From clinical phenotype to proteinopathy: molecular neuroimaging in neurodegenerative dementias

Studart-Neto, Adalberto; Coutinho, Artur Martins

doi:10.1590/0004-282X-ANP-2022-S138

Adalberto Studart-Neto

Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, São Paulo, SP, Brazil.

http://orcid.org/0000-0003-2260-5986

Artur Martins Coutinho

Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Radiologia e Oncologia, Divisão e Laboratório de Medicina Nuclear (LIM 43), São Paulo, SP, Brazil.

http://orcid.org/0000-0002-5555-4583

Correspondence:
Adalberto Studart-Neto; Email: adalbertostudartneto@gmail.com.

Conflict of interest:

There is no conflict of interest to declare.

Authors’ contributions:

ASN: contributed to study conceptualization, data curation, investigation, methodology, writing (original draft writing - review & editing) of the manuscript for important intellectual content; AMC: contributed to conceptualization, methodology, writing (original draft writing - review & editing) of the manuscript for important intellectual content.

Figures (2)
Tables (4)

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Figure 1.
Summary of the molecular imaging findings in the different neurodegenerative diseases. First line: spectrum of proteinopathies causing neurodegenerative dementias and their respective clinical phenotypes. Pathological proteins: TDP-43, FUS, Tau, beta-amyloid, and alpha-synuclein. Second line: Patterns of regional glucose hypometabolism on brain FDG-PET that suggest or support each proteinopathy.;Third line: Patterns of amyloid PET with ¹¹C-PIB in each condition. Fourth line: Patterns of uptake in dopamine transporter (DAT) SPECT or PET tracers or ¹⁸F-Fluordopa PET (SPECT images with ^99mTc-TRODAT). Fifth line: Patterns of uptake in cardiothoracic ¹²³I-mIBG scintigraphy, a tracer of the sympathetic innervation. The white arrow in the first image on the left, third line indicates hypometabolism in the left motor cortex in motor neuron disease (ALS/Mills Syndrome); yellow arrows in the last images on the right, third line: hypometabolism in both putamen and the cerebellum seen in MSA. Orange arrow in the last image on the right in the fifth line: absence of myocardial uptake of ¹²³I-mIBG seen in synucleinopathies.

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Figure 2.
Flowchart showing a proposal in the sequence of the request of molecular neuroimaging in the diagnostic investigation of cognitive and/or behavioral decline in the clinical practice. Abbreviations: FTD: frontotemporal dementia; AD: Alzheimer's disease; DLB: dementia with Lewy bodies.; PET: Positron Emission Tomography; SPECT: single photon emission tomography; FDG: ¹⁸F-Fluorodeoxyglucose; DAT: dopamine transporter; ¹²³I-mIBG: iodine-123-labeled meta-iodo-benzyl-guanidine; CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; CT: computed tomography.

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Table 1.
Patterns of regional glucose hypometabolism on brain FDG-PET in the main groups of neurodegenerative dementias.

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Table 2.
Alzheimer's disease biomarkers classified according to the pathological process (ATN system). Adapted from Jack et al.2828. Jack CR Jr , Wiste HJ, Weigand SD, Rocca WA, Knopman DS, Mielke MM, et al. Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study. Lancet Neurol. 2014 Oct;13(10):997-1005. https://doi.org/10.1016/s1474-4422(14)70194-2
https://doi.org/10.1016/s1474-4422(14)70... .

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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.2828. Jack CR Jr , Wiste HJ, Weigand SD, Rocca WA, Knopman DS, Mielke MM, et al. Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study. Lancet Neurol. 2014 Oct;13(10):997-1005. https://doi.org/10.1016/s1474-4422(14)70194-2
https://doi.org/10.1016/s1474-4422(14)70... .

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Table 4.
Advantages and disadvantages of amyloid PET.

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”)
Lewy bodies dementias	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

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

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

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.

[1] Correspondence:
Adalberto Studart-Neto; Email: adalbertostudartneto@gmail.com.

Brasil

Brasil

From clinical phenotype to proteinopathy: molecular neuroimaging in neurodegenerative dementias

Do fenótipo clínico à proteinopatia: a neuroimagem molecular nas demências neurodegenerativas

ABSTRACT