**2.1 Introduction**

Alzheimer's disease (AD) is the most common form of dementia, affecting, for example, 5.3 million Americans, and this number is expected to rise as the baby boom generation comes of age. The cause of AD is presently not entirely understood but what is clear is that it results from a complex neurodegenerative cascade that includes misfolding and aggregation of proteins such as amyloid and tau, with concomitant decline of neurotransmitter systems. As set forth by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR), a diagnosis of Alzheimer's disease (AD) requires two components: (1) clinical progressive dementia with episodic memory impairment and (2) hallmark neuropathological changes, including the presence of extracellular Aβ plaques and intraneuronal neurofibrillary tangles (NFTs) in the cortical brain (APA, 2000; McKhann, et al., 1984). Due to the difficulty of confirming histopathology *in vivo*, however, AD can only be definitively diagnosed *postmortem*. Consequently, the prevailing criteria only allow a probabilistic diagnosis of AD based on clinical phenotype. Specifically, a patient must present with manifest dementia above a certain severity threshold, impairment of two or more cognitive domains, which must cause major interference with social function, and a daily regiment to receive a clinical diagnosis of AD (APA, 2000). After confirming the presence of dementia, a clinician must exclude other conditions that might account for cognitive decline (McKhann, et al., 1984). Since the criteria's enumeration in 1984, new data has emerged - specifically, with regards to the biological basis of AD. New clinical tests, (chiefly, MRI, CT and PET), coupled with the Mini-Mental State Examination (MMSE) and ECG, may foment a clinician's ability to differentiate between forms of dementia.

While clinical-neuropsychological testing remains one of the best tools in a clinician's armamentarium, the utility of such testing is limited in many respects. Evidence suggests that AD pathology (i.e. Aβ deposition in extracellular plaques and vascular walls, tau neurofibrillary tangles (NFTs), cerebral atrophy, synaptic reduction, and neuronal loss) may develop years to decades before the appearance of cognitive deterioration (Pike, et al., 2007; Price and Morris, 1999; Thal, et al., 2002). As dementia represents a late stage in the progression of this disease, early clinical diagnosis of AD is not possible with a great degree of accuracy. Clinical-neuropsychological testing has low sensitivity and specificity in early pre-dementia stages because, in part, a mere subset of individuals that is clinically diagnosed with mild cognitive impairment (MCI), an at-risk population, will progress to AD (Forsberg, et al., 2008; Petersen, et al., 2009; Pike, et al., 2007). Even within later stages, a clinical diagnosis of AD is only probable, not definitive. Only 70 to 90% of persons that match the aforementioned criteria have their diagnoses confirmed at autopsy (Jellinger, et al., 1990; Kukull, et al., 1990). A clinical differential diagnosis of dementia remains somewhat difficult, as many of the cognitive symptoms of AD overlap with those of other neurodegenerative disorders.

for dementia from many excellent and comprehensive review articles available in the literature (Brücke, et al., 2000; Herholz, 2003, 2011; Herholz, et al., 2007; Ishii, 2002; Jagust, 2004; Kadir and Nordberg, 2010; Nordberg, 2004, 2008; Pavese and Brooks, 2009; Sioka, et

Alzheimer's disease (AD) is the most common form of dementia, affecting, for example, 5.3 million Americans, and this number is expected to rise as the baby boom generation comes of age. The cause of AD is presently not entirely understood but what is clear is that it results from a complex neurodegenerative cascade that includes misfolding and aggregation of proteins such as amyloid and tau, with concomitant decline of neurotransmitter systems. As set forth by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR), a diagnosis of Alzheimer's disease (AD) requires two components: (1) clinical progressive dementia with episodic memory impairment and (2) hallmark neuropathological changes, including the presence of extracellular Aβ plaques and intraneuronal neurofibrillary tangles (NFTs) in the cortical brain (APA, 2000; McKhann, et al., 1984). Due to the difficulty of confirming histopathology *in vivo*, however, AD can only be definitively diagnosed *postmortem*. Consequently, the prevailing criteria only allow a probabilistic diagnosis of AD based on clinical phenotype. Specifically, a patient must present with manifest dementia above a certain severity threshold, impairment of two or more cognitive domains, which must cause major interference with social function, and a daily regiment to receive a clinical diagnosis of AD (APA, 2000). After confirming the presence of dementia, a clinician must exclude other conditions that might account for cognitive decline (McKhann, et al., 1984). Since the criteria's enumeration in 1984, new data has emerged - specifically, with regards to the biological basis of AD. New clinical tests, (chiefly, MRI, CT and PET), coupled with the Mini-Mental State Examination (MMSE) and ECG, may foment a clinician's ability to

While clinical-neuropsychological testing remains one of the best tools in a clinician's armamentarium, the utility of such testing is limited in many respects. Evidence suggests that AD pathology (i.e. Aβ deposition in extracellular plaques and vascular walls, tau neurofibrillary tangles (NFTs), cerebral atrophy, synaptic reduction, and neuronal loss) may develop years to decades before the appearance of cognitive deterioration (Pike, et al., 2007; Price and Morris, 1999; Thal, et al., 2002). As dementia represents a late stage in the progression of this disease, early clinical diagnosis of AD is not possible with a great degree of accuracy. Clinical-neuropsychological testing has low sensitivity and specificity in early pre-dementia stages because, in part, a mere subset of individuals that is clinically diagnosed with mild cognitive impairment (MCI), an at-risk population, will progress to AD (Forsberg, et al., 2008; Petersen, et al., 2009; Pike, et al., 2007). Even within later stages, a clinical diagnosis of AD is only probable, not definitive. Only 70 to 90% of persons that match the aforementioned criteria have their diagnoses confirmed at autopsy (Jellinger, et al., 1990; Kukull, et al., 1990). A clinical differential diagnosis of dementia remains somewhat difficult, as many of the cognitive symptoms of AD overlap with those of other

al., 2010; Vitali, et al., 2008).

**2. Alzheimer's disease** 

differentiate between forms of dementia.

neurodegenerative disorders.

**2.1 Introduction** 

It is thus apparent that there is a great need to revise the way in which AD is conceptualized. Accurate and definitive diagnoses need to occur *ante-mortem*, in lieu of *postmortem*, and preferably in the early pre-dementia (prodromal) stage. Dubois *et al.*, having moved beyond the NINCDS-ADRDA criteria for probable AD, introduced new standards for diagnosis (Dubois, et al., 2007). They include early and significant episodic memory impairment and at least one abnormal *in vivo* biomarker- particularly, medial temporal lobe atrophy, abnormal CSF biomarkers (increased total tau concentrations, increased phosphotau concentrations, low Aß1-42 concentrations, or a combination of all three), brain Aβ load, temporoparietal hypometabolism on [18F]FDG-PET, and/or specific binding pattern with particular PET ligands. Learning more about AD biomarkers, and how they fit into the accepted paradigm for this disease, will allow for decreased dependence on unreliable clinical diagnostic criteria. Non-invasive PET imaging can be particularly useful in this context. Probes are being developed that target specific AD biomarkers, allowing us to monitor AD pathophysiology *in vivo*. The main strategies for exploration of AD pathophysiology using PET imaging have been reviewed (Jagust, 2004; Nordberg, 2004, 2008), and are outlined in the following sections.
