Keywords: Parkinson Disease - Parkinsonian Disorders - Diffusion Tensor Imaging - Single Photon
Emission Computed Tomography Computed Tomography - Melanins - Magnetic Resonance Imaging
- Diffusion Magnetic Resonance Imaging
Palavras-chave: Doença de Parkinson - Transtornos Parkinsonianos - Imagem de Tensor de Difusão - Melaninas
- Imageamento por Ressonância Magnética - Imagem de Difusão por Ressonância Magnética
INTRODUCTION
Parkinson's disease (PD) represents the most common etiology of parkinsonism and the
second most common neurodegenerative disease, with an estimated global prevalence
of more than 9 million affected individuals[1 ]-[3 ]. Driven mainly by aging and additional factors such as increasing industrialization
and declining smoking rates, this number is expected to rise to over 17 million by
2040[4 ].
In recent years, there has been a significant advance in diagnosing PD, with novel
clinical diagnostic criteria and research criteria for the prodromal disease stage,
both proposed by the Movement Disorders Society (MDS)[5 ],[6 ]. Despite these updated criteria, clinical diagnosis can often still be challenging,
especially in earlier stages of the disease and if performed by nonexperts[7 ]-[9 ]. A previous clinicopathologic study by Hughes et al., which analyzed over 100 clinically
diagnosed patients with PD, showed a relevant misdiagnosis rate of 10%[10 ]. Moreover, Adler et al. demonstrated, among patients clinically diagnosed with PD
who underwent neuropathological examination, only 53% accuracy for a clinical diagnosis
of PD in an early disease stage with less than five years duration[8 ].
Recent developments of new neuroimaging techniques have been made possible with the
emergence of high-field MR magnets, more sophisticated head coils, and improved MRI
sequences. Neuroimaging in PD has expanded its role from just excluding secondary
causes of parkinsonism to the appearance of new biomarkers that can aid in diagnosis
across different stages of the disease, as well as assisting in its differential diagnosis
with atypical parkinsonisms (AP), non-neurodegenerative causes of parkinsonism or
even other movement disorders, such as essential tremor or functional movement disorders[2 ],[11 ].
The present study describes and critically reviews the current knowledge and most
striking advances in MRI and dopamine transporter neuroimaging responsible for this
role shift.
SEARCH STRATEGY
We performed a non-systematic literature review through the PubMed database, using
the disease-specific keyword "Parkinson", together with one of the modality-specific
keywords: “magnetic resonance imaging”, “diffusion tensor”, “diffusion-weighted”,
“neuromelanin”, “nigrosome-1”, “single-photon emission computed tomography”, “dopamine
transporter imaging”. The search was restricted to articles written in English and
published between January 2010 and February 2022. All abstracts were screened for
relevance, and the most pertinent articles were then read and discussed.
STRUCTURAL IMAGING IN T1/T2 MRI
STRUCTURAL IMAGING IN T1/T2 MRI
In the early stages of PD, structural changes on conventional MRI are usually minimal
or absent[12 ]. Although not essential for the clinical diagnosis, MRI should be requested at least
one time during the disease course with two main objectives. The first is the exclusion
of secondary causes of parkinsonism in the conventional sequences of T1 and T2, such
as lesions with mass effect, demyelinating lesions, vascular alterations ([Figure 1 ]), normal pressure hydrocephalus, signs of deposit of metals (copper, iron, and manganese),
and signs of traumatic brain injury[9 ],[12 ]. The second is the search for imaging signs suggestive of AP.
Figure 1 Vascular parkinsonism. Axial FLAIR MRI shows hyperintense foci involving the basal
ganglia, thalamus, periventricular and subcortical white matter related to chronic
small vessel ischemic disease.
AP comprises a group of less common and pathologically distinct disorders than PD,
sharing their neurodegenerative condition and a parkinsonian syndrome as a clinical
hallmark. From a neuropathological perspective, they can be divided, in a simplified
way, into tauopathies, which comprises Progressive Supranuclear Palsy (PSP) and Corticobasal
Degeneration (CBD), and synucleinopathies, which comprises Multiple System Atrophy
(MSA) and Dementia with Lewy Bodies (DLB)[13 ]. Although these disorders tend to have a poor dopaminergic response and eventually
manifest other signs and symptoms that can be distinguished from PD, these features
may not be present early in the disease, and the differential diagnosis among these
entities is challenging. In turn, T1/T2 structural MRI can help identify neuroimaging
biomarkers that support the diagnosis of atypical parkinsonisms, with limited sensitivity
and reasonable specificity.
PSP is clinically manifested by symmetric parkinsonism, supranuclear vertical gaze
palsy, and early gait instability. Radiologically, the hallmark is midbrain area reduction
leading to the visual identification of the “hummingbird sign” on the sagittal plane
(specificity 99%, sensitivity 50%) and the “morning glory sign” on the axial plane
(specificity 97%, sensitivity 37%); in addition to superior cerebellar peduncles (SCP)
size reduction in the coronal plane[14 ],[15 ]. Additionally, the magnetic resonance parkinsonism index (MRPI), calculated through
the measurement of the ratios of the pons to midbrain area and middle cerebellar peduncle
(MCP) to SCP widths, has shown high sensitivity and specificity for distinguishing
PSP from PD, multiple system atrophy- parkinsonian type (MSA-P) and healthy controls[16 ],[17 ].
CBD is clinically characterized by asymmetric parkinsonism, often accompanied by dystonia,
myoclonus, and cortical deficits. Structural MRI may demonstrate frontoparietal cortical
atrophy contralateral to the most affected[18 ]. MSA is clinically characterized by various combinations of autonomic failure, parkinsonism,
and ataxia. In MSA-P, bilateral T2/FLAIR hyperintense rim lining the dorsolateral
borders of the putamen (“putaminal rim” sign), T2 putaminal hypointensity, and T1
atrophy of the putamen, cerebellum, pons, and MCP can be found. Regarding the cerebellar-predominant
type (MSA-C), T2/FLAIR cruciform pontine hyperintensity known as “hot cross bun” sign
(specificity 100%, sensitivity 58%), T2 MCP hyperintensity, and T1 atrophy of the
putamen and MCP can be observed[19 ],[20 ].
[Figure 2 ], included in this article, illustrates the radiological signs and the MRPI calculation
described above.
Figure 2 Atypical parkinsonism. Progressive supranuclear palsy. Midsagittal T1-weighted MRI
(A) shows the “hummingbird sign”, result of selective atrophy of the midbrain tegmentum,
with flattening or concave outline to the superior aspect of the midbrain, and relative
pontine preservation. Axial FLAIR-weighted MRI shows SCP atrophy (B), reduction of
anteroposterior midline midbrain diameter, at the level of the superior colliculi
on axial imaging demonstrating the “Mickey Mouse sign”, and loss of the lateral convex
margin of the tegmentum of midbrain demonstrating the “Morning Glory sign” (C). Magnetic
resonance parkinsonism index (MRPI) is calculated by multiplying the pons area to
midbrain area ratio (D), in the midsagittal plane, by the middle cerebellar peduncle
(F) width to superior cerebellar peduncle width ratio (E). Multiple system atrophy-
parkinsonian type (MSA-P): Axial FLAIR (G),Proton Density (PD) (H) and Gradient Echo
(GRE) (I) weighted MRI show linear region of high signal surrounding the lateral aspect
of the putamen flatted demonstrating the “putaminal rim sign”. Cerebellar predominant
type MSA (MSA-C). Midsagittal and axial T2-weighted (J,K) and PD-weighted MRI (L)
show disproportionate atrophy of the cerebellum and pons, specially pontine tegmentum
and middle cerebellar peduncle, with T2 hyperintensity in the pons forms a cross on
axial images, representing selective degeneration of transverse pontocerebellar tracts
and median pontine raphe (“hot cross bun sign”). Corticobasal degeneration. Right
Parasagittal T1-weighted (M) and axial FLAIR-weighted (N) MRI images show asymmetric
cortical atrophy of perirolandic gyri, most evident on the right.
IRON-SENSITIVE MRI, NIGROSOME-1 AND DORSAL NIGRAL HYPERINTENSITY
IRON-SENSITIVE MRI, NIGROSOME-1 AND DORSAL NIGRAL HYPERINTENSITY
The substantia nigra is a key structure for understanding the anatomical and functional changes that involve
neurodegeneration in PD[21 ]. The substantia nigra pars compacta (SNc), located dorsally in the midbrain, contains dopaminergic neurons
distributed in two different regions, from an immunohistochemical setting: a calbindin-rich
matrix and poor-calbindin zones, called nigrosomes. There are five nigrosomes, and
the largest, located dorsally in the substantia nigra , corresponds to nigrosome-1[9 ],[22 ].
Through high-field magnetic susceptibility-weighted imaging, the nigrosome-1 reveals
itself as a hyperintense linear, “comma” or “wedge” shaped structure in the posterior
third of the substantia nigra , labeled dorsal nigral hyperintensity[23 ],[24 ].
Medially, dorsal nigral hyperintensity is surrounded by low SWI signal intensity from
the medial lemniscus, while laterally and anterior dorsal nigral hyperintensity is
surrounded by a low signal from the pars compacta substantia nigra . Consequently, on axial imaging through high-field magnetic susceptibility-weighted
imaging, nigrosome-1, and its surrounding structures resemble the morphology of a
swallow's tail, called the “swallow-tail sign” appearance of the healthy nigrosome-1,
as shown in [Figure 3A ]
[23 ],[24 ].
Figure 3 Nigrosome-1. Assessment of the substantia nigra using 3T high resolution susceptibility-weighted
MR imaging at the level of nigrosome-1 in 2 different patients. The control subject
(A) shows normal nigrosome-1 present bilaterally (arrow) and the PD patient (B) demonstrates
right nigrosome-1 absent (arrowhead).
Conversely, while it is unclear whether it is a cause or a consequence in pathogenesis,
there is an iron overload in the substantia nigra in patients with PD[25 ]. A histopathological study shows a 31-35% increase in the total iron content of
the parkinsonian substantia nigra when compared to healthy controls[25 ],[26 ].
Consequently, through high-field magnetic susceptibility sequences on MRI, due to
iron overload in the context of nigrostriatal degeneration, loss of dorsal nigral
hyperintensity and loss of the “swallow-tail sign” can be observed in PD patients,
as shown in [Figure 3B ]
[9 ],[11 ],[27 ].
Loss of dorsal nigral hyperintensity has emerged as a potential biomarker to differentiate
PD patients from healthy controls[9 ],[17 ],[28 ],[29 ]. A recent meta-analysis including ten studies, 364 PD and 264 control patients,
demonstrated sensitivity and specificity of the absence of dorsolateral nigral hyperintensity
to differentiate between the two groups greater than 90%[28 ]. However, the same study showed that the absence of DNH was also present in 89.4%
of patients with AP disorders, probably reflecting the joint nigrostriatal degeneration
of these conditions[28 ]. Moreover, two studies demonstrated that the absence of DNH could predict ipsilateral
changes in neuroimaging of the dopamine transporter with sensitivity and specificity
greater than 80%[30 ],[31 ].
Therefore, despite an emerging potential biomarker to demonstrate nigrostriatal neurodegeneration
with apparently reasonable reproducibility to differentiate PD patients from healthy
controls, high-field iron-sensitive images seem to have little accuracy for the differential
diagnosis between neurodegenerative Parkinsonisms[9 ],[28 ].
In addition to its diagnostic value in PD, recent literature investigates the role
of iron-sensitive MRI as a possible biomarker of disease progression through different
imaging patterns depending on the stage of the disease[27 ],[32 ],[33 ]. A longitudinal study comparing neuroimaging findings in R2* relaxation imaging
and quantitative susceptibility mapping (QSM) across different disease stages showed
a significantly SNc faster increase on R2* in later-stage PD (>5 years of disease)
when compared to early-stage PD (<1year) or middle-stage PD (<5 years)[34 ].
When it comes to a potential biomarker during prodromal disease, a comparison among
healthy controls, idiopathic rapid eye movement sleep behavior disorder (iRBD) patients,
and PD patients through QSM demonstrated higher mean magnetic susceptibility values
in the bilateral substantia nigra from iRBD patients compared to healthy controls. In contrast, mean magnetic susceptibility
values were positively correlated with disease duration in the substantia nigra
[33 ]. Besides a potential diagnostic biomarker during the prodromal phase, such findings
suggest that QSM can help monitor disease progression even in its earliest stages.
Accordingly, PD patients had increased iron in the bilateral substantia nigra , globus pallidus, left red nucleus, and elevated iron levels in the bilateral substantia nigra compared with iRBD patients. This finding suggests the role of QSM as a biomarker
of disease progression, which may be maintained after the phenoconversion from iRBD
to PD[33 ].
Despite the increasing availability of high-field scanners and the use of magnetic
susceptibility sequences in the complementary investigation of suspected PD, with
emphasis on DNH assessment, there is no definitive consensus on its use yet, and the
lack of standardized imaging protocols, including spatial resolution and imaging planes,
may limit their usefulness[9 ].
NEUROMELANIN-SENSITIVE MRI
NEUROMELANIN-SENSITIVE MRI
Neuromelanin is an intracellular, dark, and insoluble pigment found in higher concentrations
in catecholaminergic neurons, especially dopaminergic neurons of the substantia nigra and noradrenergic neurons of locus coeruleus[35 ]. Neuromelanin has the property of high affinity to chelate iron and bind neurotoxic
metals that could promote neurodegeneration, and it appears to have antioxidant properties
contributing to regulating the cellular oxidative stress, protecting endogenous dopamine[36 ],[37 ].
The neuromelanin-iron complex acts as a paramagnetic agent[37 ],[38 ]. In this context, neuromelanin-sensitive MRI techniques have been improved in recent
years: on T1-weighted fast spin-echo images at high-field MRI, brain regions containing
melanin can be identified as areas of high signal intensity when compared to surrounding
brain tissue ([Figure 4A ])[37 ]-[39 ].
Figure 4 Neuromelanin. Assessment of the substantia nigra using 3T high resolution T1-weighted
MR imaging in the midbrain structures in 2 different cases. The control subject (A)
shows normal nigral hyperintensity present bilaterally (thick arrow) and the PD patient
(B) demonstrates right loss of dorsolateral nigral hyperintensity (arrowhead) and
left dorsolateral nigral hyperintensity reduced (thin arrow).
In PD, neuromelanin-containing neurons preferentially degenerate[40 ]. Consequently, through signal attenuation in regions where neurodegeneration occurs
([Figure 4B ]), neuromelanin-sensitive MRI has emerged in several studies as a potential imaging
biomarker to diagnose and track PD progression[27 ],[35 ],[38 ],[39 ].
In early PD patients, the lateral portion of the substantia nigra appears to be the topography where signal attenuation is most relevant[41 ]. Measurement of signal attenuation in the lateral portion of the substantia nigra demonstrated sensitivity and specificity greater than 70% and 80%, respectively,
comparing early-stage PD patients with healthy controls[41 ]. Interestingly, the measurement of signal attenuation at the locus coeruleus has
been shown to have greater sensitivity and specificity (82% sensitivity and 90% specificity),
which suggests early neuronal depletion in the early disease stages and highlights
the importance of emerging biomarkers in deepening the knowledge about the mechanisms
that drive neurodegeneration in PD[39 ],[41 ].
On the other hand, the role of neuromelanin-sensitive MRI as a tool for the differential
diagnosis between PD and AP presents less clear evidence, despite recent advances.
In a prior study including healthy controls and early-onset parkinsonism patients,
after a one-and-a-half year follow-up of PD, PSP, and MSA-P diagnosis, the signal
intensity of the lateral, central, and medial parts of the SNc, the locus coeruleus,
and the contrast ratios against adjacent white-matter structures were calculated.
The lateral SNc contrast ratio was lower in the PD and MSA-P groups than in the PSP
and control groups, while the contrast ratio of the locus was observed to be lower
in the PD group than in the other groups[42 ]. In another recent study, the SNc estimated in neuromelanin-sensitive MRI was significantly
smaller in PSP patients compared to PD patients and healthy controls[43 ].
As an emerging neuroimaging biomarker, there is concern about assessing coherence
and reproducibility with more well-established biomarkers such as dopamine transporter
neuroimaging. The substantia nigra area on neuromelanin-sensitive MRI appears to be directly correlated with dopamine
transporter density on SPECT neuroimaging, suggesting that neuromelanin-MRI may be
a potential biomarker to quantify substantia nigra pathology and dopaminergic loss in PD[44 ].
From the same perspective as a potential biomarker of PD progression, through longitudinal
follow-up, the substantia nigra volume and signal intensity on neuromelanin-MRI showed a more significant reduction
with longer disease duration[38 ]. The levodopa equivalent daily dose (LEDD) in patients did not correlate with any
substantia nigra MRI measurements, suggesting that dopaminergic medication did not modify neuromelanin-MRI
signal changes[38 ].
The recent literature suggests that neuromelanin-sensitive MRI is a potential biomarker
for PD, but it still lacks standardized image processing and analysis protocols, which
may limit its use in daily clinical practice[9 ],[27 ].
DIFFUSION IMAGING
Diffusion-weighted imaging and diffusion tensor imaging might be a helpful tool to
indirectly quantify the microstructural integrity through analysis of the overall
displacement of water molecules, characterized as mean diffusivity, and the degree
of displacement in space known as fractional anisotropy[12 ]. Briefly, degeneration of white matter tracts leads to an increase in mean diffusivity,
while a decrease in fractional anisotropy is expected[12 ]. Consequently, analysis of mean diffusivity and fractional anisotropy in structures
affected by neurodegeneration in PD has been a research target.
Prior studies described a significant reduction in fractional anisotropy in the substantia nigra in PD patients compared to controls[17 ],[45 ],[46 ]. Such reduction was more pronounced in the caudal portion of the substantia nigra , which is congruent with the more intense neuronal loss in this structure as neurodegeneration
progresses[45 ],[46 ]. A reduction in fractional anisotropy was also observed in the anterior olfactory
structures, in line with previous observations from olfactory disturbances in PD patients[12 ],[17 ],[47 ].
Literature data are conflicting: some studies report no fractional anisotropy or mean
diffusivity significant differences between healthy controls and early PD patients[12 ],[48 ]. One longitudinal study showed no significant differences, at the baseline, between
healthy controls and PD patients. However, after a mean follow-up of 19 months, the
PD patients showed a substantia nigra significant increased mean diffusivity and reduced fractional anisotropy. This change
observed during follow-up analysis suggests that substantia nigra diffusion measure may be a valuable biomarker of PD progression[49 ].
New image postprocessing methods, notably freewater imaging, also seem to have a promising
role as potential new biomarkers[9 ]. Freewater in the posterior substantia nigra is elevated in PD patients compared to healthy controls. In addition, freewater level
was correlated with disease duration, the severity of motor symptoms, and degree of
dopaminergic loss on neuroimaging of the dopamine transporter, suggesting that it
may be a valuable tool for diagnosing and monitoring disease progression[50 ].
Hence, diffusion-weighted, tensor, and freewater imaging can also be valuable tools
for differential diagnosis between PD and AP. A recent meta-analysis showed a 90%
sensitivity and 93% specificity of diffusion-weighted MRI to differentiate MSA-P from
PD through the analysis of putaminal diffusion, which is increased in patients with
MSA-P[51 ]. More recently, a study proposed an approach involving diffusion-weighted imaging,
free water postprocessing, in conjunction with automated analysis and machine learning
algorithms, labeled automated imaging differentiation of parkinsonism (AID-P), as
a practical and promising tool in differentiating PD from AP[52 ].
DOPAMINE TRANSPORTER IMAGING
DOPAMINE TRANSPORTER IMAGING
In addition to MRI advances, dopamine transporter neuroimaging rises as an essential
milestone in the diagnostic management of patients with parkinsonism or suspected
PD. Presynaptic dopamine transporter (DAT) consists of a transmembrane sodium chloride-dependent
protein expressed only in presynaptic dopaminergic cells, responsible for dopamine
reuptake from the synaptic cleft[53 ],[54 ]. The administration of radiotracers with high specificity for DAT combined with
single-photon emission computed tomography (SPECT) imaging technique allows the assessment
of DAT density at presynaptic terminals[53 ]. [123I]FP-CIT (123I-ioflupane) correspond to the most commonly used ligand[53 ], although there are other radiotracers also with high specificity for DAT, such
as [99mTc]TRODAT (frequently used in Brazil), [123I]β-CIT and [123I]IPT[53 ],[55 ]. Standard DAT-SPECT imaging appears as two intense symmetric “comma-shaped” regions
of activity in the striatum ([Figure 5A, 5B, 5C ]).
Figure 5 DAT-SPECT from healthy controls and from PD patients at different stages of the disease.
A standard DAT-SPECT imaging appears as two intense symmetric “comma-shaped” regions
of activity in the striatum (A, B,C). With the progression of PD, there is a decline
in radiotracer uptake that follows a gradient from posterior to anterior structures,
as shown through DAT-SPECT obtained during early (D,E,F), moderate (G,HI) and late
(J,K,L) stage of PD.
Due to neuronal loss in the nigrostriatal pathway occurring in neurodegenerative parkinsonisms,
there is a reduction in the expression of DAT on presynaptic terminals, which leads
to a reduction in radioligand striatal uptake in DAT-SPECT[53 ],[56 ]. Decreased radiotracer binding, especially in the early stages of the disease, shows
a rostrocaudal gradient pattern, with relative sparing of the caudate nucleus compared
to the putamen ([Figure 5D, 5E, 5F ]) [53 ],[56 ]. Loss in uptake also tends to be asymmetrical, as it is often more pronounced in
the contralateral side to parkinsonism[17 ],[53 ],[56 ]. Unlike other neuroimaging biomarkers previously discussed, which are mostly restricted
to the research environment, a normal DAT-SPECT has been incorporated as an absolute
exclusion criterion in the 2015 MDS clinical diagnostic criteria for PD[5 ].
Therefore, DAT-SPECT is a valuable tool in differentiating with high accuracy presynaptic
neurodegenerative parkinsonisms from other clinical conditions, such as essential
tremor and secondary parkinsonisms, such as vascular, psychogenic, or drug-induced
parkinsonism[9 ],[56 ],[57 ]. Therefore, if DAT radiotracer binding is normal, the diagnosis of neurodegenerative
parkinsonism becomes less likely[58 ]. DAT-SPECT, specifically 123I-ioflupane SPECT, commercially traded as DaTSCAN®,
has been approved by the US Food and Drug Administration (FDA) and the European Medicines
Agency as a complementary tool in the differential diagnosis between essential tremor
and PD or other neurodegenerative parkinsonism related-tremor [57 ].
However, since both PD and AP are characterized by presynaptic involvement and nigrostriatal
degeneration in their etiopathogenesis, the role of DAT-imaging in the differential
diagnosis between the two conditions seems limited[53 ],[56 ],[58 ]. Some attempts to identify different patterns of ligand uptake among these conditions
have been made, such as the recognition of more asymmetric uptake changes in patients
with PD and corticobasal degeneration at a population level compared to patients with
PSP and MSA[56 ],[59 ]. Thus, on an individual level, DAT imaging does not appear to be a reliable tool
in the discrimination of different causes of degenerative parkinsonism, and its use
is not recommended for this purpose in routine clinical practice[53 ],[56 ],[60 ].
The acronym SWEDD (scans without evidence for dopaminergic deficit) was coined after
recognizing that some patients had normal DAT imaging, despite a presumed clinical
diagnosis of PD[61 ],[62 ]. As a recent review points out, patients with SWEDD form a heterogeneous group:
most cases correspond to diverse medical conditions misdiagnosed as PD, such as essential
tremor, dystonia, secondary or psychogenic parkinsonisms, depression with psychomotor
slowness, and soft extrapyramidal signs of the elderly[62 ]. Conversely, a portion of SWEDD patients remained under the main hypothesis of PD,
and some of them converted to altered DAT imaging during their follow-up, supporting
the notion that an initial normal DAT-SPECT cannot permanently exclude early degenerative
parkinsonism[62 ].
As the term SWEDD does not represent a single clinical entity, but only an absence
of a dopaminergic imaging abnormality from a largely heterogeneous group of patients,
some authors defend that this term should be abandoned[53 ],[62 ].
Finally, increasing data regarding dopamine transporter imaging has shown its role
in the prodromal phase of PD. In patients with hyposmia, abnormal uptake on DAT-SPECT
is a predictive factor of phenoconversion to PD, while in patients with iRBD, a DAT
deficit identifies patients at short-term risk for synucleinopathy[63 ],[64 ]. DAT imaging may also help to understand the heterogeneity of PD during the prodromal
phase. Recent studies suggest two subtypes of prodromal PD according to the temporal
and spatial pattern of alpha-synuclein progression: a body-first subtype, characterized
by the early involvement of enteric autonomic nervous system and later progression
to the central nervous system via the vagus nerve, and a brain-first subtype, characterized
by the early brain involvement, with later progression to the brainstem and the peripheral
autonomic nervous system. Through a multimodal approach, early alteration in DAT imaging
helps to identify brain-first subtype prodromal disease patients[65 ],[66 ].
In conclusion, neuroimaging biomarkers in PD have made substantial progress in recent
years with the advent of high-field MRI, improved sequences, and dopamine transporter
ligands capable of assessing the integrity of the nigrostriatal pathway in vivo.
Although some of these emerging biomarkers lack validation in the earlier stages of
the disease, their role in clinical practice and diagnostic accuracy might increase
with the future establishment of standardized image processing and analysis protocols,
new forms of a multimodal approach, and machine-learning algorithms.
