Disease State Diagnosis

AD or dementia of the Alzheimer's type (DAT) is named for Alois Alzheimer, who first described the cognitive impairment and later the neuropathological hallmarks of the disease in 1907: amyloid plaques, neurofibrillary tangles (NFTs), and inflammation marked by astrocytic gliosis and reactive microglia. AD is a mentally debilitating disease with profound socio- and pharmaco-economic impact. Over 4 million individuals in the US and 15-20 million individuals worldwide have AD. AD onset typically occurs at 60-65 years, with the risk of disease doubling every 5 years above the age of 65. AD prevalence is 3% at ages 65-74 and ~50% at 85 and older. Early memory impairment, specifically episodic memory, and progressive decline in executive function are overt clinical signs of AD accompanied by drastic alterations in personality, including aggressive behavior, which make management of AD patients challenging. The mean survival time postdiagnosis ranges from 5 to 10 years and can be as long as 20 years.

AD is the most common form of dementia diagnosed, but it is an exclusionary diagnosis of other probable causes of dementia, including amnestic disorders, dementia due to multiple etiologies or other medical conditions, vascular dementia, substance intoxication, or substance withdrawal. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR)4 and the World Health Organization ICD-10 disease classification systems define AD subtypes: with early onset (<65 years), with late onset (>65 years); with delusions; with depressed mood; uncomplicated; and/or with behavioral disturbance (e.g., wandering). The primary diagnostic of any dementia is memory impairment but can include aphasia (deterioration of language function), agnosia (impairment in object recognition), apraxia (impairment in executing motor activities), and disturbances in executive function. In AD, these cognitive deficits are typically observed with disease progression, which is usually of slow onset and gradual decline. Mild cognitive impairment (MCI), characterized by isolated episodes of long-term memory impairment, may be the precusor of AD. Longitudinal studies indicate that up to 80% of MCI patients will progress to dementia within 6 years.5

The definitive diagnosis of AD is postmortem and is based on clinical documentation of dementia and neuropathological criteria. The pathological classification of AD is based on criteria established by Braak and Braak,6 the Consortium to Establish a Registry for Alzheimer Disease (CERAD),7 and/or the National Institute for Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association (NIA-RIA).8 Braak and Braak's criteria are based on an evaluation of the distribution of NFTs and neuropil threads in the brains of 83 nondemented and demented individuals at autopsy. Six stages of neuropathology were defined and correlated to cognitive function. A general progression of NFT distribution from the transentorhinal cortical area (stage I) to the entorhinal cortex (stage II), extending to the hippocampus (stage III) and increasing in number (stage IV), followed by involvement of the neocortex (stage V) and ultimately the primary cortex (stage VI), was related to cognitively normal (stage I/II), cognitively impaired (stage III/IV), and demented (stage V/VI) individuals. The CERAD criteria are based on the histopathological evaluation of three brain regions: the second frontal gyrus, the first temporal gyrus, and the supramarginal gyrus at the levels of the caudate putamen, amygdala, and parietooccipital sulcus, respectively, and the age of the patient. Neuritic plaque density is quantified in these regions and classified into three stages: stage A (<2), stage B ( b 6), and stage C ( > 30). AD is diagnosed at autopsy if patients younger than 50 years were classified as stage A; patients at 50-75 years were classified as stage B; or if patients older than 75 years were classified as stage C and had a clinical history of dementia. According to the NIA-RIA criteria, AD is categorized as low, intermediate, and of high likelihood based on both the Braak and CERAD classifications: stages I/II and A; stages III/IV and B, and stages V/VI and C, respectively. The utility of definitive disease diagnosis postmortem is however of little consequence in treating the patient, especially when the accuracy of clinical diagnosis of probable AD is in the 75-92% range. The ability to accurately diagnose and assess AD progression is critical to understanding the disease in order to develop and evaluate NCEs at a time when there is sufficient brain function remaining for restorative approaches to be efficacious.

Newer diagnostic tools for AD in living patients are being developed but require correlation with both the clinical dementia rating (CDR) and the histopathological evaluation of NFTs at autopsy in longitudinal studies for validation. Brain neuroimaging using computed tomography (CT) or magnetic resonance image (MRI) scanning to measure brain volume has been evaluated as a potential surrogate marker for disease progression.9 While reduced volume in specific brain regions (e.g., entorhinal cortex, hippocampus) can be correlated with cognitive dysfunction, it is not usually evident until significant brain atrophy has occurred and thus cannot serve as an early marker of the disease process prior to obvious clinical symptoms.9 Functional magnetic resonance imaging (fMRI), proton magnetic resonance spectroscopy, and positron emission tomography scanning are used to evaluate brain activity and its correlation to different cognitive states to aid in clinical diagnosis. Cortical hypometabolism is associated with mild cognitive disability (e.g., misplacement of objects, inability to recognize familiar faces) and can be identified in individuals having specific genetic risk factors associated with AD, e.g., ApoE4 allele, but are as of yet symptomatic.9

Blood-brain barrier-permeable molecules with affinity for the b-amyloid peptide (Ab) are also being developed as imaging agents. Most of these are derivatives of Congo Red or thioflavin that stain brain amyloid plaques. Methoxy-X04, a derivative of Congo Red, can detect plaque formation in animals, and the thioflavin T derivative, PIB, has been successfully evaluated in AD patients.9

Biomarkers are also necessitated for improved diagnosis and medical management of AD. Ab, tau, and phosphorylated tau (ptau) proteins are potential biomarkers, and clinical studies over the course of the past decade have shown that monitoring the levels of Ab42 and ptau (pthr231, pthr181, pser199) in cerebrospinal fluid (CSF) can potentially serve to discriminate AD from normal aging and other neurological disorders and can predict conversion of patients from MCI to AD, with low Ab42 levels associated with both high total and ptau levels being a distinguishing feature.10 These biomarkers are not robust in being able to distinguish AD from other forms of dementias, and alternate biomarkers are being sought using quantitative proteomic analysis to identify a panel of proteins, a molecular fingerprint that can differentiate AD and be used diagnostically - a major challenge. The National Institute of Health's BIOCARD study (Biomarkers in Older Controls at Risk for Dementia) reported 'tremendous' variability in CSF peptide markers (Ab42, tau, and ptau) between controls and patients, making the current data rate-limiting in developing an accurate biomarker.11 However, combining MRI and CSF biomarkers may improve sensitivity and specificity for AD diagnosis.

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