Steve Salloway


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  • I will focus mainly on two conditions CADASIL as a monogenic cause of ischemic small vessel disease and hereditary variants of cerebral amyloid angiopathy. At the end, I will briefly comment on Fabry disease to give you an example of a modified by treatment illustrate the complexity of SVD and as systemic condition associated with SVD and deduced pathophysiologic concepts
  • Steve Salloway

    1. 1. Applying the New Diagnostic Criteria Stephen Salloway, MD, MS; Brown Medical School
    2. 2. Disclosures <ul><li>Consultation-Elan, Janssen AI, Avid-Lilly, Pfizer, Eisai, and Bristol-Myers Squibb </li></ul><ul><li>Honorarium-Eisai Inc., Pfizer Inc, Novartis, Forest, Elan, and Athena Diagnostics </li></ul><ul><li>Data monitoring-Merck-Serono and Medivation </li></ul><ul><li>Research support-Elan, Janssen AI, Bristol-Myers Squibb, Eisai, Pfizer, Medivation, Genentech, Bayer, GE and; NIA Alzheimer’s Disease Neuroimaging Initiative, NIA Dominantly Inherited Alzheimer’s Network, the Alzheimer’s Association, The Norman and Rosalie Fain Family Foundation, the John and Happy White Foundation and the Champlin Foundation </li></ul>
    3. 3. Highlights <ul><li>The new criteria are a milestone achievement in the fight against AD </li></ul><ul><li>They recognize that AD is a multi-year illness with at risk, preclinical, mildly symptomatic, and dementia phases </li></ul><ul><li>They provide a clinical and research framework to be modified as new information becomes available </li></ul>
    4. 4. Comments <ul><li>We face a large growing population at risk for AD and eager to learn more about their risk </li></ul><ul><ul><li>10,000 Baby Boomers will turn 65 every day for the next 15 years </li></ul></ul><ul><li>Amyloid PET may be widely used by clinicians especially if there is third party reimbursement but with a limited evidence base or guidelines on what the test tells us about the risk and timing of AD, when to order it, and what to say to patients with preclinical or prodromal AD </li></ul><ul><li>There will be an explosion in use of amyloid PET studies if amyloid-based treatments prove to be effective for any stage of the disease </li></ul>
    5. 5. Issues <ul><li>Who should be tested and when? </li></ul><ul><li>Who will pay for the testing and why? </li></ul><ul><li>Research only or clinical too? </li></ul><ul><li>What to tell people at risk </li></ul><ul><li>Is it wise to test people without a remedy? </li></ul><ul><li>Making the tests more reliable with standardization, cut-offs, and automated quantitative readouts when possible </li></ul><ul><li>Combining biomarker studies to stratify risk and predict rate of decline </li></ul><ul><li>Integrating genetic data in the risk algorithm </li></ul><ul><li>Increase acceptance of LP </li></ul><ul><li>Educating providers regarding use of the tests and criteria </li></ul>
    6. 6. Case 1: Behavioral and Cognitive Decline <ul><li>68-year-old man with behavior change and cognitive decline over 4 years </li></ul><ul><li>Irritable, agitated, “road rage,” apathetic, family very concerned about impaired judgment and poor behavior control </li></ul><ul><li>Short-term memory loss — repetition, misplacing items with impaired verbal memory and attention on cognitive testing </li></ul><ul><li>Exam — irritable, disinhibited, and impulsive in the office; left during the initial exam and had to be brought back from the parking lot </li></ul>
    7. 7. <ul><li>MMSE 22, MOCA 19, 0/3 recall on the MMSE (2/3 with prompting) and 0/5 on the MOCA after a delay </li></ul><ul><li>Neuropsych testing — deficits in orientation, executive function, psychomotor speed, attention, and abstract conceptualization </li></ul><ul><li>Poor learning, retrieval, and recognition on memory tasks, made worse by executive impairment </li></ul><ul><li>CDR 1.0 </li></ul><ul><li>MRI — mild gen atrophy and mild temp horn dilatation </li></ul><ul><li>FDG PET — mild hypometabolism in L frontal and bilat ant temp lobes </li></ul>Case 1: Behavioral and Cognitive Decline (cont.)
    8. 8. Additional Testing <ul><li>ApoE genotype E4,4 </li></ul><ul><li>CSF </li></ul><ul><ul><li>Aβ42 144 pg/mL </li></ul></ul><ul><ul><li>T-tau 110 pg/mL </li></ul></ul><ul><ul><li>P-tau 42 pg/mL </li></ul></ul><ul><li>Amyloid PET </li></ul><ul><li>Diagnosis —a typical AD dementia </li></ul><ul><ul><li>Probable AD dementia (frontal behavioral variant) with high biomarker probability of AD etiology </li></ul></ul>Shaw LM, Vanderstichele H, Knapik-Czajka H, et al. Ann Neurol . 2009;65:403-413.
    9. 9. Case 2: Cognitive Impairment and Depression <ul><li>66-year-old woman with 7 years of education and mild cognitive symptoms and depression </li></ul><ul><li>Trouble recalling names and recognizing people, mildly repetitive, and mild misplacing </li></ul><ul><li>Cognitive problems began soon after breakup with boyfriend who promised to marry her. She has been tearful and upset </li></ul><ul><li>She is working full-time cleaning in an office complex, driving, and paying her bills without difficulty </li></ul><ul><li>Fam Hx — mother with late-onset dementia and brother with onset of dementia in his 70s </li></ul>
    10. 10. Case 2: Cognitive Impairment and Depression (cont.) <ul><li>Exam nl except for tearfulness when discussing the breakup from her boyfriend </li></ul><ul><li>MMSE 28, 2/3 recall and 3 rd with prompting, MOCA 23, 2/5 on delayed recall </li></ul><ul><li>Neuropsych-impaired verbal learning, recognition and recall </li></ul>
    11. 11. Case 2: Cognitive Impairment and Depression (cont.) <ul><li>MRI WNL </li></ul><ul><li>ApoE 3,4 </li></ul><ul><li>Aβ42-203, Total tau 92, Phospho tau 84, Total tau/Aβ42 0.45 </li></ul><ul><li>Amyloid PET </li></ul><ul><li>Diagnosis-Prodromal AD MCI due to AD-biomarkers are uninformative that MCI is due to AD </li></ul>
    12. 12. Case 3: Worried About AD <ul><li>46-year-old woman with a college education and minimal cognitive complaints. She works full-time and cares for her children without difficulty. She pays the household bills and does all the cooking. Her husband feels that her memory is normal and no different from his. </li></ul><ul><li>Her mother had a PS1 mutation with age of onset of 50. She has not yet been tested. </li></ul><ul><li>MRI is normal and delayed recall shows borderline impairment. </li></ul><ul><li>CDR 0 </li></ul><ul><li>Diagnosis —Dubois- suspicious for presymptomatic AD </li></ul><ul><ul><li>NIA-AA-not yet on the grid </li></ul></ul>
    13. 13. Case 4: Answering an Ad <ul><li>77-year-old man with no cognitive complaints who responded to an ad for a memory study </li></ul><ul><li>His mother had AD with onset at 80 so he thought he should get checked out. “I want the amyloid scan that everyone is talking about.” </li></ul><ul><li>MMSE 29, delayed recall WNL </li></ul><ul><li>ApoE 3,4 </li></ul><ul><li>MRI — mild cortical atrophy, “appropriate for age” </li></ul><ul><li>Composite F18 amyloid PET SUVR 1.5 </li></ul><ul><li>CDR 0 </li></ul><ul><li>Diagnosis —a symptomatic at risk for AD </li></ul><ul><ul><li>Stage 1 asymptomatic cerebral amyloidosis </li></ul></ul>
    14. 14. Future <ul><li>We are at the beginning of AD biomarker development </li></ul><ul><li>There will be increasing pressure to use new biomarkers in the clinic </li></ul><ul><li>Clinicians need evidence to guide their practice </li></ul><ul><ul><li>Reliability of the tests </li></ul></ul><ul><ul><li>What to tell people at risk </li></ul></ul><ul><ul><li>Is it wise to test people without a remedy? </li></ul></ul><ul><li>We need to increase acceptance of LP and integrate genetic information into the risk algorithm </li></ul><ul><li>Better define the plan for revising the new criteria </li></ul>