMARY The prevalence of AD in the United States is presently 4 to 4.5 million There will be an increasing epidemic as the baby boomers reach age 65 and older Therapy remains limited and recent clinical trials of monoclonal antibodies against beta amyloid plaques as well as secretase enzyme inhibitors have been negative