DEFINING BIOMARKERS AND THE ROLE OF MOLECULAR NEUROIMAGING IN THE DIAGNOSIS OF NEURODEGENERATIVE
DEMENTIAS
Biomarkers can be defined as measures or indicators of physiological or pathological
processes or responses to a therapeutic intervention[10]. An ideal biomarker should[11]: 1) reflect a fundamental aspect of pathophysiology; 2) indicate the real presence
of the pathology and not merely an increased risk; 3) exhibit high sensitivity and
specificity (80% or more); 4) be effective in predicting early or pre-clinical stages;
5) allow monitoring of disease severity or rate of progression; 6) indicate the effectiveness
of the therapeutic intervention and 7) be non-invasive, economically feasible and
available. Although this consensus was originally proposed in the context of AD, it
can also be applied to biomarkers in other neurodegenerative diseases.
The biomarkers used in neurodegenerative diseases can be schematized according to
the detection methods, including cerebrospinal fluid (CSF), serum and structural and
molecular neuroimaging biomarkers[12]. Molecular neuroimaging methods have gained prominence in the study of biomarkers
in neurodegenerative diseases for several reasons[13]. First, the molecular neuroimaging studies allow detection of pathological changes
prior to morphological changes observed in structural neuroimaging exams, such as
magnetic resonance imaging (MRI). Second, new radiotracers with affinity to bind to
pathological proteins, like amyloid β peptide (Aβ) plaques and tau protein, have increasingly
been developed. Moreover, neuroimaging allows the study of proteinopathy, its anatomical
distribution, and neuronal networks.
Molecular neuroimaging methods are based on the use of radioisotopes (or radionuclides)
for image acquisition. The basic principle is the administration of a radiotracer,
a molecule with biological properties bound to the radionuclide and whose emission
of the radioactive signal is detected by a scanner, forming a radiotracer[14]. There are two methods for acquiring molecular neuroimaging: positron emission tomography
(PET) and single photon emission tomography (SPECT)[14].
Currently the most used radioisotope in the SPECT neuroimaging study is technetium-99m
(99mTc). Radiotracers marked with 99mTc are fat-soluble compounds that cross the blood-brain
barrier and are distributed according to cerebral blood flow[14]. Therefore, most SPECT radiotracers assess brain perfusion. The advantage of SPECT
is its low acquisition cost, longer half-life, greater simplicity in radiotracer synthesis
and, consequently, greater availability. However, brain images acquired by SPECT have
lower spatial resolution, which makes them less sensitive and specific than brain
PET. Therefore, currently, the use of SPECT as a molecular neuroimaging biomarker
is not recommended, except when PET is not available.
On the other hand, the most used radionuclides in PET are carbon-11 ([11]C) and fluor-18 ([18]F), which are more unstable isotopes with shorter half-lives. Therefore, PET requires
radiopharmacy laboratories and production centers (cyclotrons) closer to the image
acquisition center, which makes the method less available and more expensive. However,
despite these disadvantages, PET images usually have a better accuracy as biomarkers
of neurodegenerative diseases. Currently, semiquantitative analysis software has been
incorporated into the routine analysis of PET scans, thus increasing the accuracy
of the diagnostic method, and allowing better inter-examiner comparison[14],[15]. Some of these software tools, such as 3D-SSP (Cortex ID Suite software, GE Healthcare
or Scenium software, Siemens Healthineers), compare the examinations with a database
of normal individuals, reporting the results as z-scores (or standard deviation) from
the mean of normality.
The oldest PET method is the use of [18]F-fluorodeoxyglucose (FDG) as a radiotracer, with which it is possible to study the
regional brain glucose metabolism (rBGM)[14],[15]. rBGM, in turn, is an indirect measure of neuronal and glial synaptic activity[16]. Therefore, areas of neuronal and synaptic injury can be indirectly determined by
regions of regional brain hypometabolism and, thus, FDG-PET plays a role as a biomarker
of neurodegeneration[17]. The regional hypometabolism pattern provides neuroanatomical information on the
neurodegenerative process which, in turn, has a good specificity for each type of
neurodegenerative dementia ([Table 1]) [18]. Not surprisingly, in several groups of neurodegenerative diseases, the pattern
of hypometabolism was included in the diagnostic criteria, as will be discussed later.
Table 1
Patterns of regional glucose hypometabolism on brain FDG-PET in the main groups of
neurodegenerative dementias.
|
Neurodegenerative dementia
|
Variants
|
Typical hypometabolism pattern
|
|
Alzheimer's disease
|
Amnestic (or limbic)
|
Temporoparietal association cortex, precuneus and posterior cingulate. In more advanced
cases, there is an extension to the prefrontal cortex.
|
|
Logopenic variant of primary progressive aphasias
|
Temporoparietal association cortex, precuneus and posterior cingulate, asymmetrical,
worse on the left
|
|
Visual (or posterior cortical atrophy)
|
Temporoparietal association cortex, precuneus and posterior cingulate with occipital
extension
|
|
dysexecutive/ behavioral
|
Temporoparietal association cortex, precuneus and posterior cingulate with frontal
extension
|
|
Corticobasal syndrome
|
Temporoparietal association cortex, precuneus and asymmetric posterior cingulate,
with involvement of the basal ganglia
|
|
Lewy bodies dementias
|
Dementia with Lewy bodies
|
Temporoparietal and occipital association cortex, precuneus with posterior cingulate
preservation (“cingulate island sign”)
|
|
Parkinson's disease dementia
|
Temporoparietal and occipital association cortex, with frontal extension, precuneus
with preservation of the posterior cingulate.
|
|
Frontotemporal dementias
|
Behavioral variant
|
Dorsolateral prefrontal cortex, orbitofrontal, anterior cingulate, anterior insula,
and anterior temporal regions. It may have an asymmetry, worse on the right.
|
|
Non-fluent variant of primary progressive aphasias
|
Left inferior frontal region and left insula, with extension to the anterior cingulate
and dorsolateral frontal region
|
|
Semantic variant of primary progressive aphasias
|
Bilateral anterior temporal pole, worse on the left.
|
|
Progressive supranuclear palsy
|
Dorsolateral, ventrolateral, and medial frontal cortex, including supplementary motor
area and premotor cortex, caudate, thalamus, and midbrain
|
|
4R tauopathy corticobasal syndrome (corticobasal degeneration)
|
Dorsolateral frontoparietal cortex, including sensorimotor cortex, thalamus, and striatum,
of asymmetrical pattern
|
PET: Positron Emission Tomography; FDG: [18F] Fluorodeoxyglucose.
Despite its good accuracy, FDG-PET is still regarded as a biomarker of neurodegeneration.
Therefore, the current frontiers of molecular neuroimaging techniques in cognitive
decline have reached the detection of misfolded protein deposits[14],[15],[18]. These new methods were only possible after the development of radiotracers that
bind specifically to these pathological proteins. In the following topics we will
address some of these molecular neuroimaging modalities in the context of the main
groups of neurodegenerative dementias.
MOLECULAR NEUROIMAGING IN ALZHEIMER'S DISEASE AND THE ATN CLASSIFICATION
AD is pathologically defined by the presence of senile plaques (extracellular deposit
of Aβ) and neurofibrillary tangles (intraneuronal accumulation of hyperphosphorylated
tau protein), in addition to signs of a neurodegenerative process (neuronal and synaptic
loss, astrogliosis and microglial activation)[12],[19]. The first diagnostic criteria were clinical, following the exclusion of others
causes associated with cognitive decline[20],[21]. However, changes in AD diagnostic criteria have been observed in recent decades
as new knowledge of AD's pathophysiology and natural history have been better elucidated.
Biomarkers played a vital role in these paradigm shifts.
In 2011, a working group from the National Institute on Aging and Alzheimer’s Association
(NIA-AA) developed the current diagnostic criteria for AD[6],[20]. These new criteria proposed the concept of stages of disease evolution, based on
the “amyloid cascade” hypothesis[9],[22]. According to this model, the disease follows a continuous course that starts from
a preclinical phase (defined as the absence of cognitive decline and the presence
of positive biomarkers for AD pathology), followed by a stage of mild cognitive impairment
(MCI) and, finally, a stage of dementia due to AD[6],[20]. For the first time, the preclinical stage, and the possibility of non-amnestic
AD variants (posterior cortical atrophy, logopenic variant of primary progressive
aphasias and dysexecutive/behavioral variant) were admitted.
In the 2011 criteria, the biomarkers are recommended only in selected cases: pre-senile
onset dementias (< 65 years), rapidly progressive dementias, atypical dementias or
for differential diagnoses with other neurodegenerative dementias. Later studies show
that these 2011 clinical criteria, without the use of biomarkers, have a sensitivity
of 70.9 to 87.3% and a low specificity of 44.3 to 70.8% when compared to pathological
diagnosis[17]. Biomarkers have also been incorporated into the diagnosis of MCI due to AD[23].
More recently, in 2018, the NIA-AA proposed new criteria for the biological definition
of AD based on biomarkers according to an “ATN” system, especially targeting clinical
trials, in which certainty of the pathological process involved is required ([Table 2]) [24]. According to the pathological process, AD biomarkers have been divided into biomarkers
of amyloid pathology (A), tau pathology (T) and neurodegeneration (N), summarizing
the ATN classification ([Table 2]) [7],[24],[25].
Table 2
Alzheimer's disease biomarkers classified according to the pathological process (ATN
system). Adapted from Jack et al.[28].
|
Pathology
|
Biomarker
|
|
Amyloid Pathology (A)
|
Decreased Aβ42 in CSF Positive amyloid PET
|
|
Tau pathology (T)
|
Increased hyperphosphorylated protein in CSF Positive tau PET
|
|
Neurodegeneration (N)
|
Increase total Tau protein in CSF Cortical atrophy on magnetic resonance imaging Regional
glucose hypometabolism on FDG-PET
|
CSF: cerebrospinal fluid; Aβ: beta-amyloid peptide; PET: Positron Emission Tomography;
FDG: [18F] Fluorodeoxyglucose.
The purpose of these 2018 criteria is to apply them in clinical research, while the
2011 criteria would remain valid for use in clinical care([Table 3]) [24],[26]. According to these 2018 criteria, AD is defined by the positivity of biomarkers
for amyloid (A+) and tau (T+), regardless of the presence or absence of neurodegeneration
(N- or +). When only Aβ (A+) is present, but without evidence of tau (T-) pathology,
the denomination should be “Alzheimer's pathological changes”. It therefore represents
the initial stage of AD (amyloidosis without tauopathy) according to the “amyloid
cascade” hypothesis. When there is positivity for tau protein (T+) and/or for neurodegeneration
(N+), but negativity for amyloid pathology (A-), the diagnosis of Alzheimer`s pathology
must be excluded, and it should be called SNAP (suspected non-Alzheimer’s pathophysiology).
The term "clinical AD syndrome" was reserved for the situation in which the patient
meets the clinical criteria for AD (amnestic or non-amnestic variants), but there
is no information on amyloid or tau biomarkers.
Table 3
Diagnostic categories according to the ATN system (Amyloid-Tau-Neurodegeneration)
within the continuum of the biological definition of Alzheimer's disease. Adapted
from Jack et al.[28].
|
ATN profile
|
Category according to biomarker profile
|
|
A- T- N-
|
Normal Alzheimer disease D biomarkers
|
|
A+ T- N-
|
Alzheimer's continuum
|
|
A+ T+ N-
|
Alzheimer's disease (without neurodegeneration)
|
|
A+ T+ N+
|
Alzheimer's disease (with neurodegeneration)
|
|
A+ T - N+
|
Alzheimer's continuum + Non-Alzheimer Pathology
|
|
A- T+ N-
|
Suspected non-Alzheimer’s pathophysiology
|
|
A- T- N+
|
Suspected non-Alzheimer’s pathophysiology
|
|
A- T+ N+
|
Suspected non-Alzheimer’s pathophysiology
|
In 2021, the International Working Group (IWG), in opposition to the 2018 NIA-AA criteria,
criticized the excessive importance of the use of biomarkers for the diagnosis of
AD[27]. They claim that several studies show an increased frequency of amyloidosis and
neurodegeneration associated with aging even in cognitively normal individuals[8],[28],[29], although the presence of amyloidosis in normal elderly is associated with higher
rates of progression to cognitive decline[8],[28],[30]-[34]. Nevertheless, the IWG recommendation is that the diagnosis of AD should be restricted
to people with A+T+ biomarkers and who have a cognitive syndrome compatible with AD[27]. This IWG definition, therefore, would fulfill the diagnosis of AD only in the MCI
and dementia states with evidence of A+T+ biomarkers, which, on the one hand, increases
specificity. On the other hand, the disease usually begins many years earlier and
studies are continuously focusing on pre-clinical diagnosis and treatment, which are
not possible when using the IWG recommendation.
Amyloid PET
Since the early 2000s, radiotracers for the detection of insoluble Aβ peptide deposited
in neuritic plaques (amyloid PET) have been widely used in AD studies[15],[18]. The first radiotracer developed was the Pittsburgh Compound-B labeled with carbon-11
(PIB), widely used in clinical research[13],[18]. Sequentially several other Aβ peptide ligands were developed, all labeled with
fluorine-18. These radiotracers (florbetapir, florbetaben and flutemetamol) are already
cleared by the US regulatory agency for commercial clinical use[18]. All these radiotracers are clinically equivalent, but those linked to fluorine-18
have the advantage of a longer half-life of 110 minutes compared to [11]C, whose half-life is only 20 minutes[14],[15],[35]. In practice, due to carbon-11’s low half-life, [11]C-PIB needs to be synthesized in a cyclotron located in the same building of the
imaging site[14],[15],[35]. But despite this disadvantage, studies with PIB have shown this to be a radioligand
with a high accuracy in the detection and anatomical location of neuritic plaques.
Studies comparing amyloid PET with post-mortem pathological diagnosis show a sensitivity
of 96% and a specificity of 100% in cases of dementia due to AD[18]. Sensitivity is not 100% because all radiopharmaceuticals have high affinity for
insoluble fibrillar amyloid in neuritic plaques, with good anatomopathological correlation,
but they are insensitive to soluble Aβ oligomers[18],[36]-[38]. Also, amyloid PET may be less sensitive in earlier stages of the disease[36], mostly because of the dichotomized nature of its interpretation: scans are usually
classified as positive or negative, which most commonly include individuals with mild
deposition as negative. Therefore, changes in CSF Aβ may precede changes in amyloid
PET. Amyloid PET is usually classified as "positive" if there is a loss of gray and
white matter differentiation in at least two of the following six areas: frontal,
temporal, lateral parietal, precuneus, anterior cingulate, and posterior cingulate
cortex([Figure 1]) [39],[40]. On the other hand, the amyloid PET image is classified as "negative" when there
is a clear contrast between gray and white and no significant uptake in the cortex.
In the quantitative analysis of amyloid PET, it was agreed to determine the standard
uptake values ratio (SUVr) of cortical areas normalized for gray matter of the cerebellum,
as this is a region that does not present significant Aβ deposits in AD[39],[40]. Interestingly, amyloid radiotracers have high affinity for the myelin sheath in
the absence of Aβ deposits, leading to their use in the investigation of demyelinating
diseases such as multiple sclerosis.
The pattern of radiotracer uptake for amyloid in the cortex follows the pattern commonly
seen in post-mortem studies, with involvement of the frontal regions, followed by
the precuneus and posterior cingulate and finally areas of temporoparietal association,
medial temporal region, primary cortical areas. and striatum[36]. Furthermore, as was already known, the distribution of amyloid pathology is not
distinguished between AD variants, unlike tau pathology, whose neuroanatomical distribution
is reflected in the clinical phenotype[41].
It is important to note that a positive amyloid PET alone does not fulfill the criteria
for the diagnosis of AD in any of the existent criteria[6],[20],[24],[26], as cognitively normal individuals, with MCI, or even with other forms of dementia
(particularly dementia with Lewy bodies) may have positive tests for the presence
of amyloid[6]. While between 70-90% of patients clinically diagnosed with AD test positive for
amyloid, about 30-40% of cognitively normal older adults over 80 years also test positive
for amyloid[6]. Rates of positive amyloid PET in cognitively normal older adults vary among studies,
some reporting high rates of 20% at around 65 years and 60% at 85 years[14]. A PET-based study of our group found 18% of amyloid positivity in controls (71.19
± 6.1 years old), and 76% in clinically-defined AD, and as low as 37% of positivity
in amnestic MCI (mean ages of 73.7 ± 7.3 and 73.0 ± 5.8, respectively)[42].
These data indicate that the process of extracellular Aβ peptide deposition is a common
process in brain aging. Therefore, diagnostic criteria based on biomarkers indicate
that the diagnosis of AD should show positivity for both amyloid and tau biomarkers
(A+T+). On the other hand, studies show that cognitively normal older adults with
positive amyloid PET have a higher chance of evolving to AD in the next 10 to 20 years,
indicating that part of these subjects may be in a prodromal or preclinical stage
of AD[43],[44]. Indeed, in older adults below 80 years of age who have cognitive decline, a negative
amyloid PET excludes the diagnosis of AD. [Table 4] summarizes the advantages and dis-advantages of amyloid PET.
Table 4
Advantages and disadvantages of amyloid PET.
|
Advantage
|
Disadvantages
|
|
Negative amyloid PET excludes AD; Very useful for differentiating pre-senile onset
dementias; Allows you to differentiate from primary tauopathies and TDP-43pathies;
Positive amyloid PET has high predictive power for conversion to AD.
|
Above 80 years of age, 30 to 40% of normal older adults have a positive amyloid PET;
Not very useful in differentiating from alpha-synucleinopathies; High cost and little
availability; Not yet incorporated into AD clinical criteria.
|
PET: Positron Emission Tomography; AD: Alzheimer disease; TDP-43: transactive response
DNA binding protein of 43 kDa.
Tau PET
Tau protein plays a role in the proteins that give support and stability to the microtubules
that are found in axons. Hyperphosphorylation of the tau protein leads to formation
of insoluble filaments, which are deposited as intracellular inclusions, ultimately
leading to cell death[12]. Tau exists in six isoforms distributed in two groups in equal proportions: three
isoforms have three repeats (tau 3R), and the other three have four repeats (tau 4R)
of the sequence of amino acids that bind to microtubules[15],[45]. AD is characterized by a tauopathy with the presence of two subtypes of tau (3R
and 4R). However, according to the amyloid cascade hypothesis, AD is considered a
tauopathy secondary to amyloid pathology[22]. Other 3R and 4R tauopathies are chronic traumatic encephalopathy, primary age-related
tauopathy (PART) and some cases of FTD by a mutation in the MAPT gene[45],[46].
On the other hand, primary tauopathies are divided between the 3R and 4R. 3R-tauopathies
are found in some cases of FTD and can aggregate in characteristic intracytoplasmic
inclusions called Pick bodies[45],[46]. The group of 4R-tauopathies includes corticobasal degeneration (CBD), progressive
supranuclear palsy (PSP), FTD with parkinsonism linked to chromosome 17 and most cases
of the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA)[45],[46].
Studies of tau biomarkers have shown a recent increase in interest for a few reasons:
failure of clinical trials of anti-amyloid therapies, a more significant correlation
between tauopathy and AD progression (unlike amyloid pathology), recent studies suggesting
pathways of tauopathy progression independent of amyloid pathology and the diagnosis
of primary tauopathies[46]-[49].
Since the 2010s, several ligands for tau protein detection (tau PET) have been developed
and validated from post-mortem comparative studies[46],[49]-[51]. [18]F-FDDNP was the first radiotracer developed, however, it had low specificity, binding
to neurofibrillary tangles and amyloid aggregates, which caused it to be discontinued[45]. Other first-generation radiopharmaceuticals have been developed: [11]C-PBB3, [18]F-flortaucipir (previously [18]F-AV1451 or [18]F-T807), [18]F-THK5317, and [18]F-THK5351 (45,46). In 2020, [18]F-flortaucipir was the first FDA-approved for clinical and commercial use[52]. These radiotracers bind to regions typically affected regions in AD patients, such
as the lateral temporal, lateral and medial parietal (precuneus) and posterior cingulate[45],[46],[49],[51]. Studies with flortaucipir in different AD phenotypes show that the distribution
of the tau protein follows the anatomical distribution associated with each cognitive
manifestation of the variants[45],[46],[49],[51].
Although these radiotracers have a higher affinity for tau protein compared to [18]F-FDDNP, they still have some affinity for other protein aggregates, such as TDP-43,
Aβ, and alpha-synuclein. For example, studies show that PET with [18]F-flortaucipir ([18]F-AV1451) has regional uptake in the semantic variant of primary progressive aphasias,
whose pathology is most commonly TDP-43[45],[46]. Furthermore, these radiotracers have low specificity in distinguishing the type
of tauopathy (3R vs. 4R) and the level of maturity of the tau deposit (pre-tangle,
mature neurofibrillary tangle, and phantom tangle), as well as the type of cell affected
(neurons versus glia). It is known, for example, that in primary tauopathies, especially
in PSP and CBD, glial cells also show deposits of hyperphosphorylated tau[45],[46]. The low affinity for other non-3R/4R tauopathies limited the use of first-generation
tracers in the clinic.
The second generation of radiotracers was more recently developed. Some examples are:
18F-MK-6240, 18F-RO-948, 18F-PI-2620, 18F-GTP1, 18F-PM-PBB3, 18F-JNJ311 and 18F-JNJ-067[45],[46]. These second-generation radiotracers have the advantage of having a higher affinity
for hyperphosphorylated tau protein and less binding to non-tau targets compared to
first-generation radiotracers[53]-[55]. Second-generation radiotracers have shown that tau PET has a good accuracy in predicting
the trajectory of cognitive decline in cognitively normal subjects or those with MCI,
superior to amyloid PET[50],[56].
Two of these tracers ([18]F-MK-6240 and [18]F-PI-2620) are in an advanced stage of testing in clinical settings and showed promising
results in 4R tauopathies, such as CBD and PSP. The main advantage of this generation
of tau PET is its use in primary tauopathies. PSP has the advantage of being exclusively
a tauopathy (unlike CBD or even FTD which can be phenotypes of different proteinopathies).
Some first-generation radiotracers show good affinities for tau deposits in other
non-AD tauopathies, and the uptake pattern may indicate whether it is a primary or
secondary AD tauopathy[45],[49]. These radiopharmaceuticals also have an affinity for monoamine oxidase B (MAO-B),
which is abundantly present in base nuclei and may lead to false positives[45],[49]. [18]F-flortaucipir, the most used first-generation tracer, cannot reliably differentiate
the types of non-AD tauopathies (PSP, CBD or FTD) and may not detect the early stages
of Braak (I to III)[57],[58]. [18]F-RO-948 was also shown to have good accuracy in differentiating AD from non-AD tauopathies
in a comparative post-mortem study[55].
If second-generation tau PET tracers continuously prove their value, they have the
potential to replace amyloid and FDG-PET in some scenarios in clinical practice (e.g.,
in the different types of tauopathies), providing “one-stop-shop” studies of pathology
and disease staging at the same time.
FDG-PET in Alzheimer's disease
Despite advances in PET ligands specific for pathological protein deposits, FDG-PET
remains the main molecular neuroimaging method available in clinical practice. Studies
show that a pattern of regional hypometabolism in areas of association temporoparietal,
medial temporal, precuneus and posterior cingulate have a high specificity for AD
ranging from 86 to 98%, compared to pathological diagnosis ([Figure 1]) [17],[35]. Its accuracy in the evaluation of AD and FTD variants is comparable to amyloid
PET, with the advantage of providing insights on disease stage[17]. Furthermore, FDG PET findings precede the structural changes seen on MRI, another
biomarker of neurodegeneration. Patients with MCI who present this “AD pattern” have
a 75 to 100% accuracy in predicting conversion to dementia[35] Interestingly, the posterior cingulate has been shown to be the region whose involvement
best predicts MCI conversion to dementia due to AD[35].
FDG-PET is also very useful in the differential diagnosis between AD and other neurodegenerative
dementia, by showing specific regional patterns of hypometabolism in each condition
([Table 1]). This good specificity even helps in the differential diagnosis between AD variants
and other groups of neurodegenerative dementias. For example, anterior cingulate hypometabolism
makes it possible to accurately differentiate a bvFTD from a dysexecutive/behavioral
variant of AD[41],[59]. In CBS, temporoparietal and posterior cingulate hypometabolism suggest an AD pathology
and predicts a positive amyloid PET with 88.5% of accuracy and 100% of positive predictive
value, whereas asymmetric hypometabolism of the dorsolateral frontoparietal cortex,
including sensorimotor cortex, thalamus, and striatum, suggests non-AD CBS (generally,
4R tauopathy)[60].
Comparative studies of tau PET and FDG-PET imaging indicate an overlap between areas
of tau protein accumulation and hypometabolism. This overlap, on the other hand, does
not occur between amyloid PET and FDG PET. This has two consequences: first, that
tauopathy correlates more directly with neuronal injury and synaptic dysfunction than
does amyloid pathology, and second, that FDG PET may be a better substitute for tau
PET than amyloid PET in places where this test is unavailable[42] by showing simultaneously specific patterns of neurodegeneration and helping to
stage the disease. This use of FDG-PET as a proxy for tau pathology was previously
foreseen[26].
Additionally, the combination of amyloid and FDG-PET provided incredibly high sensitivity
and specificity of 97% and 98%, if both are congruent, in a post-mortem study[17]. This was replicated in a PET study using the rationale of the “ATN” staging, where
an FDG-PET with an AD-pattern predicted amyloid positivity in 93% of cases (27 of
29 FDG-positive individuals), and provided alternative diagnostic hypotheses (e.g.
frontal hypometabolism suggestive of FTD) in amyloid-negative individuals[42]. However, it is essential to emphasize that according to the amyloid cascade hypothesis,
the changes in tau PET would precede those observed in FDG-PET, a less specific biomarker
of neurodegeneration.
MOLECULAR NEUROIMAGING IN DEMENTIA WITH LEWY BODIES
Dementia with Lewy bodies (DLB), like Parkinson's disease (PD) and multiple system
atrophy (MSA), is part of a group of neurodegenerative diseases characterized by the
presence of alpha-synuclein neuronal inclusions[61]. DLB is described as the second cause of neurodegenerative dementia after the age
of 65. The current diagnostic criteria for DLB were defined by a consensus in 2017
that included, among other points, biomarkers[62]. These biomarkers were classified as indicative, whose specificity is high enough
to define the probability of DLB, and supportive biomarkers, with lower sensitivity,
but with good accuracy to allow clinical suspicion. The indicative biomarkers are
polysomnography, myocardial sympathetic innervation scintigraphy, and PET/SPECT with
radiotracer for dopamine transporter (DAT). Supportive biomarkers included FDG-PET,
MRI and electroencephalogram. None of these biomarkers define the presence of alpha-synuclein
in vivo, but somehow reflect the repercussions of the pathophysiological process.
PET or SPECT using dopamine tracers aim to assess the integrity of the nigrostriatal
dopaminergic pathways through the study of dopamine transporter, a presynaptic protein
with a role in dopamine uptake[63]. The most used radiotracer is 123-I-ioflupane (DATSCAN), but some countries use
other tracers like TRODAT-1 (a tropane derivative labeled with 99mTc), whose images are acquired with SPECT, a more spread technology than PET. In DLB
and PD, there is a low uptake in basal ganglia, demonstrating the loss of dopaminergic
neurons from the nigrostriatal pathways([Figure 1]). The specificity and sensitivity to distinguish from AD is 90% and 78%, respectively,
which would justify it as an indicative biomarker[62]. It is also very useful for differentiating neurodegenerative parkinsonism from
secondary ones (such as medication), and from essential tremors. However, it would
not have good specificity to distinguish from other dementia with parkinsonism (eg,
PSP and CBD), which makes it questionable as an indicative biomarker in a patient
exclusively with parkinsonism and dementia, without other main symptoms[64].
Myocardial scintigraphy with iodine-123-labeled meta-iodo-benzyl-guanidine (123I-mIBG)
is another biomarker with good sensitivity (69%) and high specificity (87%, reaching
94% in mild cases) to differentiate DLB from AD[62]. mIBG is a molecule captured by pre-synaptic noradrenergic neurons and is therefore
a biomarker of postganglionic sympathetic innervation. In patients with DLB, there
is a denervation of sympathetic fibers in the myocardium and, consequently, there
is a low cardiac uptake of 123I-mIBG on scintigraphy. Care should be taken in diabetic patients, autonomic neuropathies,
heart disease and users of tricyclics antidepressants, as there may be false-positive
low uptake in these individuals.
FDG-PET is considered a supportive biomarker of DLB. As in AD, the pattern is usually
of temporoparietal hypometabolism. However, unlike in AD, there may be also a characteristic
occipital hypometabolism in DLB, with a sensitivity of 70% and specificity of 74%
([Figure 1]) when present[62]. In addition, there is a relative preservation of the posterior cingulate (which
is classically affected in AD), called the “posterior cingulate island sign”[65]. Amyloid PET, in turn, is of little use in distinguishing between AD and DLB, as
there is a variable frequency of deposition of amyloid pathology in patients with
DLB.
MOLECULAR NEUROIMAGING IN FRONTOTEMPORAL DEMENTIAS
Frontotemporal dementias (or frontotemporal lobar degeneration) correspond to a group
of neurodegenerative diseases where there is a selective involvement of the frontal
and temporal lobes[66]. From a clinical phenotype point of view, they comprise two large groups: the behavioral
variant (vbFTD) and primary progressive aphasias (PPA). Among the PPAs, in turn, there
are three variants: the agrammatic or non-fluent (nfvPPA) and the semantic (svPPA).
The logopenic variant of PPA is not part of the FTD syndrome, because of the common
underlying AD pathology. More recently, some authors propose a third group of FTD:
the motor variants, which would include atypical parkinsonism (PSP and CBD) or motor
neuron disease (FTD with amyotrophic lateral sclerosis)[67]. bvFTD corresponds to the second cause of degenerative dementia in the pre-senile
age group, after AD.
Just as there is phenotypic heterogeneity, FTD is characterized by pathological variability
([Figure 1]). Three proteins are associated with FTD: tau, TDP-43 (transactive response DNA
binding protein of 43 kDa) and FUS (fused in sarcoma protein). To date, there is no
specific radioligand for the last two proteins. In the case of tau protein, studies
focus mainly on the use of tau PET in AD, but some studies have been published in
samples of patients with FTD, PSP and CBD. As previously described, PSP has been studied
as a model of primary tauopathy because, unlike the other phenotypes, PSP is almost
exclusively caused by deposits of 4R-tau protein[68].
Some PET studies highlight the importance of tau protein deposition in FTD. In a study
with [18]F-flortaucipir in patients with various FTD phenotypes, including genetic forms of
FTD (MAPT and C9orf72 mutations), there was an increase in uptake in the left inferior
frontal gyrus compared to the right in cases of nfvPPA. Half of the cases of bvFTD
had increased uptake in the frontotemporal region, being more intense in MAPT mutation
carriers. Furthermore, uptake of [18]F-flortaucipir was observed in cases of svPPA and mutation of C9orf72 mutation, whose
proteinopathy is usually TDP-43[69]. In another study, using the radiopharmaceutical [18]F-MK-6240 in patients with genetic FTD, a mild uptake was noted in cases of symptomatic
MAPT carriers. Only one case of a patient with a non-tau mutation (in this case, C9orf72
mutation) showed minimal tracer uptake, suggesting that [18]F-MK-6240 may be a potential marker for primary tauopathies[70].
However, FDG-PET is still the most-used molecular neuroimaging method in FTD. The
presence of a clinical syndrome with typical pattern of hypometabolism makes the diagnosis
of FTD or PPA likely, according to diagnostic criteria[71],[72]. In bvFTD, the pattern of hypometabolism is the involvement of the orbitofrontal
region, dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate,
temporal poles, and basal ganglia, often asymmetrically ([Figure 1]). In patients whose underlying pathology is a tauopathy (particularly in Pick's
disease), anterior frontotemporal atrophy may be very pronounced compared to the posterior
temporoparietal cortex ("knife-edge" pattern). Patients with MAPT mutations present
a relatively symmetrical pattern of hypometabolism of the orbitofrontal, dorsolateral
prefrontal, and especially the anterior temporal lobes. In individuals carrying the
GRN mutations, hypometabolism is asymmetric, with extension to the parietal lobe[73]. In patients with FUS pathology, there is a characteristic involvement of the caudate
nuclei and ventral frontal cortex[73],[74].
In PPAs, hypometabolism reflects the pattern of pathology involvement within the language
neural network. In nfvPPA, the left inferior frontal cortex is affected, commonly
extending to the anterior insula. The hypometabolism of the temporal poles, more to
the left, with extension to the lateral temporal cortex, is the hallmark of the svPPA
pattern. lvPPA is characterized by left temporoparietal hypometabolism, a typical
pattern of AD[72].
