Alzheimer’s disease (AD) is the most common cause of dementia and chronic neurodegenerative disorder among the aging population. Dementia is a syndrome characterized by progressive illnesses affecting memory, thinking, behavior and everyday performance of an individual. Dementia affects older people, but 2% of people starts developing before the age of 65 years (Organization 2006). According to the Worlds Alzheimer Report 2014, 44 million of people are living with dementia all across the globe and its set to get doubled by 2030 and triples by 2050 (Prince, Albanese et al. 2014). Its estimated that 5.2 million Americans have AD in 2014 (Weuve, Hebert et al. 2014). This includes 200,000 individuals under 65 age have early onset of AD and 5 million people of age 65 and above (Weuve, Hebert et al. 2014). Women are affected more than men in AD and other dementias (Weuve, Hebert et al. 2014). Among 5 million people of above 65 years of age, 3.2 million are women and 1.8 million are men (Weuve, Hebert et al. 2014). The Multiple factors that leads to AD are age, genetics, environmental factors, head trauma, depression, diabetes mellitus, hyperlipidemia, and vascular factors. There are no treatments for AD that slows or stops the death and malfunctioning of neurons in the brain, indeed many therapies and drugs are aimed in slowing or stopping neuronal malfunction (Association 2014). Currently five drugs have been approved by the U.S food and Drug Administration to improve symptoms of AD by increasing the amount of neurotransmitters in the brain (Association 2014). It has been estimated that Medicare and Medicaid covered $150 billion of total health care for long duration care for individuals suffering for AD and other dementias (Association 2014).
Neurological and Communicative Disorders and Stroke’Alzheimer’s Disease and Related Disorders Association (NINCDS’ADRDA) in 1984 proposed a criteria which is as follows (1) clinical diagnosis of AD could only be designated as ‘probable’ while the patient was alive and could not be made definitively until Alzheimer’s pathology had been confirmed post mortem (McKhann, Drachman et al. 1984) and (2) the clinical diagnosis of AD could be assigned only when the disease had advanced to the point of causing significant functional disability and met the threshold criterion of dementia (McKhann, Drachman et al. 1984).
In 2007, IWG proposed criteria that AD could be recognized in vivo and independently of dementia in the presence of two features (Dubois, Feldman et al. 2007). The first criteria was a core clinical that require evidence of a specific episodic memory profile characterized by a low free recall that is normalized by cueing (Dubois and Albert 2004). The second is the presence of biomarker evidence on AD which include (1) structural MRI, (2) Neuroimaging using PET (18F-2-fluoro-2-deoxy-D-glucose PET [FDG PET] or 11C-labelled Pittsburgh compound B PET [PiB PET]), and (3) CSF analysis of amyloid ?? (A??) or tau protein (total tau [T-tau] and phosphorylated tau [P-tau]) concentrations (Dubois, Feldman et al. 2007)
In 2011, the NIA and Alzheimer’s association proposed guidelines to help pathologist and categorizing the brain changes with AD and other dementias (Hyman, Phelps et al. 2012). Based on the changes absorbed, they classified into three stages (a) preclinical Alzheimer’s disease, (b) mild cognitive impairment (MCI) due to Alzheimer’s disease, (c) Dementia due to Alzheimer’s disease (Hyman, Phelps et al. 2012). In pre-clinical AD, the individual have changes in the cerebrospinal fluid but they don’t develop memory loss. This reflects that Alzheimer’s related brain changes occur 20 years onset before the symptom occurs (Petersen, Smith et al. 1999, H??nninen, Hallikainen et al. 2002, Reiman, Quiroz et al. 2012). In MCI due to AD, individuals suffering from MCI has some notable changes in thinking that could be absorbed among family members and friends, but do not meet criteria for dementia (Petersen, Smith et al. 1999, H??nninen, Hallikainen et al. 2002, Reiman, Quiroz et al. 2012). Various studies show that 10 to 20% of individual of age 65 or above have MCI (Petersen, Smith et al. 1999, H??nninen, Hallikainen et al. 2002, Reiman, Quiroz et al. 2012). Its is estimated that 15% and 10% progress from MCI to dementia and AD every year (Manly, Tang et al. 2008). In Dementia due to AD, Individual is characterized by having problem in memory, thinking and behavioral symptom that affects his routine life (Association 2014).
In 2014, IWG proposed criteria for maintaining the principle of high specificity, based on the framework they classified as follows (1). Typical AD can be diagnosed in the presence of an amnestic syndrome of the hippocampal type, which could be associated with different cognitive or behavioral changes and having one of following changes in vivo AD pathology such as decreased A??42 together with increased T-tau or P-tau concentration in CSF or increased retention on amyloid tracer PET (Dubois, Feldman et al. 2014). (2) Atypical AD could be made in the presence of the following, which includes clinical phenotypes that is consistent with one of the known atypical presentation and at-least one of the following changes indicating in-vivo AD pathology (Dubois, Feldman et al. 2014). (3) Mixed AD can be made in patients with typical or atypical phenotypic feature of AD and presence of at-least one biomarker of AD pathology (Dubois, Feldman et al. 2014). (4) Preclinical states of AD require absence of clinical symptoms of AD (typical or atypical phenotypes) and inclusion of at-least one biomarker of AD pathology for identifying the presence of asymptomatic at-risk state or the presence of a proven AD autosomal dominant mutation of chromosome 1, 14 or 21 for the diagnosis of presymptomatic change (Dubois, Feldman et al. 2014). (5) To differentiate biomarkers of AD diagnosis from those of AD progression (Dubois, Feldman et al. 2014).
Dr. Alois Alzheimer, a German physician in 1906 observed pathologic abnormalities in autopsied brain of women who suffered from memory related problems, confusion and language trouble (Prince, Albanese et al. 2014). He found the presence of plaques deposits outside the neurons and tangles inside the brain cells (Prince, Albanese et al. 2014). Thus, the senile plaques and neurofibrillary tangles have became two pathological hallmarks of AD (Prince, Albanese et al. 2014).
The histological hallmarks of AD in brain are intracellular deposition of microtubule-associated tau protein called neurofibrillary tangles (NTF) and extracellular accumulation of amyloid ?? peptide (A??) in senile plaques (Bloom 2014). A?? derived from the larger glycoprotein called amyloid precursor protein (APP) can processed through two pathways amyloidogenic and non-amyloidogenic (Gandy 2005) . In amyloidogenic pathway ??-secretase and ??-secretase proteolysis APP to produce soluble amyloid precursor protein ?? (sAPP??) and a carboxyl terminal fragment CTF?? (C99) to produce A?? peptides (Gandy 2005). Alternatively APP is proteolysed by the action of ?? and ??- secretase generating soluble amino terminal fragments (sAPP??) and a carboxyl terminal fragment CTF?? (C83) to produce non amyloidogenic peptide (Esch, Keim et al. 1990, Buxbaum, Thinakaran et al. 1998).
Figure 1. Amyloidogenic and non-amyloidogenic pathways of APP
APP is cleaved by ??-?? secretases (amyloidogenic) releasing amyloid A?? peptide(s) or by ??-?? secretases (non-amyloidogenic), adapted from (Read and Suphioglu 2013)
The amino acid sequences of A?? include A??42 and A??40. During normal condition A??40 is 10-fold higher concentration level, when compared to A??42 central nervous system (CNS) (Haass, Schlossmacher et al. 1992). However during inflammation, stress and injury in the brain causes A??40 and A??42 for a dynamic change and leads to an upregulation of A??42. In AD A??42 accumulates as misfolded proteins in extracellular space (Gurol, Irizarry et al. 2006).
Tau is a microtubule-associated protein (MAP), most abundant in central and peripheral nervous system that help in assembly and stabilizing of microtubules that is crucial among the cellular morphology and trafficking (Tolnay and Probst 1999, Iqbal, Liu et al. 2010, Cohen, Guo et al. 2011). NFT is the major hallmarks of AD patients in brain. In AD, phosphorylation of tau leads to the loss of neuronal function and death. Degeneration of synapse strongly correlates with cognitive decline in AD, while soluble oligomeric tau contribute to synapse degeneration (Morris, Maeda et al. 2011). Although, the protein aggregating into NFT are unclear, number of NFT and the progression of neurodegeneration as well as dementia showed a significant positive correlation in AD (Cohen, Guo et al. 2011) (Arnaud, Robakis et al. 2006).
Figure 2. AD pathology
Deposition of A?? and tau in neurons. The boxes shows the different biomarkers which are used for examination, adapted from (Nordberg 2015)
A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic process or pharmacologic responses to a therapeutic intervention (Atkinson, Colburn et al. 2001).The pathology of neurodegenerative for individuals is provided by using imaging and fluid biomarkers (Dickerson, Wolk et al. 2013).
The CSF biomarkers play a major role in diagnosing probable AD. However, abnormality in the CSF is found long before the symptoms occur.
Amyloid beta (A??) is synthesized in brain and diffused into CSF. In cognitively normal individuals A?? appears in moderate condition, however for individuals suffering from AD has reduced A??42 in CSF which act as an useful biomarker during diagnosis (Sunderland, Linker et al. 2003). The low levels of A??42 appears at-least 20 years prior to clinical dementia in individuals with familial AD mutations (Ringman, Coppola et al. 2012). In addition, reduced levels of A??42 appear early in cognitively normal which precedes MCI by years (Fagan, Head et al. 2009). Therefore A??42 cannot be used individually as a specific biomarkers in discriminating from other dementia hence it should be combined with other biomarkers for determining specific dementia.
Tau in CSF relates with the progression of tau related pathology in cerebral cortex. Increased in the tau level in CSF for AD patients reflects the neuronal loss in brain (de Souza, Chupin et al. 2012). Similarly, like A??42 elevation in tau seems to occur at cognitive normal individuals (Fagan, Head et al. 2009). Hence its important to consider other biomarker for differential diagnosis of AD. Moreover, phosphorylated (p)-tau have 85% sensitivity and 97% specificity in discriminating AD from other neurological disorder (Tan, Yu et al. 2014). P-tau is therefore more superior to t-tau in differentiating diagnosis, thus helps in overcoming the short coming of A??42 and t-tau in differentiating diagnosis (Buerger, Zinkowski et al. 2002). CSF t-tau and p-tau occurs after A??42 initially aggregates and increases as amyloid accumulates (Buchhave, Minthon et al. 2012).
Structural MRI studies helps in subjects diagnosed with AD and MCI who consistently show change in atrophy in entorhinal cortex and hippocampus of medial temporal lobe (MTL) and cortical thinning in AD signature region are the MRI sign of emerging AD (Du, Schuff et al. 2001). MRI studies focus on normal subjects who have maternal history of AD, has reduced volume of MTL and precuneus (Berti, Mosconi et al. 2011). Voxel based analysis on whole brain determines the structural MRI could be used to identify the presence of brain atrophy in cortical regions up to 10 years before clinical symptoms of AD, with greater impact in MTL (Du, Schuff et al. 2001).
Positron Emission Tomography (PET)
PET is based on the principle of spontaneous emission of positron by the nuclei of unstable radionuclide, whose number of protons exceeds that of electrons (Granov, Tiutin et al. 2013). PET images in-vivo distribution of radiopharmaceutical substances with higher resolution and sensitivity (Fahey 2003). The positron which is a ??-particle with positive charge annihilates with an electron of negative charge, releasing equal number of gamma photons of same energy (511 keV) moving in 180 degree opposite to each other to conserve momentum (Kukekov and Fadeev 1986, Fahey 2003).
The components involved in the PET scanner are movable bed, detector, gantry and computer. The detector consist of multiple crystals attached with a photomultipliers (Granov, Tiutin et al. 2013). The interaction among the gamma photon and crystal produces scintillation which induces electric impulse in the photomultipliers and could be detected and processed using computer (Khmelev, Shiryaev et al. 2004). If the two detectors are in coincidence, then the positron emitted along the line connects the detectors which is termed as line of response (LOR) (Fahey 2003).In most of the scanners the two detectors are in coincidence, if they are detected with in 10 seconds (Fahey 2003). The sensitivity of the PET can be increased by increasing the number of detectors into a ring. The data examined from the individual is acquired in computer in the form of sinogram. There are different techniques of reconstruction such as filtered back projection (FBP), Iterative Method, OSEM are used for reconstructing an image. In modern PET scanners, LSO crystals with minimum size are used which permits high resolving capacity, high resolution, effective algorithm for image reconstruction and field of view sufficient for single stage scanning of the brain or heart (Granov, Tiutin et al. 2013).
The cyclotron, a particle accelerator provides the production of radionuclides for clinical use. Heavy particles are accelerated to a higher energy level of 5-100MeV using cyclotron (Granov, Tiutin et al. 2013). The beam of particles is focused on the target substance by using radio magnetic lens. The target material is bombarded with heavy particle to generate the required radionuclide (Granov, Tiutin et al. 2013).
The requirements of a good tracer which include higher affinity towards the target receptor, selectivity versus other receptors (Bmax / Kd of at least 10-fold,where Bmax is the density of the receptor and Kd is the concentration of the radiotracer) and good permeability (McCarthy, Halldin et al. 2009). The tracers has to be a poor substrate of p-glycoprotein if it has been developed for imaging targets in brain (Terasaki and Hosoya 1999). It has been found that low hydrogen bonding plays an important role in predicting good PET tracers (McCarthy, Halldin et al. 2009). For a good tracers, time to binding equilibrium should be long relative to washout of non-specifically bound tracer, but short relative to isotope decay (McCarthy, Halldin et al. 2009) .
PET imaging of amyloid binding agent Pittsburg compound B (PET-PiB) helps to determine the ??-amyloid (A??) and its distribution over the brain that were previously restricted to postmortem studies. The longitudinal study provided evidence relating with a direct relationship between PET-PiB and likelihood of conversion from clinical diagnosis of MCI to AD over three years (Klunk 2011). Since there is significant overlap between amyloid imaging and CSF- A??42, researchers attempt to address the areas where these two biomarkers may be equivalent and areas where one measurement could hold unique advantages (Vlassenko, Mintun et al. 2011). In addition, current hypothesis states that higher amyloid burden assessed by florbetapir 18F (18F-AV-45) amyloid PET is related with lower memory performance among clinically normal older subjects (Sperling, Johnson et al. 2013).
FDG-PET (2-deoxy-2[18F]fluoro-D-glucose) is one of the neurodegeneration biomarkers included in the new research criteria proposed for the various diagnosis of AD by the International working group (IWG) in 2007 and 2010, also in the new diagnostic criteria of AD by National Institute of Aging-Alzheimer Association (NIA-AA) (McKhann, Drachman et al. 1984, Dubois, Feldman et al. 2007, Dubois, Feldman et al. 2014). FDG-PET measures the local glucose metabolism for neuronal activity at resting state to asses cerebral function. It is evident that AD individuals has reduced FDG uptake predominantly in tempoparietal association areas, precuneus and posterior cingulate region (Minoshima, Giordani et al. 1997). These changes could be observed in subjects from 1-2 year before the onset of dementia and are closely related to cognitive impairment (Herholz 2010). Although MRI is more sensitive in detecting and monitoring hippocampal atrophy (Fox and Kennedy 2009), FDG is more sensitive in detecting neuronal dysfunction in neocortical association areas. Hence FDG is well suited for monitoring the progression of the disease syndrome (Alexander, Chen et al. 2002).
Regional functional impairment of glucose metabolism in AD is related with the severity and progression of different cognitive deficits (Langbaum, Chen et al. 2009)
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