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Page 2 of 6 Cellina et al. Neuroimmunol Neuroinflammation 2018;5:22 I http://dx.doi.org/10.20517/2347-8659.2018.15

disease (HD) [11-14] , amyotrophic lateral sclerosis (ALS) [15-17] , and multiple sclerosis (MS) [1,18-23] .

AD is a neurodegenerative chronic disorder characterized by a progressive cognitive decline; its main
etiologic mechanisms are: deposition of extracellular amyloid-β plaques, synaptic loss and evidence of
intracellular neurofibrillary inclusions with hyper-phosphorylated tau protein.

Even if autophagy plays a complex role in AD, which needs to be further characterized, the connection between
this disease and autophagy dysregulation has been already demonstrated: a pathological accumulation of
autophagosomes in neocortical of AD patients has been proved and the mutations of presenilin-1, which are
[5]
related to AD forms with early-onset, cause a block of the autophagy flux in fibroblasts in these patients [24,25] .
On the other hand, other investigators suggest that early microglial accumulation in AD delays disease
progression by promoting clearance of Aβ before formation of senile plaques, therefore having a protective
role . The ability of microglia to clear Aβ may decrease with age and progression of AD pathology .
[25]
[25]
In PD one of the pathologic features is the presence of Lewy bodies, abnormal deposits of a protein called
α-synuclein: this fact is suggestive of defects in intracellular protein clearance mechanisms and autophagic
process dysregulation .
[26]
HD is caused by expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene that
encodes the mutant huntingtin: this protein is highly expressed in neurons and participates in many cellular
functions, including vesicle and organelle transport and autophagy [13,27] . Mutant huntingtin interferes with
the correct autophagic function; therapeutic strategies that improve the clearance of this mutant protein by
autophagy reduce neuronal toxicity .
[14]
Recent genetic evidence has demonstrated that mutations in autophagy-regulatory genes can result in the
occurrence of ALS [15-17] .

MS is a chronic immune-cell-mediated disease characterized by the presence of auto-reactive T cells
target the myelin sheath in the CNS , leading to inflammation, demyelination and neuronal function
[18]
impairment. In patients affected by MS, several autophagy-related genes (e.g., ATG-16L2, ATG-9A, and ULK-1)
are overexpressed , therefore the hypothesis is that over-activation of autophagy may contribute to auto-
[1]
reactive T lymphocyte survival .
[18]
Given the pivotal roles of the autophagy in these neurodegenerative diseases, the targeting of some key
pathways of the inflammatory process provides new insights into the diagnosis and the modulation of this
process represents a new therapeutic strategy for neuroprotection .
[1]

The activated microglia plays a major role in chronic neuroinflammation, causing long-term cerebral damage
by inducing autoimmune reaction, and is observed in various CNS diseases such as stroke, MS, ALS, AD
and PD . In vivo imaging of activated microglia can provide a non-invasive and reliable detection of early
[28]
and localized neuroinflammation processes, thanks to the availability of several neuroimaging modalities .
[29]
Positron emission tomography (PET) is an imaging technique that can characterize measure and visualize
the biological processes at the molecular levels in the body .
[28]
In addition to the standard glucose metabolism [18F fluorodeoxyglucose (18F FDG) PET], a variety of targets
for inflammation imaging have been recently discovered, and the corresponding PET tracers showed high
levels of accuracy and are considered superior to FDG for imaging inflammation . The most studied
[30]
neuroinflammation related targets include translocator protein (TSPO), type 2 cannabinoid receptor (CB2R),
and cyclooxygenase (COX) .
[31]