J. Integr. Neurosci.

2023; 22(6): 172

https://doi.org/10.31083/j.jin2206172

Review
Positron Emission Tomography Molecular Imaging of the Major
Neurodegenerative Disorders: Overview and Pictorial Essay, from a
Nuclear Medicine Center’s Perspective
Ferdinando Calabria1, *,† , Mario Leporace1,† , Andrea Cimini2 , Maria Ricci3 ,
Laura Travascio4 , Antonio Bagnato1
1 Department of Nuclear Medicine and Theragnostics, Mariano Santo Hospital, 87100 Cosenza, Italy
2 Nuclear Medicine Unit, St Salvatore Hospital, 67100 L’Aquila, Italy
3 Nuclear Medicine Unit, Cardarelli Hospital, 86100 Campobasso, Italy
4 Unità Operativa Complessa (UOC) of Nuclear Medicine, Pescara Hospital, 65124 Pescara, Italy

*Correspondence: [email protected] (Ferdinando Calabria)

† These authors contributed equally.

Academic Editors: Anna Piro and Gernot Riedel

Submitted: 20 March 2023 Revised: 7 July 2023 Accepted: 31 July 2023 Published: 13 December 2023

Abstract
Computed tomography (CT) and magnetic resonance imaging (MRI) provide key structural information on brain pathophysiology.
Positron emission tomography (PET) measures metabolism in the living brain; it plays an important role in molecular neuroimaging
and is rapidly expanding its field of application to the study of neurodegenerative diseases. Different PET radiopharmaceuticals allow in
vivo characterization and quantization of biological processes at the molecular and cellular levels, from which many neurodegenerative
diseases develop. In addition, hybrid imaging tools such as PET/CT and PET/MRI support the utility of PET, enabling the anatomical
mapping of functional data. In this overview, we describe the most commonly used PET tracers in the diagnostic work-up of patients
with Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. We also briefly discuss the pathophysiological
processes of tracer uptake in the brain, detailing their specific cellular pathways in clinical cases. This overview is limited to imaging
agents already applied in human subjects, with particular emphasis on those tracers used in our department.

Keywords: PET; amyloid imaging; tau protein; molecular imaging; neurodegenerative diseases; [18 F]FDOPA; [18 F]FDG; MRI

1. Introduction damage, and lifestyle (alcohol consumption and obesity)

can be underlying determinants in both non-cognitive
Neurodegenerative diseases (NDs), such as and cognitive symptoms of NDs. On the other hand, in
Alzheimer’s disease (AD), Parkinson’s disease (PD), several patients, the leading cause of the disease seems to
and Lewy body dementia (LBD), are often associated be unclear; in some of these patients the role of infectious
with pronounced protein deposition in the brain. Al- agents is under study [6]. The main aim of neuroimaging
though NDs determine different clinical conditions with in the management of patients with NDs is to identify
a different clinical onset, they share some features, such the underlying disease. In this field, contrast-enhanced
as neuro-inflammation, the breakdown of molecular computed tomography (CT) of the brain is useful for the
cleaning pathways, and selected or generalized loss of preliminary evaluation of brain anatomy and to identify
neurons [1]. Certain neurodegenerative diseases are also structural abnormalities. Ventricular enlargement, vascular
linked to intracellular or extracellular macro-aggregates lesions, and brain atrophy are significant findings that can
in selected brain structures, which are represented by be assessed using CT in ND patients. However, these are
amyloid-beta (Aβ) for AD, tau (τ ) protein in AD and common, non-specific features of NDs and other brain
other types of dementia, α-synuclein in PD and LBD, disorders, such as aging, epilepsy, vascular damage, and in-
and Creutzfeldt-Jacob disease, which is a prion-linked fectious diseases [7]. The main advantage of the CT is that
neurodegenerative disorder [2]. Aβ is essential in signal it is widely available, although the diagnostic accuracy can
regulation, neuronal metabolism, and intracellular delivery be suboptimal, due to the low soft tissue contrast. Magnetic
of metabolites [3], and the τ protein is involved in cellular resonance imaging (MRI) is the gold standard imaging
stability, in particular of axonal microtubules [4]. Both technique for the characterization of brain morphology and
proteins aggregate and precipitate in the white and/or grey visualization of functional processes. Due to the high soft
matter, in the form of fibrillary structures or as oligomers tissue contrast and the possibility of a multi-planar brain
[5]. Naturally, some risk factors promote the development evaluation, MRI morphological sequences also enable
of clinical onset. Aging, genetic factors, brain vascular brain lesions and/or vascular damage to be diagnosed [8].

Copyright: © 2023 The Author(s). Published by IMR Press.

This is an open access article under the CC BY 4.0 license.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
MRI can also reveal patterns of neurodegeneration such
as atrophy of the temporal and parietal regions in AD
or atrophy of the frontotemporal lobes in frontotemporal
dementia (FTD) [9]. However, these patterns are generally
detectable in the advanced stages of the disease; other NDs
are not associated with brain atrophy [10]. Ventricular
enlargement is generally considered as a further non-
specific finding. Shape analysis of the brain ventricles may
show that markers, such as ventricular perimeters, can be
adequately extrapolated from MR morphological imaging
to differentiate AD from healthy controls [11]. In the last
few decades, functional MRI (fMRI) has become a valid
tool for the detection of alterations in the hippocampus
in selected AD patients. In several studies, it has been
demonstrated that fMRI can help in the detection of altered
connectivity and hippocampal co-activation in AD patients
[12,13], while arterial spin labeling (ASL) has shown
promising results in the depiction of brain metabolism Fig. 1. Glucose and [18 F]FDG cellular uptake. Glucose
and perfusion [14]. ASL-MRI and oxygen-15 labeled 18
and [ F]FDG enter the cells via glucose transporter membrane
water ([15 O]H2 O) positron emission tomography (PET) proteins (GLUTs); subsequently, both are phosphorylated by
measurements of the regional cerebral blood flow (CBF) glucose-6-phosphatase. Phosphorylated glucose can be further
are strictly correlated across different perfusion states. In
metabolized by the cells in mitochondria, while phosphorylated
fact, as is ASL-MRI, [15 O]H2 O is a useful PET tracer for
[18 F]FDG cannot be further metabolized and remains trapped in
assessing regional cerebral blood flow in both white and
the cells. FDG, fluorodeoxyglucose.
grey matter [15]. However, these techniques still need to be
improved and validated. The main goal in the examination
of ND patients is an early and specific diagnosis, in order Preliminary studies on PET imaging have focused on
to select patients who could potentially benefit from ther- brain metabolism and demonstrated that the level of cere-
apies (such as PD patients) and who could be enrolled in bral glucose metabolism is a reliable measure of neuronal
experimental treatment programs. In the past two decades, activity [16]. In line with the work of Sokoloff et al. [16],
novel radiopharmaceuticals developed for PET imaging synaptic activity is directly proportional to neuronal glucose
of the brain have enabled the diagnosis and monitoring of metabolism, as confirmed by several human resting and
several NDs concurrently. Novel PET tracers have been functional activation studies [17–19]. In healthy controls,
used to show the molecular abnormalities at the basis of the the most intense [18 F]FDG uptake occurs in the subcortical
ND under study [1], which is essential for early diagnosis putamen, caudate nucleus, and thalamus, followed by high
and for investigating potential pharmacological treatments. uptake in the cortical gray matter. The globus pallidus typi-
The aim of this review is to summarize the information cally demonstrates mild uptake, and the white matter shows
on the most widely used radiopharmaceuticals for the low uptake. On the other hand, the precuneus and poste-
diagnosis and monitoring of NDs, from the perspective of rior cingulate, parietal and frontal lobes normally show the
nuclear physicians. Considering the large number of PET highest tracer uptake [20].
tracers investigated in human studies and animal models, [18 F]FDG PET of the brain thus enables whole brain
this overview focuses only on those which, to the best of glucose metabolism to be mapped, showing different patho-
our knowledge, are the main radiopharmaceuticals used logical conditions such as epilepsy [21], brain tumors (high-
for PET imaging of NDs in humans. grade gliomas) [22], and NDs [23]. The reduction of
[18 F]FDG uptake in selected brain regions can also help
2. [18 F]FDG PET clinicians to recognize NDs, which also helps to improve
Glucose is the energy substrate of the brain. In all the differential diagnosis.
NDs, glucose consumption tends to deteriorate in selected
neurons. The glucose analogue [18 F]Fluorodeoxyglucose 2.1 [18 F]FDG PET in Dementia
([18 F]FDG) circulates in the blood, crosses the blood-brain The clinical application of [18 F]FDG PET concerns
barrier, and is highly metabolized in grey matter. In fact, regional neocortical hypometabolism as a marker used
after uptake and phosphorylation by hexokinase, [18 F]FDG to differentiate dementias, although regional patterns can
becomes trapped in neurons, enabling the imaging and mea- overlap [24]. In AD, hypometabolism can appear before at-
surement of the cerebral metabolic rate of glucose (Fig. 1). rophy is detectable [25]. Notably, there is symmetrical hy-
pometabolism in the temporal- parietal, posterior cingulate,

2
and medial temporal cortices (Fig. 2). Varying sensitivities vanced stage of the disease [30]. To improve diagnostic
and specificities for AD diagnosis have been reported. Ac- accuracy, some studies support the utility of the dual tracer
cording to Smailagic et al. [26], the sensitivity and speci- brain PET with both [18 F]FDG and amyloid tracers in the
ficity in diagnosing AD are 76% and 82% respectively in a diagnostic workup of AD (Fig. 3), depending on the clin-
population with mild cognitive impairment (MCI). ical presentation [23]. The commercial availability of hy-
brid PET/MRI scanners is also improving confidence in the
management of NDs, by the added value of simultaneous
morphological and functional evaluation of the brain. In
the early stages of AD, with structural MRI it is very dif-
ficult to differentiate the signs of atrophy in the course of
AD from those related to physiological brain aging [31].
In general, full-blown forms of atrophy are bilateral and
symmetrical, prevailing in the temporal lobes and temporal-
mesial structures, including ex vacuo enlargement of the
ventricular and cerebrospinal fluid (CSF) spaces, and spar-
ing of the primary sensorimotor cortex. Moreover, the evo-
lution of atrophy in AD is more rapid than the atrophy oc-
curring with normal aging. MRI in patients with AD can
reveal increased amounts of white matter signal hyperin-
tensity in the periventricular and deep white matter regions
on T2-weighted and T2-fluid-attenuated inversion recovery
(FLAIR) sequences.

Fig. 2. [18 F]Fluorodeoxyglucose and Alzheimer’s disease. A

67-year-old female patient with a clinical diagnosis of Alzheimer’s
disease. Axial [18 F]Fluorodeoxyglucose Positron Emission To-
mography (PET) views show hypometabolism in frontal, parietal,
and temporal regions.

However, due to the heterogeneity of examined pa-

tients, data on the diagnostic accuracy are often not avail-
able. Another study in 67 patients diagnosed with AD
variants [25] demonstrated an overall good diagnostic
performance of brain [18 F]FDG PET in examining AD Fig. 3. Dual tracer imaging. Axial brain [18 F]FDG PET view
variant-specific patterns of brain hypometabolism. This in a 48-year-old male with Mild Cognitive Impairment, showing
was demonstrated as being highly consistent at the single- hypometabolism in the left parietal region (a). Corresponding ax-
subject level and already evident in the prodromal stages, ial 18 F-Flutemetamol PET view (b) shows pathological amyloid
thus representing important markers of disease neurodegen- burden in the same region.
eration, with a highly supportive diagnostic and prognostic
role.
At pathological analysis, AD is linked to early neu- Volumetric software for quantifying hippocampal vol-
ronal loss and gliosis in the mesial-temporal cortex, and umes can also be helpful [32]. The experience with fMRI
subsequent extension to other brain structures. Pathologi- has shown that there is impaired connectivity in the default
cal hallmarks are represented by Aβ plaques and τ proteins. mode network in AD [33]. Perfusion MRI with dynamic
The earliest changes in metabolism at PET imaging can be susceptibility contrast and ASL has demonstrated decreased
usually seen in the posterior cingulate gyrus [27]. How- CBF in bilateral temporal-parietal regions and the posterior
ever, the typical pattern of reduced tracer uptake generally cingulate, consistent with regional changes detected by PET
concerns the posterior cingulate gyri, precuneus, posterior or single photon emission computed tomography (SPECT)
temporal lobes, and parietal lobes [28,29]. Metabolism im- [34,35]. PET/MRI is therefore a hot topic in dementia re-
pairment can be asymmetric between the two hemispheres, search, with an emphasis on AD, thanks to the promising
or unilateral. Hypometabolism in the frontal lobes may results of combining information from both the PET and
also be found in advanced AD patients. In NDs, sparing MRI. In a typical brain PET/MRI study protocol, the MRI
of the sensorimotor cortex may also be observed in an ad- acquisition can take up to 60 minutes, while the PET scan

3
 hypometabolic regions include the frontal and anterior tem-
poral lobes, cingulate gyri, uncus, insula, basal ganglia, and
medial thalamus. Hypometabolism is generally asymmet-
ric (Fig. 4), with a sensitivity and specificity of 88% and
91%, respectively [11].

Fig. 4. Dual tracer imaging of frontotemporal dementia. In a

68-year-old male patient with clinical suspicion of frontotemporal
dementia, [18 F]FDG PET views show selected hypometabolism in
the right frontal and temporal regions (a, arrows), confirming the
diagnosis. Correlative [18 F]Flutemetamol PET (b) supported clin-
Fig. 5. PET/MRI and Lewy Body Dementia (LBD). A 60-year-
ical and imaging findings, excluding pathological amyloid burden
old woman with clinical suspicion of LBD dementia (cognitive
in the brain.
impairment, parkinsonism, and visual hallucinations), examined
by PET/MRI with [18 F]FDG: PET maximum-intensity projection
can take 15 minutes. However, unlike PET/CT, the acquisi- (a) shows diffuse hypometabolism in the brain, particularly in
tion protocol is simultaneous, minimizing motion artifacts. parietal and temporal regions and in the occipital lobes, as evi-
Furthermore, hybrid PET/MRI corrects for the partial vol- dent in correlative axial PET/MRI views. (b) MRI displayed mild
ume effect by improving the quantitative analysis of tracer ventricular enlargement and mild diffuse atrophy (c).
activity on brain volume. MRI co-registered with PET can
also provide valuable insights into the differential diagno-
sis of AD by combining structural and advanced functional Brain [18 F]FDG PET is therefore the method of choice
techniques in a predefined multimodal protocol. PET/MRI in the diagnosis of such disease, since the hallmark MRI
facilitates the correlation of CBF, morpho-structural abnor- feature is frontal and temporal lobe atrophy, with relative
malities with glucose metabolism, and amyloid plaque ar- preservation of the posterior areas, which may be detectable
rangement [36]. CBF derived from ASL has proven to be only in the advanced stage [40]. Also in this clinical setting,
comparable with [18 F]FDG PET in the differential diagno- interesting indications are provided by fMRI. In FTD pa-
sis of AD, FTD, and dementia with Lewy bodies (DLB) tients, MRI with ASL sequences can detect the following:
[37,38]. In a PET/MRI study with functional sequences, frontotemporal hypoperfusion compared with cognitively
in patients with AD, the intrinsic connectivity between the normal subjects with sparing of the parietal and occipital
hippocampus and the precuneus was found to be signifi- brain regions; greater perfusion in the parietal lobe com-
cantly reduced and the glucose metabolism was reduced in pared with AD; absence of anatomical abnormalities under-
the precuneus but was unchanged in the hippocampus [39]. lying the areas of hypoperfusion; and decreased perfusion
All these features could improve confidence in diagnosing in the frontal cortex correlated with cognitive impairment,
AD and managing such patients. However, it is important to thus ASL-MRI can estimate the severity of FTD [41].
consider that a comprehensive neuropsychological exami- [18 F]FDG PET/MRI imaging may thus reveal a strict
nation in a mixed sample of neurological patients should relationship between hypoperfusion and hypometabolism;
form the basis of the diagnostic workup of AD patients, however, the areas of hypometabolism are more extensive
while imaging could be of help in reaching the final diag- than the hypoperfused areas [42]. Similarly to AD, relative
nosis. On the other hand, decisions based on cognitive test sparing of the sensory-motor cortex is usually found.
results alone appear limited. The clinical impression based Among dementias, Lewy Body Dementia (LBD) is the
on anamnestic and clinical information obtained by the neu- second most common ND in patients over 65 years of age.
ropsychological examiner plays a crucial role in the identi- The classic clinical triad includes fluctuating levels of cog-
fication of AD patients in routine clinical practice. In FTD, nitive arousal, parkinsonism, and visual hallucinations. The

4
Fig. 6. PET imaging of cortico-basal degeneration. A 59-year-old man was examined for clinical suspicion of corticobasal degen-
eration by [18 F]FDG PET/CT of the brain. Axial PET views (a) clearly show severe asymmetrical left hemisphere hypometabolism
and reduction in uptake in the right cerebellar hemisphere (crossed cerebellar diaschisis). Correlative CT (b) supported the diagnosis by
showing ipsilateral ventricular enlargement and atrophy.

pattern of glucose metabolism impairment on [18 F]FDG evaluation of ND patients. However, the current availabil-
PET is usually represented by bilateral parietal and poste- ity of hybrid PET/MRI scanners is currently insufficient to
rior temporal deficit of tracer uptake and hypometabolism replace conventional PET/CT imaging.
in the posterior cingulate gyrus [24]. Early diagnosis of A multimodal approach should, however, be com-
DLB has been challenging, particularly in the context of dif- bined with clinical examinations. The use of novel PET
ferentiation with Parkinson’s disease-related dementia and radiopharmaceuticals, such as Aβ and τ tracers, could fur-
other forms, such as AD and rapidly progressive demen- ther aid towards an in-depth understanding of this highly
tia. In fact, unlike other types of dementia, impairment of disabling disease [49]. On this topic, structural MRI does
glucose metabolism of the occipital lobes is not uncommon not seem to be useful since the MRI findings of DLB are
(Fig. 5), which is an imaging feature congruent with the nonspecific. Brain MRI studies have demonstrated vari-
clinical diagnosis of LBD [24]. Another feature sugges- able volume loss of white and cortical matter with relative
tive of early diagnosis of LBD is the relative preservation preservation of the hippocampus [50]. Compared with AD-
of amygdala metabolism, recently defined by Pillai et al. related forms of atrophy, most studies have reported that pa-
[43] as the amygdala sign. Functional MRI, especially on tients with dementia DLB had less severe temporal atrophy
hybrid scanners, could improve the diagnosis by highlight- [51,52]. However, an association between hypometabolism
ing a lack of connectivity between cortical regions [44]. and hypoperfusion correlating with [18 F]FDG PET studies
FTD is a neurodegenerative disorder presenting with and ASL in MRI has been demonstrated [53].
degeneration of the frontal and temporal lobes. No ap-
proved pharmacological interventions for FTD are avail- 2.2 [18 F]FDG PET in Parkinson’s Disease and
able [45]. Patients often present social impairment and dis- Parkinsonism
inhibited, impulsive behavior [46]. In patients with FTD, [18 F]FDG PET is useful in the management of patients
a significant association between higher levels of educa- with cognitive impairment; however, it cannot easily de-
tion and lower brain glucose metabolism is seen, supporting tect the reduction in metabolism in the striatum, due to its
the cognitive reserve hypothesis—defined as the ability to high rate of normal distribution in healthy brain structures.
maintain cognitive functions relatively well at a given level [18 F]FDG PET can thus only support the diagnosis of PD,
of pathology—as reported in a recent paper by Beyer et al. by characterizing specific uptake patterns when the clinical
[47]. Although no pharmacological treatment is available diagnosis of parkinsonism or PD is unclear [54,55]. Thus,
for FTD, a precise diagnosis is needed to rule out psychi- in line with available data, brain [18 F]FDG PET may play a
atric disorders that are characterized by disinhibition and limited role in the diagnosis of parkinsonism [56,57], with
cognitive impairment [48]. the emphasis on the diagnosis of the dementia complex as-
MRI is also able to overcome the limitations of PET sociated with PD, which occurs in a significant minority of
imaging, by improving temporal and soft tissue contrast and PD patients. Eggers et al. [58] examined a cohort of 64
motion artifacts, and reducing patient exposure to radiation. PD patients, with both akinetic-rigid and tremor-dominant
In our opinion, PET/MRI will play a predominant role in the features, using [18 F]fluoro-L-phenylalanine ([18 F]FDOPA)

5
Fig. 7. Brain vascular injury. A 57-year-old man with Fig. 8. Uptake of amyloid PET tracers in relation to the depo-
Hodgkin’s lymphoma was examined by whole-body PET (a), sition of Aβ plaques in the brain.
showing pathological [18 F]FDG uptake in right inguinal lym-
phadenopathies. Axial PET/CT detail of the basicranium (b)
There are similar concerns regarding progressive supranu-
shows focal hypometabolism in the left putamen, due to deep brain
clear palsy (PSP) and multiple-system atrophy (MSA). PSP
infarct, as confirmed during patient anamnesis. patients generally show hypometabolism in the medial and
dorsolateral prefrontal cortex, caudate, thalamus, and up-
and [18 F]FDG PET of the brain. They showed a clear differ- per brainstem. MSA patients have a hypometabolic stria-
ence between the two subgroups of patients in the ventral tum and cerebellum [65–67]. Positive brain [18 F]FDG PET
striatum, reporting a significantly lower neuronal glucose findings in such patients could also represent a gatekeeper
metabolism within the ventral striatum for akinetic-rigid for subsequent PET imaging with τ protein tracers, in or-
patients compared with those with tremor-dominant symp- der to improve the diagnosis, as one study recently demon-
tomatology. These studies could provide significant infor- strated [68]. In this latter study performed on 117 pa-
mation on the pathogenesis of PD and its complex molec- tients with parkinsonian syndromes, [18 F]FDG PET was
ular mechanisms [59]. However, despite the widespread found to be very useful in clinical routine evaluation of sus-
use of [18 F]FDG PET in clinical practice and extensive re- pected dementia related to parkinsonian syndromes, with
search, there is still very limited evidence for the use of a satisfactory differential diagnosis in two thirds of pa-
[18 F]FDG PET in PD patients. According to the majority tients. One third of patients would have potentially prof-
of researchers, [18 F]FDG PET is a clinically useful imaging ited from further evaluation by more specific tracers. In the
biomarker only for idiopathic PD and atypical parkinson- future, the radiomics signature with metabolic, structural,
ism or parkinsonian syndromes associated with dementia and metabolic information provided by hybrid [18 F]FDG
[60]. The potential impact of [18 F]FDG PET in this afore- PET/MRI should hopefully be diagnostically effective in
mentioned clinical setting could be of special interest, by distinguishing between PD and MSA, as reported by Hu
highlighting the different patterns of hypometabolism in se- et al. [69] who examined 90 patients. A possible role
lected brain regions. Corticobasal degeneration (CBD) is for [18 F]FDG PET imaging may be also hypothesized in
a form of neuronal degeneration, a dementia involving the identifying those patients with post-ischemic vascular la-
loss of cognitive functions as well as movement and vision. cunae causing tremor (Fig. 7), thus excluding NDs [70], or
The loss of neurons in this disease is generally asymmetrical rare neurological conditions involving a movement disor-
or unilateral (Fig. 6), concerning only one brain hemisphere der [71,72].
[61]. For this reason, [18 F]FDG may be a reliable marker of
disease, helping to easily identify the disease location and 3. Amyloid Imaging
extension. AD is the most common neurodegenerative disease
In the early stages of CBD, MRI generally does not causing dementia in the elderly. Histopathology defines
reveal any changes. As the disease progresses, asymmetric this disease as linked to the accumulation Aβ plaques and
cortical atrophy involving the frontal-parietal lobes, corpus hyperphosphorylated neurofibrillary τ protein. Thus, the
callosum, and ipsilateral cerebellar peduncle may become Aβ plaques are the pathognomonic signs of AD, and their
evident. FLAIR sequences can show hyperintensity of appearance in the brain is an early event in the pathogen-
white matter tissue signal in the atrophic frontoparietal sulci esis. The first amyloid tracer was the Pittsburgh com-
[62]. The putamen and globus pallidum may appear hy- pound, used to image brain amyloid plaques. This tracer
pointense on T2-weighted images. Volume in the basal gan- is labeled with 11 C; the short half-life decay of the nu-
glia and hippocampus, unlike in AD, is conserved [63,64]. clide does not support its use in routine clinical applica-

6
tions [73]. Three fluorinated types of amyloid radiopharma-
ceuticals are therefore currently employed for PET/CT and
PET/MRI: [18 F]Florbetapir, [18 F]Flutemetamol (Fig. 8),
and [18 F]Florbetaben [74,75].
All fluorinated types of amyloid radiopharmaceuti-
cals have demonstrated a high diagnostic accuracy (sen-
sitivity 88–96%, specificity 80–100%) in the detection of
Aβ plaques, in comparison with postmortem data [76–78].
Imaging Aβ plaques with fluorinated-tracer PET is there-
fore becoming the most useful tool aimed at the in vivo
detection of brain plaque density and increasing the diag-
nostic accuracy in cognitively impaired patients. Negative
PET scans of patients with amyloid tracers generally show
physiological distribution of the radiopharmaceutical in the Fig. 10. Dual tracer imaging of Alzheimer’s Disease. [18 F]FDG
white matter, particularly evident in the axial slices of the and [18 F]Flutemetamol PET scans in a 61-year-old man examined
basicranium, which has been defined as the “sign of the sea- due to clinical suspicion of Alzheimer’s disease. [18 F]FDG 3D-
horses” (Fig. 9). PET and axial PET (a) show severe hypometabolism in the parietal
and temporal cortex, bilaterally, congruent with the clinical diag-
nosis. [18 F]-Flutemetamol 3D-PET and correlative axial images
(b) confirm the diagnosis, showing a pathological amyloid burden
in the parietal, temporal, and frontal lobes, in both hemispheres.

vasive testing such as the amyloid PET [79]. In selected

patients with cognitive impairment, current evidence sug-
gests that amyloid imaging provides diagnostic clarity and
significantly changes clinical management, while reducing
the overall number of investigations. The advent of amyloid
tracers in the PET imaging of dementia is encouraging stud-
ies on asymptomatic/paucisymptomatic patients who could
benefit from new clinical prevention trials, particularly us-
Fig. 9. Amyloid imaging. A 48-year-old woman with mild cog- ing monoclonal antibodies [83].
nitive impairment was examined by [18 F]Flutemetamol PET. The
scan did not show pathological tracer uptake; axial PET view
4. Tau Imaging
of the basicranium shows physiological tracer distribution in the The amyloidic, intracellular nature of neurofibrillary
white matter (sign of the seahorses). tangles is at the root of synaptic dysfunction and degenera-
tion occurring in several types of dementia [84].

In positive patients, amyloid accumulation is detected 4.1 Tau Imaging in AD

by a high tracer uptake in parietal cortices, temporal lobes, AD accounts for the vast majority of tauopathies ac-
and the anterior and posterior cingulates. Some variability cording to data from Braak et al. [85]. For this reason,
can be observed among patients, in particular in the case most studies on PET with τ protein radiopharmaceuticals
of MCI, while the involvement of frontal lobes usually oc- have been carried out on AD. Deposits of τ protein gener-
curs in advanced stages of the disease [79]. This variability ally begin in the entorhinal cortex, moving to the inferolat-
led to the development of a particular dual phase PET, on a eral temporal cortex and medial parietal lobe, finally, being
single day or in separate imaging sessions, including imag- detected in the cortex (Fig. 11).
ing of the brain with both [18 F]FDG and an amyloid tracer Age-related tracer accumulation can therefore be ob-
(Fig. 10), in order to assess the glucose metabolism of the served in the medial temporal lobe, while high levels of
cortex and possible amyloid burden [80,81]. tracer enhancement may be detected in cortical areas, such
However, despite the overall good diagnostic accu- as the posterior cingulate, inferior lateral temporal regions,
racy, the validation processes are still incomplete, and and also frontal and parietal regions [86]. The cortical depo-
the real impact on clinical outcome and cost-effectiveness sition of the τ protein is generally associated with dementia
needs to be assessed [82]. Future blood biomarkers will and AD [87,88] and can be documented by τ protein tracers
probably play an important screening role in AD, selecting such as [18 F]Flortaucipir [89]. [18 F]Flortaucipir has been
patients who would benefit from more expensive and in- most frequently reported as physiologically enhanced in the

7
 vivo. [18 F]FDOPA penetrate the cells carried by the L-type
amino acid transporters 1 and 2. These transporters are in-
volved in the permeability to the blood-brain barrier of the
tracer. Subsequently, this radiopharmaceutical is converted
into [18 F]Fluorodopamine by the amino acid decarboxylase
in central nervous system (Fig. 12). In the brain, faint up-
take is normally registered in the cortex and white matter.
The target tissue is only represented by the basal ganglia,
thus enabling the identification of cellular damage in the
caudate and putamen nuclei.

Fig. 11. PET imaging with τ tracers. The PET τ tracers present
high in vivo affinity with neuronal neurofibrillary tangles.

basal ganglia, substantia nigra, choroid plexus, meninges,

and vessels, as off-target binding. The recent approval by
the Food and Drug Administration of this novel PET τ pro-
tein agent marks a step forward in the field of AD research
and creates opportunities for second-generation τ protein
tracers to advance PET imaging into the clinic [90].
Several studies have confirmed that the association be-
tween τ protein accumulation and cognitive impairment is
stronger than that known for Aβ tracers. In AD patients,
a close relationship has been shown between τ protein Fig. 12. Intracellular uptake of [18 F]FDOPA in the brain.
PET results and the patterns of cortical hypometabolism
on [18 F]FDG PET, despite a significant interindividual dif-
ference in the distribution of τ protein pathology across SPECT imaging with cocaine analogues is used to
the brain [91]. The anti-τ protein therapy landscape is study the integrity of dopaminergic neurons in PD pa-
rapidly evolving, with multiple ongoing trials on the post- tients [94]. Several studies have demonstrated the lack of
translational modification of τ protein, immunotherapy, [18 F]FDOPA uptake in the striatum of PD patients [95]
and inhibitors of τ protein aggregation, targeting the pro- compared with healthy controls (Fig. 13). Other studies
duction of τ protein and the reduction in intracellular τ pro- have supported the potential of [18 F]FDOPA in the early
tein levels [92]. diagnosis of early stage of PD and in the differential diag-
nosis of essential tremor [96] (Fig. 14), demonstrating that
4.2 Tau Imaging in Other Types of Dementia on the contralateral to symptoms side the striatal uptake is
decreased more than the other side [97].
Moderate uptake τ protein tracers can be observed on
The mean annual rate of decreased [18 F]FDOPA accu-
PET imaging of DLB [92]. In addition, patients with PD de-
mulation in PD patients has been reported to be 8–12% in
mentia complex show an increased τ protein burden [93],
the putamen, and 4–6% in the caudate; on the other hand, in
confirming a multifactorial process in the development of
healthy volunteers this value is less than 1% in both struc-
cognitive impairment in this significant minority of PD pa-
tures [98]. Following Braak’s hypothesis [85], tracer up-
tients, involving α-synuclein, τ protein deposition, and Aβ
take is lower in the putamen than in the caudate nuclei,
deposition. However, [18 F]Flortaucipir is useful in differ-
thus indicating the earlier involvement of the putamens in
entiating between AD dementia and non-AD neurodegen-
the natural progression of the disease. Conversely, a lack
erative disorders, based on different thresholds applied to
of [18 F]FDOPA uptake in the striatum may also be identi-
the medial-basal and lateral temporal cortex tracer uptake
fied in juvenile PD, due to the rapid loss of striatal neurons
[84].
[99]. The most important goal in PET imaging of the stria-
tum with [18 F]FDOPA is probably the differential diagnosis
5. [18 F]FDOPA with other parkinsonian syndromes, such as PSP, MSA and
[18 F]-fluoro-L-phenylalanine ([18 F]FDOPA) is the CBD. In fact, only PD patients adequately respond to anti-
precursor of L-DiOxyPhenylAlanine (L-DOPA) of lev- Parkinson drug therapy. Otsuka et al. [100] preliminar-
odopamine, and follows the same metabolic pathway in ily investigated the [18 F]FDOPA uptake in 10 patients with

8
 cant association in PD patients between the reduction in up-
take in the striatum and in the olfactory tract, suggesting an-
other criterion to distinguish between PD and other move-
ment disorders. SPECT imaging with cocaine analogues is
widely used in the management of PD patients [104] and
is the main reference standard for evaluating the diagnos-
tic performance of [18 F]FDOPA PET in the management
of movement disorders. The literature demonstrates a good
correlation between striatal [18 F]FDOPA uptake and striatal
123
I-ioflupane uptake, with similar values of sensitivity and
specificity in PD patients [105,106]. In addition, better re-
producibility of [18 F]FDOPA PET imaging has been noted,
Fig. 13. Physiological [18 F]FDOPA bio-distribution. Nor- due to the shorter half-life of the tracer, the shorter time of
mal distribution of [18 F]FDOPA in the striatum on PET (a) and the investigation, and the better resolution power of the PET
PET/CT (b) axial details of the basicranium, in a 56-year-old man scanner. In a recent study, the possible role of [18 F]FDOPA
examined for essential tremor and suspicion of Parkinson’s dis- in the imaging of the nigrostriatal pathway and sympathetic
ease. cardiac innervation was also proposed. This approach is
important as quantification of myocardial [18 F]FDOPA up-
take may help in differentiating patients with and without
Parkinson’s [107].

6. Translocator Protein
Radiopharmaceuticals
Translocator protein (TSPO) is a mitochondrial outer
membrane 18 kDa protein, located at contact sites be-
tween the outer and inner mitochondrial membrane, ini-
tially known for taking up benzodiazepine in peripheral
tissues [108]. Its functions, including cholesterol trans-
port and steroid hormone synthesis, mitochondrial respi-
ration, permeability pore opening, apoptosis, and prolifer-
ation, are still being investigated. Steroidogenic tissues,
Fig. 14. [18 F]FDOPA and Parkinson’s Disease. [18 F]FDOPA such as glandular and secretory, are particularly abundant in
axial PET (a) and PET/CT (b) details of the basicranium, in a TSPO, while the brain and liver express low levels of TSPO
60-year-old man evaluated for Parkinson’s disease in an advanced [109]. A non-mitochondrial localization has been reported
clinical stage, showing severe bilateral reduction in tracer uptake [110,111], for instance in red blood cells, endoplasmic retic-
in the putamen nuclei and moderate-to-severe reduction in uptake ulum, and nuclear membranes of erythroblasts, although its
in both caudate nuclei. role has yet to be determined.
TSPO is a channel with five alpha transmembrane he-
lices, able to form homodimers and a multimeric complex
MSA and eight patients with PD. The [18 F]FDOPA accu-
including the voltage-dependent anion channel 1 (VDAC1)
mulation was lower by a similar amount in the putamen of
[112], the ATPase family AAA domain-containing protein
both groups, while there was a greater reduction in uptake
3 (ATAD3), and the inner mitochondrial membrane cy-
in the caudate in MSA patients. These findings have been
tochrome P450 side-chain cleavage enzyme (CYP11A1), a
confirmed elsewhere. A greater reduction in uptake in the
signal transduction complex involved in intracellular Ca++
caudate of PSP and CBD patients in comparison with PD
pathways [113].
patients has been reported [101,102]. However, the overlap
In the healthy central nervous system, TSPO is ex-
between these populations was too great for a meaningful
pressed at a low baseline level, not homogeneously, in sev-
differentiation.
eral brain regions including the cerebellum and choroid
Concerning the clinical implications of Braak’s hy- plexus, with the ependyma of the ventricular system show-
pothesis [85], which considers that the earliest signs of PD, ing higher TSPO staining levels. Moreover, TSPO levels
such as hyposmia, sleep disorders and constipation may are higher in white matter than in gray matter. Astrocytes
precede the motor features of the disease by several years, and microglia do not display constitutive TSPO expression,
some researchers have increasingly focused on the non- while endothelial cells and the pericytes of blood vessels
motor symptoms in order to detect early PD and to slow or do [113]. TSPO may be overexpressed in activated mi-
stop its progression. Scherfler et al. [103] found a signifi- croglia and upregulated in astrocytes in the central nervous

9
system, due to ischemic damage or neurodegenerative dis- thors read and approved the final manuscript. All authors
eases such as AD, PD, and multiple sclerosis [114–116]; have participated sufficiently in the work and agreed to be
therefore, TSPO is a biomarker of neuroinflammation and accountable for all aspects of the work.
related diseases. In particular, abnormal protein aggregate
accumulation, typically found in neurodegenerative disor- Ethics Approval and Consent to Participate
ders, triggers the brain immune response through upregula- Not applicable.
tion of TSPO on activated microglia.
First and second generation TSPO ligands [117–119] Acknowledgment
have been developed for PET imaging of neuroinflam-
mation, labeled with either 11 C or, lately, 18 F, in an at- Not applicable.
tempt to overcome the short half-life of 11 C, the low brain
uptake and penetration of the intact blood-brain barrier Funding
[120,121], and with binding affinity to TSPO suitable to This research received no external funding.
PET imaging. Both first- (e.g., [11 C]PK11195) and second-
generation (e.g., [11 C]PBR28n and [18 F]DPA714) tracers Conflict of Interest
correlate well with amyloid and τ protein PET imaging The authors declare no conflict of interest.
[119,122], linking the presence of beta fibrils and tangles
to neuroinflammation in both MCI and AD. At the pre- References
symptomatic stage, neuroinflammation is associated with
amyloid imaging in a subgroup of patients [123], interest- [1] Domínguez-Fernández C, Egiguren-Ortiz J, Razquin J, Gómez-
Galán M, De Las Heras-García L, Paredes-Rodríguez E, et al.
ingly at a very early stage of neuroinflammation. In FTD, Review of Technological Challenges in Personalised Medicine
which comprises different clinical syndromes, TSPO PET and Early Diagnosis of Neurodegenerative Disorders. Interna-
is positive in frontal and temporal lobes in the behavioral tional Journal of Molecular Sciences. 2023; 24: 3321.
variant, in the temporal pole in semantic dementia, and in [2] Obergassel J, Lohmann L, Meuth SG, Wiendl H, Grauer O,
the premotor cortex in non-fluent primary progressive apha- Nelke C. An enigmatic case of cortical anopsia: Antemortem
diagnosis of a 14-3-3 negative Heidenhain-variant MM1-sCJD.
sia, correlating neuroinflammation to the location of pathol- Prion. 2020; 14: 24–28.
ogy [119]. However, the results are not uniform in PD pa- [3] Perugini P, Hassan K, Genta I, Modena T, Pavanetto F, Cetta G,
tients. et al. Intracellular delivery of liposome-encapsulated prolidase
in cultured fibroblasts from prolidase-deficient patients. Journal
7. Conclusions of Controlled Release. 2005; 102: 181–190.
[4] Biel D, Luan Y, Brendel M, Hager P, Dewenter A, Moscoso A,
The molecular imaging of NDs provided by PET et al. Combining tau-PET and fMRI meta-analyses for patient-
imaging enables the in vivo evaluation of specific molecular centered prediction of cognitive decline in Alzheimer’s disease.
pathways with novel radiopharmaceuticals for personalized Alzheimer’s Research & Therapy. 2022; 14: 166.
[5] Caballero MÁA, Song Z, Rubinski A, Duering M, Dichgans M,
patient care. [18 F]FDG still remains the standard among
Park DC, et al. Age-dependent amyloid deposition is associated
tracers, due to its intrinsic molecular properties. As an ana- with white matter alterations in cognitively normal adults during
logue of glucose, this tracer can clearly identify cortical and the adult life span. Alzheimer’s & Dementia. 2020; 16: 651–
subcortical functional changes in patients with cognitive 661.
impairment and/or movement disorders. Amyloid tracers [6] Piekut T, Hurła M, Banaszek N, Szejn P, Dorszewska J, Kozub-
ski W, et al. Infectious agents and Alzheimer’s disease. Journal
are becoming a reference tool in the clinical management of
of Integrative Neuroscience. 2022; 21: 73.
dementia, due to the high specificity. Potential added value [7] Ito M, Hatazawa J, Yamaura H, Matsuzawa T. Age-related brain
could be provided in the future imaging of the τ protein, in atrophy and mental deterioration–a study with computed tomog-
order to explore multiple physiopathological features of the raphy. The British Journal of Radiology. 1981; 54: 384–390.
diseases under study. In selected patients with movement [8] Ota M, Nemoto K, Nemoto M, Numata Y, Kitabatake A, Ya-
mada Y, et al. Structural Cerebral Network Differences in
disorders, [18 F]FDOPA still plays an effective role in the
Prodromal Alzheimer’s Disease and Prodromal Dementia with
assessment and monitoring of the disease over time. Lewy Bodies. Dementia and Geriatric Cognitive Disorders.
2022; 51: 421–427.
Author Contributions [9] Risacher SL, Apostolova LG. Neuroimaging in Dementia. Con-
tinuum. 2023; 29: 219–254.
FC designed the paper, and wrote the text. ML wrote [10] Tyler SEB, Tyler LDK. Pathways to healing: Plants with ther-
the hybrid imaging section, made figures, figure legends, apeutic potential for neurodegenerative diseases. IBRO Neuro-
and bibliographic research. AC, MR, and LT made bib- science Reports. 2023; 14: 210–234.
liographic research on tau, translocator protein and amy- [11] Young PNE, Estarellas M, Coomans E, Srikrishna M, Beaumont
loid imaging. AB conducted bibliographic research on H, Maass A, et al. Imaging biomarkers in neurodegeneration:
current and future practices. Alzheimer’s Research & Therapy.
[18 F]FDOPA and [18 F]Fluorodeoxyglucose imaging. All 2020; 12: 49.
authors read and approved the final manuscript. All authors [12] Yan S, Zheng C, Cui B, Qi Z, Zhao Z, An Y, et al. Multiparamet-
contributed to editorial changes in the manuscript. All au- ric imaging hippocampal neurodegeneration and functional con-

10
 nectivity with simultaneous PET/MRI in Alzheimer’s disease. L, et al. Individual cerebral metabolic deficits in Alzheimer’s
Eur J Nucl Med Mol Imaging. 2020;47:2440–2452. disease and amnestic mild cognitive impairment: an FDG PET
[13] Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode study. European Journal of Nuclear Medicine and Molecular
network activity distinguishes Alzheimer’s disease from healthy Imaging. 2008; 35: 1357–1366.
aging: evidence from functional MRI. Proceedings of the Na- [30] Liu YS, Wang YM, Zha DJ. Brain Functional and Structural
tional Academy of Sciences of the United States of America. Changes in Alzheimer’s Disease With Sleep Disorders: A Sys-
2004; 101: 4637–4642. tematic Review. Frontiers in Psychiatry. 2021; 12: 772068.
[14] Dijsselhof MBJ, Barboure M, Stritt M, Nordhøy W, Wink AM, [31] Jack CR, Jr, Dickson DW, Parisi JE, Xu YC, Cha RH, O’Brien
Beck D, et al. The value of arterial spin labelling perfusion MRI PC, et al. Antemortem MRI findings correlate with hippocampal
in brain age prediction. Human Brain Mapping. 2023; 44: 2754– neuropathology in typical aging and dementia. Neurology. 2002;
2766. 58: 750–757.
[15] Puig O, Henriksen OM, Vestergaard MB, Hansen AE, Andersen [32] Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR,
FL, Ladefoged CN, et al. Comparison of simultaneous arterial Jr, Weiner MW, et al. Robust atrophy rate measurement in
spin labeling MRI and 15 O-H2 O PET measurements of regional Alzheimer’s disease using multi-site serial MRI: tissue-specific
cerebral blood flow in rest and altered perfusion states. Journal intensity normalization and parameter selection. NeuroImage.
of Cerebral Blood Flow and Metabolism. 2020; 40: 1621–1633. 2010; 50: 516–523.
[16] Sokoloff L. Relation between physiological function and energy [33] Hohenfeld C, Werner CJ, Reetz K. Resting-state connectivity in
metabolism in the central nervous system. Journal of Neuro- neurodegenerative disorders: Is there potential for an imaging
chemistry. 1977; 29: 13–26. biomarker? NeuroImage. Clinical. 2018; 18: 849–870.
[17] Gallucci M, Limbucci N, Catalucci A, Caulo M. Neurodegener- [34] Kufer J, Preibisch C, Epp S, Göttler J, Schmitzer L, Zimmer C, et
ative diseases. Radiologic Clinics of North America. 2008; 46: al. Imaging effective oxygen diffusivity in the human brain with
799–817, vii. multiparametric magnetic resonance imaging. Journal of Cere-
[18] Coleman RE. Positron emission tomography diagnosis of bral Blood Flow and Metabolism. 2022; 42: 349–363.
Alzheimer’s disease. Neuroimaging Clinics of North America. [35] Alsop DC, Detre JA, Grossman M. Assessment of cerebral blood
2005; 15: 837–846, x. flow in Alzheimer’s disease by spin-labeled magnetic resonance
[19] Silverman DHS, Alavi A. PET imaging in the assessment of imaging. Annals of Neurology. 2000; 47: 93–100.
normal and impaired cognitive function. Radiologic Clinics of [36] Rakheja R, Chandarana H, Ponzo F, Seltzer AL, Beltran LS,
North America. 2005; 43: 67–77, x. Geppert C, et al. Fluorodeoxyglucose positron emission tomog-
[20] Mérida I, Jung J, Bouvard S, Le Bars D, Lancelot S, Lavenne F, raphy/magnetic resonance imaging: current status, future as-
et al. CERMEP-IDB-MRXFDG: a database of 37 normal adult pects. PET Clinics. 2014; 9: 237–252.
human brain [18 F]FDG PET, T1 and FLAIR MRI, and CT im- [37] Verfaillie SCJ, Adriaanse SM, Binnewijzend MAA, Benedictus
ages available for research. EJNMMI Research. 2021; 11: 91. MR, Ossenkoppele R, Wattjes MP, et al. Cerebral perfusion and
[21] Calabria FF, Cascini GL, Gambardella A, Labate A, Cherubini glucose metabolism in Alzheimer’s disease and frontotemporal
A, Gullà D, et al. Ictal 18F-FDG PET/MRI in a Patient With Cor- dementia: two sides of the same coin? European Radiology.
tical Heterotopia and Focal Epilepsy. Clinical Nuclear Medicine. 2015; 25: 3050–3059.
2017; 42: 768–769. [38] Steketee RME, Bron EE, Meijboom R, Houston GC, Klein S,
[22] Withofs N, Kumar R, Alavi A, Hustinx R. Facts and Fictions Mutsaerts HJMM, et al. Early-stage differentiation between pre-
About [18 F]FDG versus Other Tracers in Managing Patients senile Alzheimer’s disease and frontotemporal dementia using
with Brain Tumors: It Is Time to Rectify the Ongoing Miscon- arterial spin labeling MRI. European Radiology. 2016; 26: 244–
ceptions. PET Clinics. 2022; 17: 327–342. 253.
[23] Chételat G, Arbizu J, Barthel H, Garibotto V, Law I, Morbelli S, [39] Tahmasian M, Pasquini L, Scherr M, Meng C, Förster S, Mulej
et al. Amyloid-PET and 18 F-FDG-PET in the diagnostic investi- Bratec S, et al. The lower hippocampus global connectivity, the
gation of Alzheimer’s disease and other dementias. The Lancet. higher its local metabolism in Alzheimer disease. Neurology.
Neurology. 2020; 19: 951–962. 2015; 84: 1956–1963.
[24] Brown RKJ, Bohnen NI, Wong KK, Minoshima S, Frey KA. [40] Živanović M, Aracki Trenkić A, Milošević V, Stojanov D, Mišić
Brain PET in suspected dementia: patterns of altered FDG M, Radovanović M, et al. The role of magnetic resonance imag-
metabolism. Radiographics. 2014; 34: 684–701. ing in the diagnosis and prognosis of dementia. Biomolecules &
[25] Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon Biomedicine. 2023; 23: 209–224.
MJ. Pre-clinical detection of Alzheimer’s disease using FDG- [41] Du AT, Jahng GH, Hayasaka S, Kramer JH, Rosen HJ, Gorno-
PET, with or without amyloid imaging. Journal of Alzheimer’s Tempini ML, et al. Hypoperfusion in frontotemporal dementia
Disease. 2010; 20: 843–854. and Alzheimer disease by arterial spin labeling MRI. Neurology.
[26] Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne 2006; 67: 1215–1220.
O, Sachpekidis C. 18 F-FDG PET for the early diagnosis of [42] Anazodo UC, Finger E, Kwan BYM, Pavlosky W, Warrington
Alzheimer’s disease dementia and other dementias in people JC, Günther M, et al. Using simultaneous PET/MRI to compare
with mild cognitive impairment (MCI). The Cochrane Database the accuracy of diagnosing frontotemporal dementia by arterial
of Systematic Reviews. 2015; 1: CD010632. spin labelling MRI and FDG-PET. NeuroImage. Clinical. 2017;
[27] Bergeron D, Beauregard JM, Soucy JP, Verret L, Poulin 17: 405–414.
S, Matias-Guiu JA, et al. Posterior Cingulate Cortex Hy- [43] Pillai JA, Wu G, Tousi B, Larvie M, Léger GC, Leverenz JB.
pometabolism in Non-Amnestic Variants of Alzheimer’s Dis- Amygdala sign, a FDG-PET signature of dementia with Lewy
ease. Journal of Alzheimer’s Disease. 2020; 77: 1569–1577. Bodies. Parkinsonism & Related Disorders. 2019; 64: 300–303.
[28] Choo IH, Lee DY, Youn JC, Jhoo JH, Kim KW, Lee DS, et al. [44] Zorzi G, Cecchin D, Bussè C, Perini G, Corbetta M, Cagnin
Topographic patterns of brain functional impairment progres- A. Changes of Metabolic Connectivity in Dementia with Lewy
sion according to clinical severity staging in 116 Alzheimer dis- Bodies with Visual Hallucinations: A 18 F-Fluorodeoxyglucose
ease patients: FDG-PET study. Alzheimer Disease and Associ- Positron Emission Tomography/Magnetic Resonance Study.
ated Disorders. 2007; 21: 77–84. Brain Connectivity. 2021; 11: 518–528.
[29] Del Sole A, Clerici F, Chiti A, Lecchi M, Mariani C, Maggiore [45] Peet BT, Spina S, Mundada N, La Joie R. Neuroimaging in

11
 Frontotemporal Dementia: Heterogeneity and Relationships Peller PJ. Structural and functional imaging in parkinsonian syn-
with Underlying Neuropathology. Neurotherapeutics. 2021; 18: dromes. Radiographics. 2014; 34: 1273–1292.
728–752. [63] Koyama M, Yagishita A, Nakata Y, Hayashi M, Bandoh M,
[46] Foster NL. Validating FDG-PET as a biomarker for frontotem- Mizutani T. Imaging of corticobasal degeneration syndrome.
poral dementia. Experimental Neurology. 2003; 184: S2–S8. Neuroradiology. 2007; 49: 905–912.
[47] Beyer L, Meyer-Wilmes J, Schönecker S, Schnabel J, Sauer- [64] Savoiardo M. Differential diagnosis of Parkinson’s disease and
beck J, Scheifele M, et al. Cognitive reserve hypothesis in fron- atypical parkinsonian disorders by magnetic resonance imaging.
totemporal dementia: A FDG-PET study. NeuroImage. Clinical. Neurological Sciences. 2003; 24: S35–S37.
2021; 29: 102535. [65] Amtage F, Maurer C, Hellwig S, Tüscher O, Kreft A, Weiller
[48] Ducharme S, Dols A, Laforce R, Devenney E, Kumfor F, C, et al. Functional correlates of vertical gaze palsy and other
van den Stock J, et al. Recommendations to distinguish be- ocular motor deficits in PSP: an FDG-PET study. Parkinsonism
havioural variant frontotemporal dementia from psychiatric dis- & Related Disorders. 2014; 20: 898–906.
orders. Brain. 2020; 143: 1632–1650. [66] Park HK, Kim JS, Im KC, Oh SJ, Kim MJ, Lee JH, et al. Func-
[49] Yousaf T, Dervenoulas G, Valkimadi PE, Politis M. Neuroimag- tional brain imaging in pure akinesia with gait freezing: [18F]
ing in Lewy body dementia. Journal of Neurology. 2019; 266: FDG PET and [18F] FP-CIT PET analyses. Movement Disor-
1–26. ders. 2009; 24: 237–245.
[50] Burton EJ, Karas G, Paling SM, Barber R, Williams ED, Ballard [67] Roh JH, Suh MK, Kim EJ, Go SM, Na DL, Seo SW. Glucose
CG, et al. Patterns of cerebral atrophy in dementia with Lewy metabolism in progressive nonfluent aphasia with and without
bodies using voxel-based morphometry. NeuroImage. 2002; 17: parkinsonism. Neurology. 2010; 75: 1022–1024.
618–630. [68] Beyer L, Meyer-Wilmes J, Schönecker S, Schnabel J, Brendel E,
[51] Blanc F, Colloby SJ, Cretin B, de Sousa PL, Demuynck C, Prix C, et al. Clinical Routine FDG-PET Imaging of Suspected
O’Brien JT, et al. Grey matter atrophy in prodromal stage of de- Progressive Supranuclear Palsy and Corticobasal Degeneration:
mentia with Lewy bodies and Alzheimer’s disease. Alzheimer’s A Gatekeeper for Subsequent Tau-PET Imaging? Frontiers in
Research & Therapy. 2016; 8: 31. Neurology. 2018; 9: 483.
[52] Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, [69] Hu X, Sun X, Hu F, Liu F, Ruan W, Wu T, et al. Multivari-
O’Brien JT. Medial temporal lobe atrophy on MRI in demen- ate radiomics models based on 18 F-FDG hybrid PET/MRI for
tia with Lewy bodies. Neurology. 1999; 52: 1153–1158. distinguishing between Parkinson’s disease and multiple system
[53] Ceccarini J, Bourgeois S, Van Weehaeghe D, Goffin K, Vanden- atrophy. European Journal of Nuclear Medicine and Molecular
berghe R, Vandenbulcke M, et al. Direct prospective comparison Imaging. 2021; 48: 3469–3481.
of 18 F-FDG PET and arterial spin labelling MR using simulta- [70] Kim J, Choi KH, Song HC, Kim JT, Park MS, Cho KH. 18 F-FDG
neous PET/MR in patients referred for diagnosis of dementia. PET/CT imaging factors that predict ischaemic stroke in cancer
European Journal of Nuclear Medicine and Molecular Imaging. patients. European Journal of Nuclear Medicine and Molecular
2020; 47: 2142–2154. Imaging. 2016; 43: 2228–2235.
[54] Garraux G, Phillips C, Schrouff J, Kreisler A, Lemaire C, [71] Calabria F, Ciccariello G, Falcone C, Cascini GL, Schillaci O. A
Degueldre C, et al. Multiclass classification of FDG PET scans case of Fahr’s disease examined by multi-modal imaging. Euro-
for the distinction between Parkinson’s disease and atypical pean Journal of Nuclear Medicine and Molecular Imaging. 2015;
parkinsonian syndromes. NeuroImage. Clinical. 2013; 2: 883– 42: 2098–2099.
893. [72] Timmers ER, Klamer MR, Marapin RS, Lammertsma AA, de
[55] Calabria FF, Calabria E, Gangemi V, Cascini GL. Current status Jong BM, Dierckx RAJO, et al. [18 F]FDG PET in conditions
and future challenges of brain imaging with (18)F-DOPA PET associated with hyperkinetic movement disorders and ataxia: a
for movement disorders. Hellenic Journal of Nuclear Medicine. systematic review. European Journal of Nuclear Medicine and
2016; 19: 33–41. Molecular Imaging. 2023; 50: 1954–1973.
[56] Meyer PT, Frings L, Rücker G, Hellwig S. 18 F-FDG PET in [73] Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt
Parkinsonism: Differential Diagnosis and Evaluation of Cogni- DP, et al. Imaging brain amyloid in Alzheimer’s disease with
tive Impairment. Journal of Nuclear Medicine. 2017; 58: 1888– Pittsburgh Compound-B. Annals of Neurology. 2004; 55: 306–
1898. 319.
[57] Akdemir ÜÖ, Tokçaer AB, Karakuş A, Kapucu LÖ. Brain 18F- [74] Trembath L, Newell M, Devous MD, Sr. Technical Considera-
FDG PET imaging in the differential diagnosis of parkinsonism. tions in Brain Amyloid PET Imaging with 18F-Florbetapir. Jour-
Clinical Nuclear Medicine. 2014; 39: e220–e226. nal of Nuclear Medicine Technology. 2015; 43: 175–184.
[58] Eggers C, Schwartz F, Pedrosa DJ, Kracht L, Timmermann [75] Müller EG, Edwin TH, Strand BH, Stokke C, Revheim
L. Parkinson’s disease subtypes show a specific link between ME, Knapskog AB. Is Amyloid Burden Measured by 18F-
dopaminergic and glucose metabolism in the striatum. PLoS Flutemetamol PET Associated with Progression in Clinical
ONE. 2014; 9: e96629. Alzheimer’s Disease? Journal of Alzheimer’s Disease. 2022; 85:
[59] Piro A, Tagarelli A, Nicoletti G, Fletcher R, Quattrone A. Color 197–205.
vision impairment in Parkinson’s disease. Journal of Parkinson’s [76] Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE,
Disease. 2014; 4: 317–319. Doraiswamy PM, et al. Cerebral PET with florbetapir com-
[60] Walker Z, Gandolfo F, Orini S, Garibotto V, Agosta F, Ar- pared with neuropathology at autopsy for detection of neuritic
bizu J, et al. Clinical utility of FDG PET in Parkinson’s disease amyloid-β plaques: a prospective cohort study. The Lancet.
and atypical parkinsonism associated with dementia. European Neurology. 2012; 11: 669–678.
Journal of Nuclear Medicine and Molecular Imaging. 2018; 45: [77] Curtis C, Gamez JE, Singh U, Sadowsky CH, Villena T, Sabbagh
1534–1545. MN, et al. Phase 3 trial of flutemetamol labeled with radioactive
[61] Constantinides VC, Paraskevas GP, Paraskevas PG, Stefanis fluorine 18 imaging and neuritic plaque density. JAMA Neurol-
L, Kapaki E. Corticobasal degeneration and corticobasal syn- ogy. 2015; 72: 287–294.
drome: A review. Clinical Parkinsonism & Related Disorders. [78] Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y,
2019; 1: 66–71. et al. Florbetaben PET imaging to detect amyloid beta plaques
[62] Broski SM, Hunt CH, Johnson GB, Morreale RF, Lowe VJ, in Alzheimer’s disease: phase 3 study. Alzheimer’s & Dementia.

12
 2015; 11: 964–974. Molecular Imaging. 2015; 42: 1062–1070.
[79] Kolanko MA, Win Z, Loreto F, Patel N, Carswell C, Gontsarova [97] Hilker R, Schweitzer K, Coburger S, Ghaemi M, Weisenbach S,
A, et al. Amyloid PET imaging in clinical practice. Practical Jacobs AH, et al. Nonlinear progression of Parkinson disease as
Neurology. 2020; 20: 451–462. determined by serial positron emission tomographic imaging of
[80] Filippi L, Chiaravalloti A, Bagni O, Schillaci O. 18 F-labeled ra- striatal fluorodopa F 18 activity. Archives of Neurology. 2005;
diopharmaceuticals for the molecular neuroimaging of amyloid 62: 378–382.
plaques in Alzheimer’s disease. American Journal of Nuclear [98] Nurmi E, Ruottinen HM, Bergman J, Haaparanta M, Solin O,
Medicine and Molecular Imaging. 2018; 8: 268–281. Sonninen P, et al. Rate of progression in Parkinson’s disease:
[81] Ricci M, Cimini A, Chiaravalloti A, Filippi L, Schillaci O. a 6-[18F]fluoro-L-dopa PET study. Movement Disorders. 2001;
Positron Emission Tomography (PET) and Neuroimaging in the 16: 608–615.
Personalized Approach to Neurodegenerative Causes of Demen- [99] Pal PK, Leung J, Hedrich K, Samii A, Lieberman A, Nausieda
tia. International Journal of Molecular Sciences. 2020; 21: 7481. PA, et al. [18F]-Dopa positron emission tomography imaging in
[82] Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, early-stage, non-parkin juvenile parkinsonism. Movement Dis-
Chiotis K, et al. Strategic roadmap for an early diagnosis of orders. 2002; 17: 789–794.
Alzheimer’s disease based on biomarkers. The Lancet. Neurol- [100] Otsuka M, Ichiya Y, Hosokawa S, Kuwabara Y, Tahara T,
ogy. 2017; 16: 661–676. Fukumura T, et al. Striatal blood flow, glucose metabolism and
[83] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee 18F-dopa uptake: difference in Parkinson’s disease and atypical
M, et al. Lecanemab in Early Alzheimer’s Disease. The New parkinsonism. Journal of Neurology, Neurosurgery, and Psychi-
England Journal of Medicine. 2023; 388: 9–21. atry. 1991; 54: 898–904.
[84] Schöll M, Maass A, Mattsson N, Ashton NJ, Blennow K, Zetter- [101] Sawle GV, Brooks DJ, Marsden CD, Frackowiak RS. Cor-
berg H, et al. Biomarkers for tau pathology. Molecular and Cel- ticobasal degeneration. A unique pattern of regional cortical
lular Neurosciences. 2019; 97: 18–33. oxygen hypometabolism and striatal fluorodopa uptake demon-
[85] Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the strated by positron emission tomography. Brain. 1991; 114:
pathologic process in Alzheimer disease: age categories from 1 541–556.
to 100 years. Journal of Neuropathology and Experimental Neu- [102] Goldstein DS, Holmes C, Bentho O, Sato T, Moak J, Sharabi
rology. 2011; 70: 960–969. Y, et al. Biomarkers to detect central dopamine deficiency and
[86] Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, distinguish Parkinson disease from multiple system atrophy.
Rodriguez-Vieitez E, et al. Tau PET imaging in neurodegener- Parkinsonism & Related Disorders. 2008; 14: 600–607.
ative tauopathies-still a challenge. Molecular Psychiatry. 2019; [103] Scherfler C, Esterhammer R, Nocker M, Mahlknecht P, Stock-
24: 1112–1134. ner H, Warwitz B, et al. Correlation of dopaminergic terminal
[87] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A dysfunction and microstructural abnormalities of the basal gan-
protein factor essential for microtubule assembly. Proceedings glia and the olfactory tract in Parkinson’s disease. Brain. 2013;
of the National Academy of Sciences of the United States of 136: 3028–3037.
America. 1975; 72: 1858–1862. [104] Nissen T, Malek N, Grosset KA, Newman EJ, Patterson J,
[88] Prezel E, Elie A, Delaroche J, Stoppin-Mellet V, Bosc C, Serre Hadley D, et al. Baseline [(123) I]FP-CIT SPECT (DaTSCAN)
L, et al. Tau can switch microtubule network organizations: severity correlates with medication use at 3 years in Parkinson’s
from random networks to dynamic and stable bundles. Molecu- disease. Acta Neurologica Scandinavica. 2014; 129: 204–208.
lar Biology of the Cell. 2018; 29: 154–165. [105] Eshuis SA, Jager PL, Maguire RP, Jonkman S, Dierckx RA,
[89] Fleisher AS, Pontecorvo MJ, Devous MD, Sr, Lu M, Arora Leenders KL. Direct comparison of FP-CIT SPECT and F-
AK, Truocchio SP, et al. Positron Emission Tomography Imag- DOPA PET in patients with Parkinson’s disease and healthy
ing With [18F]flortaucipir and Postmortem Assessment of controls. European Journal of Nuclear Medicine and Molecular
Alzheimer Disease Neuropathologic Changes. JAMA Neurol- Imaging. 2009; 36: 454–462.
ogy. 2020; 77: 829–839. [106] Ishikawa T, Dhawan V, Kazumata K, Chaly T, Mandel F,
[90] Jie CVML, Treyer V, Schibli R, Mu L. TauvidTM : The First Neumeyer J, et al. Comparative nigrostriatal dopaminergic
FDA-Approved PET Tracer for Imaging Tau Pathology in imaging with iodine-123-beta CIT-FP/SPECT and fluorine-18-
Alzheimer’s Disease. Pharmaceuticals. 2021; 14: 110. FDOPA/PET. Journal of Nuclear Medicine. 1996; 37: 1760–
[91] Ossenkoppele R, van der Kant R, Hansson O. Tau biomarkers in 1765.
Alzheimer’s disease: towards implementation in clinical prac- [107] Kuten J, Linevitz A, Lerman H, Freedman N, Kestenbaum M,
tice and trials. The Lancet. Neurology. 2022; 21: 726–734. Shiner T, et al. [18F] FDOPA PET may confirm the clinical diag-
[92] Smith R, Schöll M, Londos E, Ohlsson T, Hansson O. 18 F-AV- nosis of Parkinson’s disease by imaging the nigro-striatal path-
1451 in Parkinson’s Disease with and without dementia and in way and the sympathetic cardiac innervation: Proof-of-concept
Dementia with Lewy Bodies. Scientific Reports. 2018; 8: 4717. study. Journal of Integrative Neuroscience. 2020; 19: 489–494.
[93] Irwin DJ, Lee VMY, Trojanowski JQ. Parkinson’s disease [108] Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, La-
dementia: convergence of α-synuclein, tau and amyloid-β capère JJ, Lindemann P, et al. Translocator protein (18kDa):
pathologies. Nature Reviews. Neuroscience. 2013; 14: 626– new nomenclature for the peripheral-type benzodiazepine recep-
636. tor based on its structure and molecular function. Trends in Phar-
[94] Pavese N, Kiferle L, Piccini P. Neuroprotection and imaging macological Sciences. 2006; 27: 402–409.
studies in Parkinson’s disease. Parkinsonism & Related Disor- [109] Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L,
ders. 2009; 15: S33–S37. Weisinger G, et al. Enigma of the peripheral benzodiazepine re-
[95] Darcourt J, Schiazza A, Sapin N, Dufour M, Ouvrier MJ, ceptor. Pharmacological Reviews. 1999; 51: 629–650.
Benisvy D, et al. 18F-FDOPA PET for the diagnosis of parkin- [110] Olson JM, Ciliax BJ, Mancini WR, Young AB. Presence of
sonian syndromes. The Quarterly Journal of Nuclear Medicine peripheral-type benzodiazepine binding sites on human ery-
and Molecular Imaging. 2014; 58: 355–365. throcyte membranes. European Journal of Pharmacology. 1988;
[96] Picco A, Morbelli S, Piccardo A, Arnaldi D, Girtler N, Brug- 152: 47–53.
nolo A, et al. Brain (18)F-DOPA PET and cognition in de novo [111] Fan J, Rone MB, Papadopoulos V. Translocator protein 2 is in-
Parkinson’s disease. European Journal of Nuclear Medicine and volved in cholesterol redistribution during erythropoiesis. The

13
 Journal of Biological Chemistry. 2009; 284: 30484–30497. [118] Corica F, De Feo MS, Gorica J, Sidrak MMA, Conte M, Filippi
[112] Morin D, Musman J, Pons S, Berdeaux A, Ghaleh B. Mito- L, et al. PET Imaging of Neuro-Inflammation with Tracers Tar-
chondrial translocator protein (TSPO): From physiology to car- geting the Translocator Protein (TSPO), a Systematic Review:
dioprotection. Biochemical Pharmacology. 2016; 105: 1–13. From Bench to Bedside. Diagnostics. 2023; 13: 1029.
[113] Nutma E, Ceyzériat K, Amor S, Tsartsalis S, Millet P, Owen [119] Masdeu JC, Pascual B, Fujita M. Imaging Neuroinflammation
DR, et al. Cellular sources of TSPO expression in healthy in Neurodegenerative Disorders. Journal of Nuclear Medicine.
and diseased brain. European Journal of Nuclear Medicine and 2022; 63: 45S–52S.
Molecular Imaging. 2021; 49: 146–163. [120] Wimberley C, Lavisse S, Hillmer A, Hinz R, Turkheimer F,
[114] Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): Zanotti-Fregonara P. Kinetic modeling and parameter estimation
molecular sensor of brain injury and repair. Pharmacology & of TSPO PET imaging in the human brain. European Journal of
Therapeutics. 2008; 118: 1–17. Nuclear Medicine and Molecular Imaging. 2021; 49: 246–256.
[115] Guilarte TR. TSPO in diverse CNS pathologies and psychiatric [121] Zanotti-Fregonara P, Pascual B, Rizzo G, Yu M, Pal N, Beers
disease: A critical review and a way forward. Pharmacology & D, et al. Head-to-Head Comparison of 11 C-PBR28 and 18 F-
Therapeutics. 2019; 194: 44–58. GE180 for Quantification of the Translocator Protein in the Hu-
[116] Mattner F, Staykova M, Berghofer P, Wong HJ, Fordham S, man Brain. Journal of Nuclear Medicine. 2018; 59: 1260–1266.
Callaghan P, et al. Central nervous system expression and PET [122] Cogswell PM, Fan AP. Multimodal comparisons of QSM and
imaging of the translocator protein in relapsing-remitting ex- PET in neurodegeneration and aging. NeuroImage. 2023; 273:
perimental autoimmune encephalomyelitis. Journal of Nuclear 120068.
Medicine. 2013; 54: 291–298. [123] Toppala S, Ekblad LL, Tuisku J, Helin S, Johansson JJ, Laine
[117] Werry EL, Bright FM, Piguet O, Ittner LM, Halliday GM, H, et al. Association of Early β -Amyloid Accumulation and
Hodges JR, et al. Recent Developments in TSPO PET Imag- Neuroinflammation Measured With [11 C]PBR28 in Elderly In-
ing as A Biomarker of Neuroinflammation in Neurodegenerative dividuals Without Dementia. Neurology. 2021; 96: e1608–
Disorders. International Journal of Molecular Sciences. 2019; e1619.
20: 3161.

14