Objective
The objective of this study is to compare amyloid β (Aβ) PET positive and negative patients to their neuropsychological profiles. There is a definitive link between Aβ deposits and cognitive disorders such as MCI or Alzheimer’s disease (AD), but does its presence justify the costly imaging tests based on its clinical context?
Background
Amnestic MCI is largely considered prodromal to AD/dementia in a high majority of cases. [1] Many studies have shown a positive correlation between Aβ PET positive individuals and their likelihood to progress to AD. Aβ deposits in the brain are not always a sign of AD or even MCI, and many elderly people live normal lives with elevated levels. The presence of Aβ in the brain should be carefully considered alongside other tests before making a clinical diagnosis of MCI or AD.
Methods
130 subjects from Barrow Neurological Institute (Phoenix, AZ) were included in this study. Amyloid PET report data was pulled from Dignity Health St. Joseph’s Hospital and Medical Center Outpatient Imaging. Amyloid PET scans obtained by using F-18 florbetapir compound and reviewed by an expert radiologist providing a qualitative status of amyloid-beta positive (+) or negative (-). All data was anonymized and categorized into positive amyloid PET, negative amyloid PET, and clinical diagnosis based on neuropsychological profiles.
Results
The demographic data indicated that 38.5% of the 91 patients diagnosed as amnestic MCI were amyloid PET negative while 61.5% were amyloid PET positive. Of the 39 patients diagnosed as Dementia or AD 15.4% were amyloid PET negative and 84.6% were amyloid PET positive. Correlational analysis between diagnosis and neuropsychological variables suggests that some variables correlate well while others do not. There is a significant correlation between diagnosis and dementia rating scale (DRS) r(24) = -.762, between diagnosis and TrailsB Test r(39) = .397, between diagnosis and phonetic fluency r(30) = -.383, between diagnosis and semantic fluency r(29) = -.369, and between diagnosis and the Boston Naming Test (BNT) r(36) = -.312. Comparing the PET positive and PET negative groups there is a marginal significance in the Boston Naming Test (T=1.945, P=.060) suggesting PET positive individuals test lower than PET negative.
Conclusion
Based on all the results of this study, amyloid PET is still a clinical indicator that an individual might be MCI or dementia/AD, but it has its exceptions. A small number of patients diagnosed as dementia/AD had a negative amyloid PET suggesting that beta amyloid plaques are not the only cause of the disease. There is a strong suggestion that amyloid plaques are a major factor in the progression of dementia or AD, however the results from an amyloid PET cannot be directly related to a diagnosis.

Alzheimer’s disease (AD) is a progressive cognitive and behavior disorder that is characterized by the deposition of extracellular Aβ plaques, intracellular neurofibrillary tangles, and neuroinflammation. Aβ is generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and, subsequently, y- secretase. In recent years, there has been an increasing interest in studying and understanding inflammation as a therapeutic target for AD. Inflammation manifests in the brain in the form of activated microglia and astrocytes. These cells are able to release high levels of inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α). TNF-α is a major cytokine, which is involved in early inflammatory events and plays a role in the progression of AD pathology. There are currently no treatments that target chronic neuroinflammation. However, previous work in our laboratory with transgenic mice modeling AD suggested that the anti-cancer drug lenalidomide could lower neuroinflammation and slow AD progression, though the cellular and molecular mechanisms are yet to be elucidated. Here we hypothesized that lenalidomide can modulate TNF-α production in microglia and decrease amyloidogenesis. Using immortal cell lines mimicking several brain cell types, we discovered that lenalidomide is likely to decrease inflammation by modulating microglia cells rather than neurons or astrocytes. In addition, the drug may prevent the overexpression of BACE1 upon inflammation, thus blocking the overproduction of Aβ. If confirmed, these results could lead to a better understanding of how inflammation regulates Aβ synthesis and provide novel cellular and molecular therapeutic targets to control the progression AD.

A prominent aspect of Alzheimer’s disease (AD) is the presence of neuroinflammation is mediated by the activation of microglial cells, which are the immune cells in the central nervous system (CNS) that express an array of cytokines that may promote an inflammatory response. The main cytokines produced are: tumor necrosis factor-alpha (TNF-), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The presence of these cytokines in the CNS may lead to neuronal death, to the production of toxic chemicals (such as nitric oxide), and to the generation of amyloid beta (a major pathological feature of AD). Previous studies have shown that modulation of the inflammatory response in the nervous system can potentially prevent and/or delay the onset of neurodegenerative diseases such as AD. Therefore, it is important to identify the process that induces CNS inflammation. For example, mitochondrial lysates have been found to produce an inflammatory response due to their ability to stimulate TNF-, Aβ, and APP mRNA [10]. Interestingly, extracellular mitochondria have been detected in the brain due to neurons degrading old mitochondria extracellularly. Therefore, we set out to study the effect of whole mitochondria isolated by differential centrifugation from human neuroblastoma cells (BE(2)-M17 cells) on the neuroinflammatory response in a human microglia model (THP-1 cells). Despite our best efforts, in the end it was unclear whether the mitochondrial fraction or other cellular components induced the inflammatory response we observed. Thus, further work with an improved mitochondrial isolation method should be carried out to address this issue.

Vascular inflammation plays a key role in the development and progression of cardiovascular disease. High fat diet has been associated with cardiovascular risk (1). Therefore, as poor nutrition and poor diet become more widespread, the number of people at risk to cardiovascular disease increases. We hypothesized that using the cancer drug lenalidomide would reverse the inflammation caused by high fat conditions. Human aortic vascular smooth muscle cells were used as an in vitro model to analyze the effect of lenalidomide on high fat diet induced inflammation. Palmitate, a saturated fatty acid was used to induce inflammation. Since lenalidomide has been shown to inhibit cytokine production and attenuate oxidative stress, we investigated whether lenalidomide alters select markers of vascular inflammation in vascular smooth muscle treated with high fat exposure using palmitate. These markers were cyclooxygenase-2 (COX-2) protein levels, TNF-α pro-inflammatory cytokine levels, and superoxide ions. Lenalidomide (5 µM) reversed COX-2 protein expression in cells exposed to high fat conditions (100 µM palmitate). In conclusion, high fat exposure elicits an inflammatory response in cultured primary human vascular smooth muscle, but this response appears to be independent of local cytokine or ROS production. Lenalidomide, although effective at reversing palmitate-induced COX-2, alone augments the pro-inflammatory mediators, COX-2 and TNF-α as well as promotes oxidative stress independent of high fat exposure in human vascular smooth muscle cells.