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1 : ALZHEIMERS AND DEMENTIA UPDATE TOMA 2006 G. BARRY ROBBINS, D.O., FACN Associate Professor and Chair Department of Neurobehavioral Sciences KCOM a college of ATSU
2 :
3 : Goals Epidemiology Memory in typical aging Mild cognitive impairment Dementia syndromes Anterograde Amnesic Syndrome of AD Dementia due to Cerebrovascular disease Dementia Associated with Parkinsonism: Dementia with Lewy Bodies Cognitive-Behavioral Syndrome of FTD Rapidly Progressive Dementias - Creutzfeldt-Jakob Disease Mental Status and functional Assessments Laboratory Evaluations Hierarchical Approach to Diagnosing Dementia Progress and Future Direction in the Diagnosis of Dementia
4 : Number of People Age 65 and Over, by Age Group, Selected Years 1990-2000 and Projected 2010-2050 Federal Interagency Forum on Aging-Related Statistics 2004, Older Americans
5 : Future Demographics On January 1, 2011, as the baby boomers begin to celebrate their 65th birthdays, 10,000 people will turn 65 every day—this will continue for 20 years. Alliance for Aging Research By 2030, the number of older Americans is projected to have more than doubled to over 70 million—representing nearly 20% of the population. Federal Interagency Forum on Aging-Related Statistics 2004, Older Americans
6 : Epidemiology of Dementia 18 million worldwide 4.5 million USA 14 million Americans are likely to be stricken by 2050. Incidence - increases steadily 0.5% / year @ 65yrs 8% / year @ 85yrs Prevalence 3 % @ 65yrs 47 % after 85yrs
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8 : Prevalence of Dementia in USA Ages 40-65 1 in 1000 Ages 65-70 1 in 50 Ages 70-80 1 in 20 Age 80+ 1 in 5
9 : Alzheimer’s Disease Prevalence and Incidence 4.5 million Americans suffer from Alzheimer’s disease. That number has more than doubled since 1980. Hebert et al. 2003, Alzheimer Disease in the US Population 360,000 new cases of Alzheimer’s disease are diagnosed every year—980 every day, 40 every hour. Cummings and Cole 2002, Alzheimer Disease
10 : Dementia World Prevalence The total number of people with dementia in the world: 11 million in 1980 18 million in 2000 40 million in 2025. By 2025: there will be four times as many people with dementia in the developing world as there were in 1980 71% of people with dementia will live in developing countries.
11 : Memory in typical aging Myth: “Forgetfulness” is an inevitable consequence of aging. Typical aging per se does not degrade memory - - - disease does. Everyday forgetfulness occurs in most Easy to overlook genuine memory lapses in dementia Misleads people with normal brain function who fear development of AD
12 : Pseudo-Dementia Younger patient become preoccupied with memory loss – anxiety is the enemy of recall. Some sharp or compulsive persons notice a normal slipping with age with ready recall or word-finding. (May require psychometrics to distinguish) “Psychomotor retardation” associated with severe depression - more abrupt onset (Some older patients have combined organic dementia and severe depression)
13 : Clinical Definition of Dementia Key principles Patient has experienced a decline from some previous higher level of functioning The dementia “significantly interferes with work or usual social activities” Transparent vs blurred for families and physicians Comorbid conditions Marital and child-parent relationships
14 : Psychometric Definition of Dementia Deficits apparent in > 1 Cognitive Domain Recent memory – ability to learn, retain, and retrieve newly acquired information Language – ability to comprehend and express verbal information Visuospatial function – ability to manipulate and synthesize nonverbal, geographic, or graphic information Executive function – ability to perform abstract reasoning, solve problems, plan for future events, mentally manipulate more than one idea at a time, maintain mental focus in the face of distraction, or shift mental effort easily
15 : Diagnostic Criteria for Dementia Presence of at least 2 of the following impairments. Impaired learning and impaired retention of new or recently acquired information (short-term memory) Impaired handling of complex tasks Impaired reasoning ability (Abstract thinking) Impaired spatial ability and orientation (constructional difficulty and agnosia) The impairments interfere with work or usual social activities or relationships with others The impairments represent a notable decline from a previous level of functioning The impairments do not occur exclusively during the course of delirium The impairments are not better explained by a major psychiatric diagnosis
16 : Mild cognitive impairment Easy to recognize MCI ( a large intermediate zone between the cognitively normal elderly and those with dementia Impairment in at least 1 cognitive domain (usually recent memory) but who function independently in daily affairs.
17 : Pathogenesis of Mild Cognitive Impairment
18 : Mild cognitive impairment (MCI) 2 Variants Recognized Amnesic type Most common Preclinical manifestation of AD Most common - Impaired performance on delayed recall Multiple cognitive domains - localized impairment of other cognitive domains Less common Signal non-AD clinical syndromes
19 : MCI (Amnesic type) Presence of a new memory complaint, preferably corroborated by an informant Objective evidence of impairment of short-term memory (for age) Normal general cognitive functions No substantial interference with work, usual social activities, or other activities of daily living No dementia, according to criteria Need Psychometric and laboratory evaluation to distinguish
20 : Pittsburg Compound-B (PiB) PiB Identifies Alzheimer’s disease in vivo Those with high IQs who test normal on MMSE FTLD from Alzheimer’s disease PiB binds in the cortex or posterior cingulate gyrus 50-60% MCI patients progress to Alzheimer’s disease within 5 years Earlier identification of patients who have amyloid plaques – will lead to earlier treatment J. NeuroSci, Aug 24, 2005
21 : Dementia Syndromes Anterograde Amnesic Syndrome of AD Dementia due to Cerebrovascular disease Dementia Associated with Parkinsonism: Dementia with Lewy Bodies Cognitive-Behavioral Syndrome of FTD Not All Dementing Illnesses Are Alike Syndrome overlap is common
22 : 5% 10% 65% 5% 7% 8% Dementia with Lewy bodies Parkinson’s disease Diffuse Lewy body disease Lewy body variant of AD Vascular dementias and AD Other dementias Frontal lobe dementia Creutzfeldt-Jakob disease Corticobasal degeneration Progressive supranuclear palsy Many others AD and dementia with Lewy bodies Vascular dementias Multi-infarct dementia Binswanger’s disease AD Small et al, 1997; APA, 1997; Morris, 1994. Differential Diagnosis of Dementia
23 : Genetics of Alzheimer’s Disease
24 : AD Risk Factors AGE* Head injury Family history Low education Most individuals with dementia are not recognized early in clinical practice Now is the time to begin improving the detection rate of symptomatic dementia
25 : Neurological Disease: Alzheimer’s Disease The Burden of Neurological Disease – The Human Burden Almost half of all people with Alzheimer’s disease have four or more chronic conditions. Partnership for Solutions 2002, Alzheimer’s Disease: The impact of multiple chronic conditions Approximately three quarters of Alzheimer’s patients are admitted to a nursing home within five years of diagnosis. PhRMA 2004, Medicines Reduce the Burden of Alzheimer’s Disease State and federal Medicaid spending on nursing home care for beneficiaries with Alzheimer’s disease was $19 billion in 2000. The Lewin Group 2004, Saving Lives, Saving Money
26 : Neurological Disease: Alzheimer’s Disease The Burden of Neurological Disease – The Economic Burden Alzheimer’s disease is draining more than $100 billion annually from the nation’s economy, costing American businesses $61 billion a year. Alliance for Aging Research 2004, Task Force on Aging: Research and funding The cost of care for a person with Alzheimer’s disease in a facility is approximately $64,000 per year. Alliance for Aging Research 2004, Task Force on Aging: Research and funding Medicare spends $91 billion each year on caring for those with Alzheimer’s disease. Alzheimer’s Association
27 : Alzheimer’s Disease The Future Cost of Neurological Disease Medicare spending for those with Alzheimer’s disease will triple by 2015—to $189 billion from $62 billion in 2000. By 2050, Medicare will be spending more than $1 trillion on beneficiaries with Alzheimer’s and related dementias. The Lewin Group 2004, Saving Lives, Saving Money
28 : Diagnostic Criteria for the Anterograde Amnesic Syndrome of Alzheimer’s Disease Presence of major impairments in learning and retaining new information (memory) and at least 1 of the following impairments Handling complex tasks Reasoning ability Spatial ability and orientation Language Impairments notably interfere with work or usual social activities or relationships with others Impairments represent a notable decline from a previous level of functioning
29 : Diagnostic Criteria (cont’) Impairments are insidious in onset and progressive Impairments do not occur exclusively during the course of delirium Impairments are not better explained by a major psychiatric diagnosis Impairments are not better explained by a systemic disease or another brain disease
30 : Amnesic Syndrome of AD Most common observations noticed by Informants Pervasive forgetfulness Failure to pay bills Taking medications incorrectly Problems with time orientation Personality changes Apathy Loss of interest in previous past-times and activities Loss of initiative Insight is lost early (anosognosia)
31 : Alzheimer’s Disease Spect Scan
32 : Diagnostic Criteria for Dementia with Cerebrovascular Disease Similar Criteria as AD Important Characteristics Onset or dramatic worsening of existing impairments that occurred within 3 months of a stroke (focal neurological deficit) Presence of bilateral brain infarctions (involving cortical or subcortical gray matter structures
33 : Dementia Due to Cerebrovascular Disease (VaD) Infarctions may be silent Non dominant hemisphere Micro infarctions (lacunar infarctions) Severe white matter disease 5+% of dementia patients have pure VaD 15+% have Vad and AD 1 in 10 to 1 in 5 patients with dementia have a VaD component Initial cognitive symptoms depend on location of infarction
34 : VaD Prognosis worse that that of AD Mean survival of AD = 6 years Mean survival of VaD = 3 years VaD benefits from cholinesterase inhibitors Treat Risk factors Hypertension Diabetes mellitus Anti-platelet drugs ?
35 : Vascular Dementia
36 : Vascular Dementia Spect Scan
37 : Dementia Associated with Parkinsonism: Dementia with Lewy Bodies (DLB) Similar criteria as AD Must have at least 2 of the following: Parkinsonism Prominent, fully formed visual hallucinations Substantial fluctuations in alertness or cognition REM sleep behavior disorder
38 : DLB Common Cognitive Deficits that distinguish DLB from AD DLB Slightly better confrontational naming and verbal memory Worse executive function and visuospatial functions More apathetic
39 : DBL Treatment Prognosis – faster progression and shorter survival than AD Treatment involves several strategies Cognitive impairment Neuropsychiatric features Motor dysfunction Autonomic dysfunction Sleep disorders
40 : Progressive Supranuclear Palsy (PSP) Cognitive deficits are milder Apathy Slowing of cognitive processing Memory deficits Distinguished from AD and DLB by: Prominent parkinsonian signs Gait and balance disorder - falling Brainstem abnormalities
41 : Progressive Supranuclear Palsy Facial appearance “Poker face”
42 : Progressive Supranuclear Palsy Retrocollis (neck extension)
43 : Progressive Supranuclear Palsy Paresis of vertical gaze (Downward paresis)
44 : Cognitive-Behavioral Syndrome of Frontotemporal Dementia (FTD) Early manifestations of either of the following impairments: Decline in regulation of personal or social interpersonal conduct Loss of empathy for the feelings of others Socially inappropriate behaviors that are rude, caustic, irresponsible, or sexually explicit Mental rigidity Inflexibility in interpersonal relationships or emotional blunting Decline in personal hygiene and grooming Altered dietary habits Impaired reasoning or impaired handling of complex tasks out of proportion to impairments of recent memory or to spatial abilities
45 : FTD Uncommon Dramatic presentation suggests a psychiatric disorder Principal manifestations are changes in: Personality Comportment Judgment Diagnosis Neuroimaging
46 : Neuropathology of FTD Involves 1 of 3 non-AD pathologies Pick Body-positive, tau-positive, frontotemporal predominate degenerative dementia Tau-positive CBD Degenerative disorder with frontotemporal predominance that is Tau-negative and lacks other distinctive histology
47 : Fronto-Temporal Dementia Spect scan
48 : Rapidly Progressive Dementias Potentially reversible conditions Autoimmune encephalopathy Toxic Medication misuse, overuse, adverse effects Alcohol related Metabolic disturbances Thyroid, vitamin B12, electrolyte, hepatic, renal and calcium-based disturbances Depressive disorders Acute stroke Structural lesions – neoplasm, CSDH, NPH Sub-acute/chronic encephalitis Fatal, irreversible conditions Creutzfeldt-Jakob Disease Paraneoplastic limbic encephalitis
49 : Clinical CJD – 80% occurrence between 50-70 yrs. Vague feelings of fatigue Disordered sleep Decreased appetite Memory loss Confusion Uncharacteristic behavior 1/3 1/3 1/3 Initial Symptoms
50 : New England Journal of Medicine, vol. 339, Nov.-Dec. 1998 Major Clinical Signs in Sporadic Creutzfeldt-Jakob Disease Cognitive deficits (dementia), including 100 psychiatric and behavioral abnormalities Myoclonus >80 Pyramidal tract signs >50 Cerebellar signs >50 Extrapyramidal signs >50 Cortical visual deficits >20 Abnormal extraocular movements >20 Lower-motor-neuron signs <20 Vestibular dysfunction <20 Seizures <20 Sensory deficits <20 Autonomic abnormalities <20 Sign Frequency %
51 : New England Journal of Medicine, vol. 339, Nov.-Dec. 1998 Comparison of New-Variant and Sporadic Creutzfeldt-Jakob Disease Mean age at onset (yr) 29 60 Mean duration of disease (mo) 14 5 Most consistent and prominent Psychiatric, sensory Dementia, early signs symptoms Myoclonus Cerebellar signs (% of patients) 100 40 Electroencephalographic periodic 0 94 complexes (% of patients) Pathological changes Diffuse amyloid sparse plaques Plaques plaques in 10% Characteristic New Variant Sporadic
52 : Mental Status and functional Assessments History taking and Assessment of Function Mental Status Examinations Neurological Examination Integration of MS testing and Informant’s Assessments
53 : Assessment of Daily Activities Recalling recent events and conversations Keeping track of personal items (e.g., keys, wallet, purse, glasses) Writing checks, paying bills, balancing a checkbook Assembling tax records, business affairs, or papers Shopping alone for clothes, household necessities, or groceries Playing a game of skill, working on a hobby Heating water, making a cup of coffee, turning off stove Preparing a balanced meal Keeping track of current events Paying attention to, understanding, discussing a TV show, book or magazine Remembering appointments, family occasions, holidays, medications Traveling out of the neighborhood, driving, arranging to take buses
54 : Mental Status Assessment Interview the spouse informant separately Down plays in front of patient Informant unaware, denies, or impaired Repeat assessment in 1 week Mild dementia MMSE is insensitive Short Test of Mental Status (STMS) – Mayo Screen with the Mini-Cog (3-5 minutes) Clock drawing test Recall of 3 unrelated objects
55 : Mini-Cog Assessment for Dementia Combines An un-cued 3 – item recall test Clock-drawing test (CDT) Administered in appx. 3 minutes Instruct the patient to listen carefully to and remember 3 unrelated words and then to repeat the words Instruct the patient on CDT Ask the patient to repeat the 3 previously presented words
56 :
57 : Scoring of the CDT Give 1 point for each recalled word after the CDT distracter. Score 1 – 3 A score of 0 indicates a positive screen for dementia A score of 1 or 2 with an abnormal CDT indicates a positive screen for dementia A score of 1 or 2 with a normal CDT indicates a negative screen for dementia A score of 3 indicates a negative screen for dementia CDT is normal if all numbers are present in the correct sequence and position, and the hands readably display the requested time. Int J Geriatr Psychiatry 2000 15(11): 1021-1027
58 : The Clock Draw Test Cognitive Assessment Time: 5.00 Score: 7 (normal) Time: 'no real time' Score: 2 (demented) Thalmann et al 1996. Time: .10.30 Score: 3 (demented) Time: 1/4 past 25 Score: 3 (demented) Diagnosing AD in primary care cognitive assessment
59 : Laboratory Evaluation of Dementia Psychometric testing CBC, electrolyte panel, calcium, Serum Urea Nitrogen, Creatinine, glucose Vitamin B12 Thyrotropin MRI EEG – for CJD CSF – for CJD or rapidly progressive dementias
60 : Hierarchical Approach to Diagnosing Dementia
61 : Neurological Disease: Alzheimer’s Disease The Human Value A recent study showed that memantine (Namenda), a NMDA receptor antagonist approved to treat moderate-to-severe Alzheimer’s, significantly slows cognitive decline and reduces the need for caregiving by 45.8 hours per month. Reisberg et al. 2003, Memantine in Moderate-to-Severe Alzheimer’s Disease Donepezil (Aricept), a cholinesterase inhibitor, has been found to slow progression of Alzheimer’s disease in its early stages, delaying the need for nursing home care by an average of 30 months . Provenzano et al. 2001, Delays in Nursing Home Placement for Patients with Alzheimer’s Disease Associated with Donepezil
62 : Neurological Disease: Alzheimer’s Disease The Economic Value Research shows that use of donepezil leads to a four-fold increase in drug costs; however, it significantly lowers overall medical costs, reducing medical treatment and prescription drug costs by $3,891 per patient, per year. Hill et al. 2002, The Effect of Donepezil Therapy on Health Care Costs in a Managed Care Plan Galantamine (Razadyne), a cholinesterase inhibitor, delays Alzheimer’s patients’ need for full-time care, with overall cost savings estimated at $4,256 per patient. Caro et al. 2003, Rational Choice of Cholinesterase Inhibitor for the Treatment of Alzheimer’s
63 : Functional Features of the Cholinergic System
64 : Progress and Future Direction in the Diagnosis of Dementia Our understanding of dementia has advanced remarkably in the past 20 years As primary care physicians see more patients with dementia and as more of these physicians are trained to perform mental status examinations, confidence and success in diagnosing dementia should increase In the next decade, the focus may shift to earlier diagnosis and identification of individuals without dementia who are at risk of AD or other specific forms of dementia The highly likely development of effective preventive or arrestive therapies in the next 20 years will substantially increase the need for early, accurate clinical diagnosis
65 : Alzheimer’s Disease Senile Plaque
66 : Plaques and Tangles In Alzheimer’s Disease
67 : Neurotrophins A study led by researchers at the San Francisco VA Center and the University of North Carolina, Chapel Hill has identified several new compounds that could play a role in preventing or treating and other degenerative conditions of the nervous system. In culture, the compounds bind with a receptor found in the brain and called p75NTR. In the body, p75NTR is a binding site for molecules known as neurotrophins, which normally promote the growth and development of neurons and other cells but, according to other studies, can also kill them, depending on how and where they bind to a cell.
68 : Reduction of A? burden in entorhinal cortex In PDAPP mice following A? injection
69 : Healthy Longevity Plan Memory exercises – crossword, brainteasers Daily walks Balanced diet - 5 small meals a day Omega-3 fats Antioxidants Whole grains Relaxation exercises
70 : Cardiovascular Disease: Heart Disease and Stroke The Human Value Death Rates for Coronary Heart Disease, 1950-1998 National Center for Chronic Disease Prevention and Health Promotion 2003, The Burden of Chronic Disease and the Future of Public Health


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