The present monographic issue of the Quarterly Journal of Nuclear Medicine and Molecular Imaging is dedicated to the role of functional imaging in the broad field of neurodegenerative disorders, with a special focus on some of the most relevant topics of the last decades, of the present time and of the near future. Functional neuroimaging is close to reach the time in which it will be routinely implemented in clinical practice and in which the principles of "molecular imaging" will aid clinical diagnosis disclosing the fine extra- and intracellular deposit of protein aggregates and neuroinflammation markers. The almost simultaneous advancement in nuclear medicine techniques, i.e., PET-MRI, along with the development of new tracers and the implementation of more and more sophisticated image analysis software will assign to neuroimaging a preeminent role in the diagnostic algorithm both in neurological and psychiatric practice

Capriotti, G

Pagani, Marco

Sonni, I

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AFFILIATED TO
THE SOCIETY OF RADIOPHARMACEUTICAL SCIENCES
THE INTERNATIONAL RESEARCH GROUP OF IMMUNOSCINTIGRAPHY AND THERAPY ( IRIST)
Vol. 58 - No. 4 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 329
and of our present time is 18F-FDG-PET, which is 
undoubtedly one of our giants. It still plays a key 
role in brain imaging, and most certainly it will in 
the near future. 
Karl Herholz in his review aims at providing a valu-
able guidance to physicians reading brain 18F-FDG-
PET scans in neurodegenerative disorders by describ-
ing the criteria for data acquisition and reconstruction 
protocols. The characteristic findings of Alzheimer-
related hypometabolism are described and compared 
with other related pathological conditions. This com-
plete review gives also tips on how to display the 
scans as well as a detailed description of the patterns 
of 18F-FDG distribution in the most common dement-
ing disorders. It is an exhaustive compendium for all 
physicians interested in neuroimaging.
FDG-PET and MRI have extensively been used to 
investigate the functional and anatomical changes, 
respectively, occurring in patients with amyotrophic 
lateral sclerosis (ALS).1 The review by Quartuccio et 
al. describes how PET, which has not been used yet 
in clinical routine for the evaluation of patients with 
ALS, can be used as a potential tool in the diagnos-
tic algorithm of the disease. Recent studies 2, 3 sug-
gested a possible role of FDG-PET as ALS biomarker 
highlighting the need, common to all neuroimaging 
1Institute of Cognitive Sciences and Technologies
CNR, Rome, Italy 
2Nuclear Medicine Unit
Department of Medical-Surgical Sciences
and Translational Medicine
Faculty of Medicine and Psychology
“Sapienza” University, Rome, Italy
M. PAGANI 1, I. SONNI 2, G. CAPRIOTTI 2
Functional imaging in neurodegenerative disorders:
past, present and future
[…] we are like dwarves perched on the shoulders of giants, 
and thus we are able to see more and farther than the latter. 
And this is not at all because of the acuteness of our sight
 or the stature of our body, but because we are carried aloft
 and elevated by the magnitude of the giants […] 
Bernard of Chartres 
The present monographic issue of the Quarterly Journal of Nuclear Medicine and Molecular Im-
aging is dedicated to the role of functional imaging 
in the broad field of neurodegenerative disorders, 
with a special focus on some of the most relevant 
topics of the last decades, of the present time and 
of the near future. Functional neuroimaging is close 
to reach the time in which it will be routinely im-
plemented in clinical practice and in which the 
principles of “molecular imaging” will aid clinical 
diagnosis disclosing the fine extra- and intracellular 
deposit of protein aggregates and neuroinflamma-
tion markers. The almost simultaneous advancement 
in nuclear medicine techniques, i.e., PET-MRI, along 
with the development of new tracers and the im-
plementation of more and more sophisticated im-
age analysis software will assign to neuroimaging a 
preeminent role in the diagnostic algorithm both in 
neurological and psychiatric practice.
To reconnect with the introductive quote by Ber-
nard of Chartres, from our point of view nuclear 
medicine has also “giants and dwarves”. The undis-
puted ruler in nuclear medicine for the past decades 
Corresponding author: M. Pagani, Institute of Cognitive Sciences and 
Technologies, CNR, Rome, Italy.
Anno: 2014
Mese: December
Volume: 58
No: 4
Rivista: THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Cod Rivista: Q J NUCL MED MOL IMAGING
Lavoro: 2777-JNU
titolo breve: Functional imaging in neurodegenerative disorders: past, present and future
primo autore: PAGANI
pagine: 329-31
PET IN NEURODEGENERATIVE DISORDERS
Guest Editor: M. Pagani and G. Capriotti
EDITORIAL
Q J NUCL MED MOL IMAGING 2014;58:329-31
PAGANI FUNCTIONAL IMAGING IN NEURODEGENERATIVE DISORDERS: PAST, PRESENT AND FUTURE
330 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING December 2014
tant role in cognitive functions.10, 11 The authors also 
examined the relationship between nAChRs avail-
ability, cognitive impairment and motor/non-motor 
symptoms in AD and PD respectively. Future direc-
tions of research in the imaging of the cholinergic 
system are oriented to the development of new ra-
dioligands targeting the α4β 2 subtype with more 
favorable characteristics, or to other interesting sub-
types of nAChR, such as the α6 subunit, which plays 
an important role in the modulation of the dopami-
nergic system, and the α7 subunit. 
A new interesting perspective on disclosing the 
neurobiology of neurodegenerative disorders is 
given by the group from Fukui. Okazawa and col-
leagues describe oxidative stress and mitochondrial 
dysfunction as the most probable molecular mecha-
nisms involved in the neuronal impairment of sever-
al neurodegenerative disorders. The ability of some 
PET radioligands, the most promising being Cu-la-
beled ATSM, of imaging in vivo the pathophysiologi-
cal changes occurring in the brain areas exposed to 
oxidative stress is very intriguing as well as the pos-
sibility to investigate such conditions from a novel 
point of view. Despite only a few studies have been 
conducted in this field so far, this is a very interest-
ing direction for research in the near future. 
We end the overview with the paper dedicated to 
Aβ and tau imaging in dementia, the very hot topic 
in neuroimaging of the present time and definitely 
of the near future. Several efforts have been made in 
the last decade to develop tracers allowing in vivo vi-
sualization of the two pathological hallmarks of AD, 
namely extracellular amyloid plaques 12 (consisting of 
insoluble fibrillary β-amyloid peptides) and intracel-
lular tau aggregates, the neurofibrillary tangles (NFT). 
Zwan and colleagues, of the group of Villemagne 
in Melbourne, describe the long path which led to 
the development of PET selective Aβ radiotracers, 
selective tau radiotracers and also non-selective pan-
amyloid tracers, showing affinity for both Aβ plaques 
and NFT. While several studies have already been 
published on Aβ imaging, which is already moving 
into clinical practice, little has been written so far on 
the most recently developed tau radiotracers and the 
debate about their clinical utility and the preference 
torward either of them has just started. 
Functional imaging in the field of neurodegenerative 
disorders will most likely see progresses in leaps 
and bounds in the near future, we can’t wait to see 
them and to come to know who will be the next 
“giant”. 
studies, of recruiting large cohorts of patients, irre-
spectively if in a single center or in a multicenter 
study. This will result in robust statistics and will 
contribute to reliably describe metabolic patterns 
typical of neurodegenerative disorders to be used as 
biomarkers in clinical practice.
18F-DOPA could also be considered a giant hav-
ing been the most widely used 18F-labelled tracer 
for dopaminergic imaging for several years.4 Despite 
the “seniority” of 18F-DOPA the radiopharmaceuti-
cal is seldom used in the clinical daily practice. The 
aim of Darcourt and colleagues in their review is to 
demonstrate that 18F-DOPA is now mature for the 
purpose. The old debate about adaptive changes oc-
curring in early stages of Parkinson’s disease (i.e., 
up-regulation of the AADC enzyme), which could 
lead to an underestimation of the nigro-striatal loss 
in the early phases of the disease,4 is described in 
detail with the authors coming to the conclusion 
that the sensitivity of 18F-DOPA, is comparable to 
that of DaT imaging and therefore 18F-DOPA can be 
considered mature for the diagnosis of parkinsonian 
syndromes in clinical routine. 
The topic of the review written by Arnaldi et al. is 
the premotor phase of Parkinson’s disease (PD). The 
main non-motor symptoms of PD, such as hypos-
mia, mood alterations, REM sleep behavior disorder 
(RBD) and constipation, are described.5-8 Amongst 
them, RBD, given its low prevalence in the gener-
al population, is depicted as the best target for the 
identification of PD in the pre-motor phase, espe-
cially if present in association with other non-motor 
symptoms of PD.9 The correct identifications of PD 
patients in the pre-motor phase could facilitate the 
development of neuroprotective and neuromodula-
tory strategies in early stages of disease. The role 
of dopaminergic and non-dopaminergic imaging, as 
well as the study of cortical functions in pre-motor 
PD is described in the paper and, as a new future 
perspective, the authors introduce to the readers a 
very active area of research which is oriented to the 
development of specific radioligands for the imag-
ing of α-synuclein. 
The importance of the cholinergic system in the 
pathogenesis of AD and PD is extensively reviewed 
by the group of Sabri in Liepzig. The focus of Meyer 
et al. is basically oriented to the role of PET and 
SPECT in imaging the most abundant subtype of 
nicotinic acetylcholine receptors (nAChRs), the α4β 
2 subtype, which is expressed on the postsynaptic 
side of the cholinergic neurons and plays an impor-
FUNCTIONAL IMAGING IN NEURODEGENERATIVE DISORDERS: PAST, PRESENT AND FUTURE PAGANI
Vol. 58 - No. 4 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 331
 7. Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a 
parkinsonian disorder or dementia in 81% of older men initially 
diagnosed with idiopathic rapid eye movement sleep behavior 
disorder: a 16-year update on a previously reported series. Sleep 
Medicine 2013;14:744-8.
 8. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb 
JD et al. Frequency of bowel movements and the future risk of 
Parkinson’s disease. Neurology 2001;57:456-62. 
 9. Gaenslen A, Wurster I, Brockmann K, Huber H, Godau J, Faust 
B et al. Prodromal features for Parkinson’s disease - baseline 
data from the TREND study. European Journal of Neurology 
2014;21:766-72.
10. Gotti C and Clementi F. Neuronal nicotinic receptors: from struc-
ture to pathology. Prog Neurobiol. 2004;74:363-96.
11. Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott 
M et al. Nicotinic receptor subtypes in human brain age-
ing, Alzheimer and Lewy body diseases. Eur J Pharmacol 
2000;393:215-22.
12. Masters CL, Selkoe DJ. Biochemistry of amyloid beta-protein and 
amyloiddeposits in Alzheimer disease. Cold Spring Harb Per-
spect Med 2012;2:a006262.
References
 1. Chiò A, Pagani M, Agosta F, Calvo A, Cistaro A, Filippi M. Neuro 
imaging in Amyotrophic Lateral Sclerosis: insight into structural 
and functional changes. Lancet Neurol 2014;13:1228-40.
 2. Pagani M, Chio A, Valentini MC, Oberg J, Nobili F, Calvo A et 
al. Functional pattern of brain FDG-PET in amyotrophic lateral 
sclerosis. Neurology 2014;83:1067-74
 3. Van Laere K, Vanhee A, Verschueren J, De Coster L, Driesen A, 
Dupont P et al. Value of 18fluorodeoxyglucose-positron-emis-
sion tomography in amyotrophic lateral sclerosis: a prospective 
study. JAMA Neurol 2014;71:553-61.
 4. Varrone A, Halldin C. New developments of dopaminergic imaging 
in Parkinson’s disease. Q J Nucl Med Mol Imaging 2012;56:68-82.
 5. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BLF, Wolters EC, 
Berendse HW. Idiopathic hyposmia as a preclinical sign of Par-
kinson’s disease. Annals of Neurology 2004;56:173-81.
 6. Shiba M, Bower JH, Maraganore DM, McDonnell SK, Peterson 
BJ, Ahlskog JE et al. Anxiety disorders and depressive disorders 
preceding Parkinson’s disease: a case-control study. Movement 
Disorders 2000;15:669-77.
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Functional imaging in neurodegenerative disorders: past, present and future

Pagani M

SONNI, IDA

CAPRIOTTI, Gabriela

Archivio della ricerca- Università di Roma La Sapienza

Functional imaging in neurodegenerative disorders: past, present and future.

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Functional imaging in neurodegenerative disorders: past, present and future

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