1 MCI Criteria Two Contrasting Theories of Incorporating - - PDF document

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A Scientific Update on Alzheimer’s Disease: Etiology, Diagnosis and Treatment

Mark W. Bondi, Ph.D., ABPP/CN

Professor of Psychiatry UC San Diego School of Medicine Director, Neuropsychological Assessment Unit VA San Diego Healthcare System

Research was supported by NIA grants P50 AG05131, R01 AG049810 & K24 AG026431. Dr. Bondi has received financial support from Oxford Univ Press, Takeda Pharmaceutical Co. and Novartis Pharmaceutical Co. There are no other financial disclosures to report.

NAMS Annual Conference Thursday, October 4th, 2018, 11:50 am – 12:10 pm

Alzheimers Disease

Auguste D.

Clinical observation alone made the case appear so unusual that it could not be classified as one of the recognized illnesses; it showed anatomical characteristics which set it apart from all recognized cases. The first symptom the 51-year old woman showed was the idea that she was jealous of her husband.

Soon she developed a rapid loss of memory.

Gross Anatomic Changes In Alzheimers Disease

Neurofibrillary tangles Amyloid plaques Brain atrophy and neuron loss Structure: MRI whole brain atrophy regional atrophy Function: FMRI ¯ activation; ­ deactiv PET, SPECT ¯ glucose use

Biochemical changes: oxidative damage, inflammation, synaptic damage

Biochemistry: CSF ¯ Ab42 ­ tau, p-tau MRI Spectroscopy PET – Amyloid Plasma Ab

Biomarkers for Alzheimers Disease

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Table 3 MCI criteria incorporating biomarkers Diagnostic category Biomarker probability

• f AD etiology

Ab (PET or CSF) Neuronal injury (tau, FDG, sMRI) MCI–core clinical criteria Uninformative Conflicting/indeterminant/untested Conflicting/indeterminant/untested MCI due to AD—intermediate likelihood Intermediate Positive Untested Untested Positive MCI due to AD—high likelihood Highest Positive Positive MCI—unlikely due to AD Lowest Negative Negative Abbreviations:AD,Alzheimer’sdisease;Ab,amyloidbetapeptide;PET,positronemissiontomography;CSF,cerebrospinalfluid;FDG,fluorodeoxyglucose; sMRI, structural magnetic resonance imaging.

MCI Criteria Incorporating Biomarkers

Albert et al. (2011). Alz & Dem.

Two Contrasting Theories of Alzheimer’s Disease Pathogenesis

Amyloid Cascade Model Braak’s Continuum Model

Jack et al. (2010). Lancet Neurol.

Proposed Staging Framework of the Cascade Of Events in Preclinical Alzheimer’s Disease

Preclinical Alzheimer’s Disease Criteria Incorporating Biomarkers

Sperling et al. (2011). Alz & Dem.

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Anti-Amyloid Trial in Mild to Moderate AD

Salloway, Sperling et al. (2014). New Engl J Med.

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Breitner (2015). Neurology.

Neuropathologic Hallmarks Of AD: Evolution of Neurofibrillary Changes

Stages I / II (pre AD) Stages III / IV (early AD) Stages V / VI (clinical AD)

Neurofibrillary changes limited to entorhinal and transentorhinal (TE) regions Severe involvement of TE regions; moderate changes in hippocampus; mild changes in some cortical association areas Cortical association areas severely involved;

• nly primary sensory

and motor areas spared Braak & Braak. (1991). Acta Neuropathol.

Ø Learning and Memory

Cognitive Abilities Affected by AD

Ø Language and Semantic Memory Ø Executive Functions / Attention Ø Visuospatial / Constructional Ability

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Continuum of AD Tau Pathology: From Brainstem to Cortex

Braak et al. (2011). J Neuropath Exp Neurol. “…the pathologic process associated with sporadic AD commences with intraneuritic formation of pretangle material in the lower brainstem rather than in the transentorhinal region…”

Locus Coeruleus

Stages of AD-Associated Tau Pathology

Braak et al. (2011). J Neuropath Exp Neurol. Braak & Del Tredici (2015). Brain. Shafiei et al. (2017). Front Aging Neurosci.

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• β
• β
• β

The Two-Hit Vascular Hypothesis For Alzheimer’s Disease

Zlokovic (2011). Nat Rev Neurosci. Zlokovic (2011). Nat Rev Neurosci.

• β
• β
• β

Current AD Biomarker Methods Vascular Biomarker Methods

The Two-Hit Vascular Hypothesis The Two-Hit Vascular Hypothesis For Alzheimer’s Disease

Zlokovic (2011). Nat Rev Neurosci.

• β
• The work aimed at characterizing markers of brainstem tau

pathology or vascular pathology represents a shift away from the strictures of the amyloid cascade model and may advance our understanding of AD pathogenesis. If successful, it will drive a number of fundamental shifts in biomarker strategies, drug discovery and therapeutics.

Concluding Comments