Research ArticleClinical Investigation

18F-FDG PET Imaging in Neurodegenerative Dementing Disorders: Insights into Subtype Classification, Emerging Disease Categories, and Mixed Dementia with Copathologies

Satoshi Minoshima, Donna Cross, Tanyaluck Thientunyakit, Norman L. Foster and Alexander Drzezga
Journal of Nuclear Medicine June 2022, 63 (Supplement 1) 2S-12S; DOI: https://doi.org/10.2967/jnumed.121.263194

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    18F-FDG and cerebral blood flow (CBF) PET. Crossed cerebellar diaschisis (CCD) (A) seen in a right (Rt.) middle cerebral artery (MCA) stroke. Decreased glucose metabolism (18F-FDG) and perfusion (CBF) in contralateral left (Lt.) cerebellar hemisphere (white arrow) where no ischemic injury is present. Decreased 18F-FDG uptake and CBF are secondary to deactivation of cortico–ponto–cerebellar tract (“remote effect”). Such remote effects are known to occur in neurodegenerative disorders. 18F-FDG uptake not only reflects local pathology, but also could reflect remote pathology. Knowledge of cortical pathways is crucial for scan interpretation. (B) Coupling between glucose metabolism (18F-FDG) and CBF in AD measured by PET and 3D-SSP analysis. Statistical t maps (top 2 rows) represent regional hypometabolism and hypoperfusion seen in a group of AD patients. Both 18F-FDG and CBF PET show similar regional changes, though CBF PET appears slightly less sensitive. Ratio maps between CBF and 18F-FDG (bottom row) indicate that metabolic-flow coupling is relatively preserved in areas both affected and not affected by AD. This observation supports use of various flow-related measurements such as perfusion SPECT, early flow images obtained as a part of amyloid PET or tau PET, or MRI-based perfusion imaging for dementia evaluation.

  • FIGURE 2.
    FIGURE 2.

    3D-SSP. Original transaxial images are anatomically standardized in the stereotactic coordinate system, and gray matter activity is extracted on a pixel-by-pixel basis by the 3D-SSP algorithm. Extracted data are then compared with a normal database (mean and SD), which is composed of similarly processed PET scans from multiple normal subjects. Differences between individual data and normal database are expressed as z score maps.

  • FIGURE 3.
    FIGURE 3.

    18F-FDG PET scan of patient with progressive mild cognitive decline. Original transaxial images (top 6 rows, black and white) demonstrate very mild metabolic reductions in parietal association cortex and posterior cingulate cortex/precuneus. However, such mild changes cannot be appreciated consistently. 3D-SSP z score maps (bottom row, from left to right: right lateral, left lateral, superior, inferior, anterior, posterior, right medial, and left medial views) from same patient demonstrate apparent metabolic reductions in posterior cingulate cortex/precuneus as well as parietal association cortex bilaterally seen on lateral, superior, and posterior views. Statistical mapping, if used appropriately, improves diagnostic accuracy and consistency.

  • FIGURE 4.
    FIGURE 4.

    18F-FDG PET 3D-SSP maps from representative cases of AD, DLB, versus bvFTD. Red indicates more severe hypometabolism. Mild cases (A) and severe cases (B) are shown.

  • FIGURE 5.
    FIGURE 5.

    18F-FDG PET 3D-SSP z score maps of representative cases of FTLD/FTD variants, bvFTD, svPPA, nfvPPA, lvPPA, and PSP (A) and LATE, AD, DLB, and FUS (B, z score maps superimposed on reference MR image). The case of nfvPPA presented here shows bilateral temporofrontal involvement with right side slightly more prominent than left. LATE demonstrates prominent involvement of medial temporal lobe and hippocampus (white arrows) and medial and orbital frontal cortices. 18F-FDG uptake in medial temporal lobe is relatively mild in AD and DLB. FUS demonstrates pattern involving frontal and anterior temporal lobes, resembling FTLD/FLD spectrum.

  • FIGURE 6.
    FIGURE 6.

    Cooccurrence of 4 major proteinopathies: amyloid, tau, α-synuclein, and TDP-43, and overlapping neurodegenerative disorders: AD, DLB, FTLD, PART, and LATE. Emerging proteinopathies such as fused in sarcoma (FUS), which belongs to the FET family of proteins (FUS, EWS, TAF15), have been identified in FTLD, comorbid with other proteinopathies, and awaiting further characterization. Pathologic diagnosis of neurodegenerative disorders involves new markers, and further investigations of clinicopathologic correlations including imaging will allow more precise antemortem diagnosis in the future.

  • FIGURE 7.
    FIGURE 7.

    Example of mixed dementia, PSP+AD. Antemortem 18F-FDG PET: transaxial images (top 4 rows) and 3D-SSP z score maps (bottom row, from the left to right: right lateral, left lateral, right medial, and left medial, anterior, posterior, superior, inferior views). Findings are consistent with PSP (white arrows) and AD (arrowheads). Left-dominant pathologies associated with crossed-cerebellar diaschisis in right cerebellar hemisphere. It is important to note that these findings do not necessarily preclude other mixed pathologies. However, the frontal findings best explained the patient’s clinical symptoms.

Tables

  • TABLE 1

    Differential Diagnosis of Neurodegenerative Dementing Disorders by 18F-FDG PET

    Major differential diagnosis: standard of care
     Alzheimer disease (AD)
     Frontotemporal dementia (FTD)
     Dementia with Lewy bodies (DLB)
    Subtype Classification of FTLD/FTD
     Behavioral variant FTD (bvFTD) and Pick’s disease (PiD)
     Primary progressive aphasia (PPA)
      Semantic variant PPA (svPPA) or semantic dementia   (SD)
      Nonfluent variant PPA (nfvPPA) or progressive   nonfluent aphasia (PNFA)
      Logopenic variant PPA (lvPPA) or logopenic   progressive aphasia (LPA)
     Movement disorders
      Progressive supranuclear palsy (PSP)
      Corticobasal degeneration (CBD)
    Recently recognized neurodegenerative disorders
     Limbic-predominant age-related TDP-43  encephalopathy (LATE)
     Hippocampus sclerosis (HS)
     Primary age-related tauopathy (PART)
     Argyrophilic grain disease (AGD)
     Fused in sarcoma (FUS)
    Mixed dementia with copathologies and overlapping disorders
     AD and vascular dementia (VaD)
     Dementia with multiple neurodegenerative copathologies  +/− VaD
  • TABLE 2

    Examples of Mixed/Comorbid Neurodegenerative Dementing Disorders

    Mixed/comorbid neurodegenerative dementing disordersReference
    AD and TDP-43, cerebral amyloid angiopathy(91)
    AD and corticobasal syndrome, FTLD-TDP, Lewy body disease(92)
    AD and CBD(93)
    AD and tauopathy, TDP-43(72)
    AD and DLB with TDP-43, tau, α-synuclein pathologies(94)
    DLB and AD pathology(95)
    FTLD-tau and AD and vascular copathologies(96)
    PSP and AD(97)
    PSP and AD and PD(98)
    PSP and AD, AGD, CBD, Lewy body disease(99)
    PiD and AD(100)
    PiD and AD, cerebral amyloid angiopathy, Lewy body disease(101)
    PiD and PSP(102)

    • PiD = Pick’s disease.

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