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Alzheimer’s Disease The Amyloid Theory: Time to Move on. Prepared and Presented by Aly H. Abayazeed, MBchB Neuroradiology Fellow.

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Presentation on theme: "Alzheimer’s Disease The Amyloid Theory: Time to Move on. Prepared and Presented by Aly H. Abayazeed, MBchB Neuroradiology Fellow."— Presentation transcript:

1 Alzheimer’s Disease The Amyloid Theory: Time to Move on. Prepared and Presented by Aly H. Abayazeed, MBchB Neuroradiology Fellow

2 What We Will Talk About? The History. Why is it important ? How is it diagnosed clinically ? What is the role of Radiology ? What are AD genetics ? What is the Amyloid Theory and Why is it failing us ? What’s next and how can Radiology be part of the future ?

3 The History


5 The Problem

6 The Disease 4.5 million in the US. Incidence doubles every 5 years after age 60. 14 million individuals by 2050. Most leading cause to nursing home placement. 140 billion dollars/year (health care, nursing home and lost productivity)

7 The Clinical Diagnosis

8 Progressive dementia. Early onset or Late onset (95%). Begins with isolated memory impairment. Declarative memory domain most profoundly affected early. Diagnosis: progressive deficit in more than one cognitive domain, usually memory plus another, after other possible causes of dementia have been excluded. “possible” or “probable”. 1 1. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’sdisease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease.Neurology1984;34:939–944.

9 Amnestic MCI Considered to be the earliest form of AD. Within 5 years about 80% of aMCI convert to AD. Non-memory MCI syndromes are likely early manifestation of other dementias. aMCI Normal Alzheimer

10 The Radiology Factor

11 The Amyloid Theory (overview)

12 The Radiology Factor Exclusion LymphomaNPHHeubner

13 The Radiology Factor Diagnostic Structural 1. Visual Assessment

14 The Radiology Factor Diagnostic Structural 2. ROI Tissue Volume Measurement

15 The Radiology Factor 3. VBM Lateral Temporal Prefrontal Cortex Parietal Cortex Medial temporal

16 MRS: Depressed NAA and Elevated mI. DTI: Increased ADC of water and Abnormal FA. MR perfusion: DCE/DSC/ more recently ASL modalities. Bilateral temporal parietal decrease in CBF. fMRI: Task-activation fMRI in aMCI patients, and, Resting state fMRI for AD. The Radiology Factor Other Modalities

17 P IB, most commonly studied. Have a very short half life. F rontal lobes, posterior cingulate and temporal parietal cortex. Cerebellum is control. 2 positive gyri are considered sufficient for the diagnosis.  Atrophy <−>  PIB −>  Cognitive decline. 1 1 0-30% Cognitively normal have PIB uptake. The Radiology Factor Amyloid Imaging

18 The Radiology Factor


20 N ormal anatomic variation between individuals limits the diagnostic utility of cross-sectional structural MRI obtained at a SINGLE point in time. LONGITUDINAL measures with serial MRIs is of better diagnostic value. R ates of WHOLE brain atrophy in AD: 1.5 to 3%. Rates of HIPPOCAMPUS atrophy in AD: 4 to 6% W e need to develop automated techniques for GRAY matter VOLUME MEASUREMENTS and apply it to our clinical practice. M RS: Depressed NAA and elevated mI. fMRI can show INCREASED activity in AD and aMCI patients. A SL: Might be a helpful tool in the future. A myloid imaging: Sensitive but not specific. Doesn’t significantly change with progression of disease. C ognitive decline MIRRORS structural atrophy where there is no increase in Amyloid deposition. Imaging Take Home Points

21 The Genetic Factor

22 The Amyloid Theory (overview)

23 How Does The Genetics Fit In The Amyloid Theory Chromosome 21 APPAβ Chromosome 14 PS1Secretase Chromosome 1 PS2Secretase Chromosome 19 APOE E4/E4

24 The Genetic Factor

25 Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or no- genetic factors. “Conflicting Reports”

26 Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene locate on CH19, particularly in the late-onset FAD families.

27 CONCLUSIONS: The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women.

28 The Amyloid Theory



31 The Flaws The association of neurofibrillary tangles more clearly relevant to the dementia of AD than the presence of amyloid containing neuritic plaques. 1 Many drugs that were invented to remove or stop amyloid have failed to improve patient’s symptoms. The amount of Amyloid deposition doesn’t correlate with the degree of volume atrophy (10mg in a 1400gm brain). Only 2% of population have PSN mutations. Of those only 50% develop AD in their life time. 50% of APO E4/E4 who are 80-years-old lack AD. African Americans with APOE4 don’t show the disease. (Absent in Nigerian AD with matching controls). 1. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82:239–59

32 So What Do We Think Is Really Causing AD ?

33 The Vascular Theory



36 What Are We Doing AT UMASS ?

37 New England Stroke & Research Center David Drachman MDMatthew Gounis PhD

38 The Study Simvastatin (40 mg/day) for one month. Then add L-Arginine (2 gm qid) for a month. Then add Tetrahydrobiopterin (BH4), 20 mg/kg for 2 months. So, for the last 2 months of the study he will be on all three drugs. The statin increases endothelial nitric oxide production (eNOS) and function; the L-Arginine supplies nitrogen; and the BH4 is a critical cofactor for the process. NOTCH is secreted by the endothelial cells in response to elevated eNOS. ASL (PLD 1600, 1900, 2100ms) Time “0”, 1 month, 2 month and 4 month.

39 #1 #2 #3 #4 Session Subject 1, ASL, PLD = 1600 ms

40 The Study Goals To have better understanding of the underlying vascular pathogenesis of AD and to validate the vascular theory. Proposal and trial of new treatment of AD. To evaluate and establish the diagnostic and prognostic utility of ASL in the imaging of patients with AD.

41 Thank You

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