P OSITRON - EMISSION TOMOGRAPHY (PET) S CAN

PET is a nuclear medicine functional imaging method. It is widely used both in clinical practice and in research. PET helps to monitor metabolic processes in the body aiding in the detection of various diseases, including diseases associated with amyloid. Even though CSF and PET evaluate different amyloid forms, studies have reported a good degree of consistency between these 2 biomarkers (Jansen et al. 2015). PET presents in vivo quantitative cross-sectional impressions of various biochemical and physiological mechanisms like metabolism, blood circulation, and oxygen consumption. Artificially created positron-emitting radionuclides called tracers are introduced inside a biologically active molecule which is later injected usually into the bloodstream of an individual. 11C-labelled 2-[4′-(methylamino) phenyl]-6-hydroxybenzothiazole known as Pittsburgh Compound-B (11C-PiB) and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) are some of the commonly used tracers. PiB-PET is utilized to identify Aβ deposition in the brain while FDG-PET aids in the measurement of metabolic rates of glucose in the brain (Berti et al. 2010).

So far there have been no standard guidelines to decide the positivity of PiB-PET scans for pathological amyloid accumulation. Observers classify the scans based on the uptake and retention threshold of PiB. Cerebral PET scans can be assessed by two methods. One focuses on the whole brain with the voxel-based method and another one focuses on specific regions with a region-of-interest (ROI) method (Ashburner & Friston 2000). Usually, neuro-anatomical image skilled professionals manually analyse two-dimensional scans of specific domains in case of ROI method. However, newer voxel-based methods are automated and are proving to be more effective than conventional ROI approach. There are several ways to measure PiB retention namely standardized uptake value ratio (SUVR) and distribution volume ratio (DVR).

SUVR estimates the activities in the ROI and compares it with a normalized period while DVR compares the distribution ratio between ROI and reference area. Researchers have also been studying the time interval between the injection of PIB and acquisition in the cerebral domains (He et al. 2015).

2.4.1 PiB uptake in normal aging

There have been inconsistent results concerning differences in Aβ status between subjective cognitively impaired and cognitively normal individuals (Amariglio et al. 2012, Chételat et al.

2010). Furthermore, Aβ accumulation on PET scans has been observed in both symptomatic

AD and asymptomatic elderly individuals. Around one-fourth or more of the nondemented persons aged over 75 years have been documented with a moderate amount of neuritic plaques (Bennett et al. 2006). Healthy older, neurologically normal persons can show important neuropathology, as amyloid deposition has been observed during autopsy (Dickson et al. 1992).

PiB imaging for amyloid has shown uptake in the same brain areas as reflected in the earliest autopsy studies (Braak & Braak 1997).

Amyloid PET scanning has offered the possibility of determining cerebral amyloid load, and exploring the timeline of its development among nondemented, MCI and AD individuals. Like AD, the sequence of PiB uptake seems to be quite similar in the cognitively normal individuals.

The prefrontal cortex, lateral temporal cortex, striatum, and lateral and medial parietal regions are involved. The uptake can be more focal, as indicated by several studies reporting frequent deposition in prefrontal cortex and precuneus / posterior cingulate (Rowe et al. 2007, Villemagne et al. 2008) implying the necessity of further investigation.

2.4.2 PiB uptake in mild cognitive impairment

Prediction of the conversion from MCI to AD dementia with elevated PiB uptake has been reported (Forsberg et al. 2008, Pike et al. 2007), but approximately 40 percent of the people who fulfil the clinical characteristics of MCI do not advance to clinical dementia (Busse et al.

2006). However, the progression from MCI to dementia is more likely in individuals with positive amyloid status and apparent (Petersen et al. 2016) if the decline is persistent with time.

The amnestic form of MCI has been most predictive for the progression to dementia. An association between PiB uptake and impaired episodic memory performance has been seen among healthy and MCI individuals in several studies (Pike et al. 2007).

Studies have shown that AD patients have PiB uptake in frontal, parietal and temporal regions in comparison to a healthy aging population (Klunk et al. 2004, Scheinin et al. 2009). MCI population has also shown a similar trend (Jack et al. 2008, Kemppainen et al. 2007). Elevated uptake in posterior cingulate has also been reported (Forsberg et al. 2008, Kemppainen et al.

2007) but region-specific pattern was reported only in MCI non-converters. Nevertheless, no substantial difference was found between the non-converters and the converters (Villain et al.

2012).

2.4.3 PiB uptake in Alzheimer’s disease

In AD research and clinical trials, PiB-PET scanning is starting to be utilized more widely, and it has also become available in specialized clinics. PET scans comprise various analysis monitoring the non-specific metabolic developments in AD patients targeting several neurotransmitter mechanisms as well as pathological developments including the accumulation of Aβ (Rinne & Någren 2010). To explore the development of the AD pathology, it is important to assess Aβ deposition within the disease process longitudinally (Hatashita et al. 2019).

According to a few longitudinal studies, PiB-PET scanning has demonstrated that amyloid accumulation rises as healthy individuals develop dementia but reduces during advanced stages of AD (Jack et al. 2013, Villemagne et al. 2013) Furthermore, it has been possible to differentiate AD from FTD with PiB imaging (Drzezga 2008, Rabinovici et al. 2007) which is important for the prognosis and symptomatic treatment.

Assessment regarding the amyloid-PET scan sensitivity compared to autopsy has been done.

Clear relations have been observed between PiB uptake in vivo and the outcomes of region-specific investigations of amyloid deposition from post-mortem examinations (Ikonomovic et al. 2008, Kadir et al. 2011). However, region-specific investigations of PiB uptake have also provided some conflicting findings in AD patients. Some of the studies have shown no clear variations between regions (Villain et al. 2012) while few showed there was significant solitary uptake in the medial prefrontal cortex (Scheinin et al. 2009). Aβ accumulation was reported within the frontal, parietal, temporal, and cingulate cortex in some of the PiB-PET studies (Rinne et al. 2010, Villemagne et al. 2011).

According to a systematic review by Zhang et al. (2014), PiB showed high sensitivity but lower specificity for identifying people with MCI who developed AD dementia. The false-negative outcomes might be due to the fact that PiB-PET may not be efficient to identify some types of amyloid deposits (Leinonen et al. 2008). On the other hand, the false-positive results implied that PiB-PET imaging might also act as a biomarker for additional neurodegenerative conditions or neurological diseases in individuals without any symptoms (Chen et al. 2014).

Furthermore, PiB attaches with β-amyloid in the vascular surface specifically concerning to cerebral amyloid angiopathy (Zhang et al. 2014).

2.4.4 PiB uptake in Parkinson's disease dementia and Lewy body dementia

PD patients possess six times greater risk of progression to dementia compared to healthy controls (Edison et al. 2008). Patients with PD take a few years to many years to develop dementia (Lim et al. 2019). Studies have explored potential common pathophysiological pathways between PD and AD. Prevalence of amyloid positivity from different PET studies varied between 0%-38% in non-demented PD patients, while 16.6-33% were reported in demented patients with PD (Lim et al. 2019).

Edison et al. study in 2008 suggested that PiB uptake is detected besides the usual Lewy body deposition in patients with DLB as well as in PD patients, but amyloid deposition was lower compared to DLB patients. Reports from studies revealed that most of the DLB individuals show cortical Aβ plaques (Jellinger & Attems 2006) in contrast to patients with PD with dementia (Jendroska et al. 1996, Mastaglia et al. 2003). In a study by Kantarci et al. in 2010, DLB patients showed significantly lower global PiB retention compared to AD patients but higher than cognitively normal individuals. However, while DLB patients had frontal Aβ plaques, temporoparietal deposition was less than in AD. This might be due to the topographical amyloid pathophysiology of these diseases.