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KEY FACTS

Terminology
- Group of heterogeneous neurodegenerative disorders characterized by prominent language and word-finding difficulties
- This includes logopenic-variant primary progressive aphasia (lvPPA), semantic-variant primary progressive aphasia (svPPA), and nonfluent/agrammatic-variant primary progressive aphasia (nfvPPA)
Imaging
- Hypometabolism within critical brain areas on F-18 FDG PET - lvPPA: Left precuneus and temporoparietal region - svPPA: Left anterior temporal lobe - nfvPPA: Left inferior frontal lobe and insula
Top Differential Diagnoses
- Alzheimer disease (AD)
- Frontotemporal dementia (FTD) (behavioral variant)
- Vascular dementia
Pathology
- lvPPA is within AD spectrum
- svPPA and nfvPPA are within FTD spectrum
Clinical Issues
- Progressive language and word-finding difficulties - lvPPA: Impaired single-word retrieval, impaired repetition of sentences/phrases - svPPA: Impaired single-word comprehension/naming, object knowledge - nfvPPA: Agrammatism in language production, apraxia of speech
- No cure exists for primary progressive aphasias - Patients with lvPPA may be eligible for amyloid-binding therapies
- Engagement of social services and supportive care can aid with patients, families, and caregivers

TERMINOLOGY

Abbreviations
- Primary progressive aphasia (PPA)
Definitions
- Group of heterogeneous neurodegenerative disorders characterized by prominent language and word-finding difficulties
- Classically grouped, given their language-predominant symptoms, though they are separate pathologic processes

IMAGING

General Features

Best diagnostic clue

- Hypometabolism within critical brain areas on F-18 FDG PET
- Classically involves left cerebral hemisphere, given majority of people are left language dominant
- MR will demonstrate volume loss in affected areas in late-stage disease

Location

- Logopenic-variant PPA (lvPPA): Involves left precuneus and left temporoparietal region
- Semantic-variant PPA (svPPA): Involves left anterior temporal lobe
- Nonfluent/agrammatic PPA (nfvPPA): Involves left inferior frontal lobe and left insula

Imaging Recommendations

Best imaging tool

- F-18 FDG PET
        - Prominent, asymmetric hypometabolism within affected left cerebral hemispheric structures
- MR
        - Initially used to assess for alternative etiologies that could cause symptoms (i.e., neoplasm, infarct, infection, trauma)
        - Qualitative and quantitative volume assessment can be performed to identify areas of neurodegeneration in late-stage disease
- Amyloid PET
        - Positive in majority of lvPPA cases
        - Negative in svPPA and nfvPPA
        - Interpreted as "scant to few" (negative) or "moderate to frequent" (positive) β-amyloid neuritic plaques (Aβs)

Protocol advice

- MR
        - DWI/ADC, T2/FLAIR, and SWI/GRE performed to assess for alternative etiologies (vascular insults, neoplasms, infection)
        - 3D T1 MR to assess for subtle volume loss; can perform quantitative volumetric analysis
- F-18 FDG PET
        - Patient preparation
                  - Patient should fast, stop IV fluids containing dextrose, and stop parenteral feeding for 4-6 hours; blood sugar should be < 150 mg/dL
                  - Place patient in quiet, dimly lit room for 30 minutes prior to examination
        - Radiopharmaceutical: F-18 FDG
        - Dose: 7-10 mCi (260-370 MBq)
        - Dosimetry: Bladder is critical organ
        - Image acquisition: 45-60 minutes post injection
- Amyloid PET
        - No patient preparation necessary
        - Radiopharmaceutical: F-18 florbetapir (or other amyloid-based tracers)
        - Dose: ~ 10 mCi (370 MBq) for F-18 florbetapir
        - Dosimetry: Gallbladder, bowel, intestines are critical organs
        - Image acquisition: 30-50 minutes post injection for F-18 florbetapir

DIFFERENTIAL DIAGNOSIS

Alzheimer Disease (Classic Type)
- Most common dementia
- Memory impairment is prominent symptom
- Language difficulties typically reserved for advanced disease
- F-18 FDG PET demonstrates more symmetric temporoparietal hypometabolism
- Positive on amyloid PET
Frontotemporal Dementia (Behavioral Variant)
- Classically presents with behavioral and personality changes
- F-18 FDG PET demonstrates symmetric anterior frontal and temporal hypometabolism
- MR demonstrates corresponding atrophy in frontotemporal lobes
Vascular Dementia
- 2nd most common cause of dementia
- MR shows scattered infarcts of varying ages, typically in deep gray nuclei or within vascular territory
- Left middle cerebral artery (MCA) territory infarcts can affect areas involved in language and communication
Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)
- Recently described neurodegenerative disease that classically occurs in older adult patients (> 80 years old)
- Typically does not present with language difficulties
- F-18 FDG PET demonstrates hypometabolism within anterior temporal lobes and insula, usually bilateral

PATHOLOGY

General Features
- Undetermined cause, likely secondary to combination of genetic, lifestyle, and environmental factors
Staging, Grading, & Classification
- Diagnostic criteria - lvPPA - Core criteria: Impaired single-word retrieval, impaired repetition of sentences/phrases - Other features: Speech errors in spontaneous speech, spared single-word comprehension and object knowledge, spared motor speech, absence of frank agrammatism - svPPA - Core criteria: Impaired confrontation naming, impaired single-word comprehension - Other features: Impaired object knowledge, surface dyslexia/dysgraphia, spared repetition, spared speech production - nfvPPA - Core criteria: Agrammatism in language production, effortful/halting speech with speech sound errors and distortions (apraxia) - Other features: Impaired comprehension of syntactically complex sentences, spared single-word comprehension, spared object knowledge
Gross Pathologic & Surgical Features
- Late-stage disease demonstrates prominent volume loss within affected regions
- Increased sulcal volume within left cerebral hemisphere
- lvPPA is believed to be within Alzheimer disease (AD) spectrum - Associated with Aβ and τ neurofibrillary tangles (τ-NFT) (80% of cases)
- svPPA and nfvPPA are believed to be within frontotemporal dementia spectrum - svPPA is associated with TDP-43 - nfvPPA is associated with 4-repeat τ isoform (4R-τ)

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Progressive word-finding and language difficulties
        - lvPPA: Impaired single-word retrieval, impaired repetition of sentences/phrases
        - svPPA: Impaired single-word comprehension/naming, object knowledge
        - nfvPPA: Agrammatism in language production, apraxia of speech
- Delayed diagnosis can occur given lack of apparent memory loss or behavioral symptoms

Other signs/symptoms

- Late-stage disease will have memory loss/dementia
- Psychiatric issues (i.e., depression, anxiety) may be present

Natural History & Prognosis
- Progressive language and word-finding difficulties - End-stage disease presents with near-complete inability to communicate
- Memory loss is less evident in early disease and can present later in disease course - Significant distinction from AD, where memory loss is primary symptom and language difficulties are seen later in disease course
- No prominent behavioral, anger, or dysexecutive symptoms - Distinct from behavioral-variant frontotemporal dementia, where behavioral issues are evident early in disease course
Treatment
- No cure exists for PPAs
- lvPPA patients may be eligible for amyloid-targeting therapy
- No disease-modifying therapies exist for svPPA or nfvPPA
- Speech therapy and rehabilitation can aid in improving communication with caregivers/family
- Engagement of social services and supportive care can aid with patients, families, and caregivers

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls
- F-18 FDG PET - Asymmetric hypometabolism within left temporoparietal region (lvPPA), left temporal pole (svPPA), or left inferior frontal lobe and insula (nfvPPA)
- MR - Asymmetric left cerebral hemispheric volume loss within affected areas
Reporting Tips
- Identify asymmetric hypometabolism if present
- Describe key brain areas that are affected to convey specificity of underlying disease process
- Exclude alternative etiologies and identify normal areas of metabolism on F-18 FDG PET
- Consider additional imaging, such as amyloid PET, for suspected lvPPA, which would be beneficial for assessing candidacy for amyloid-targeting therapies

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References

Selected References

Images

Selected Images

A diagnostic decision tree for clinical diagnosis of primary progressive aphasia (PPA) subtypes is shown along with a 3D surface rendering of an FDG brain PET, indicating key areas of involvement in each PPA subtype: Nonfluent-variant PPA (nfvPPA), logopenic-variant PPA (lvPPA), semantic-variant PPA (svPPA).

Brain surface map of F-18 FDG PET in a patient with lvPPA demonstrates hypometabolism throughout the left temporoparietal region. Notice the asymmetry compared to the contralateral temporal lobe .

Axial F-18 florbetapir at the level of the lateral ventricles in a patient with lvPPA demonstrates diffuse radiotracer uptake throughout the supratentorial gray matter , consistent with moderate to frequent amyloid neuritic plaques.

Brain surface map of F-18 FDG PET in a patient with svPPA demonstrates focal hypometabolism in the anterior left temporal lobe. Notice how it is fairly localized to the anterior pole and asymmetric when compared to the contralateral side .

Brain surface map of F-18 FDG PET in a patient with nfvPPA demonstrates focal hypometabolism in the inferior left frontal lobe. This may be underrepresented on the surface map due to its location immediately adjacent to the mesial temporal lobe , so make sure to attend to this region on cross-sectional reformats.

Additional Images

Brain surface rendering of F-18 FDG PET of the brain in a patient with lvPPA demonstrates statistically significant areas of hypometabolism in the left temporoparietal region relative to an age-matched database.

Brain surface rendering of F-18 FDG PET of the brain in a patient with nfvPPA demonstrates statistically significant areas of hypometabolism within the left inferior frontal lobe relative to an age-matched database.

Brain surface rendering of F-18 FDG PET of the brain in a patient with svPPA demonstrates statistically significant areas of hypometabolism within the left anterior temporal lobe relative to an age-matched database.

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Pathology

Clinical Issues

TERMINOLOGY

Abbreviations

Definitions

IMAGING

General Features

Best diagnostic clue

Location

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)

PATHOLOGY

General Features

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Other signs/symptoms

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls

Reporting Tips

References

Selected References

Images

Selected Images

Additional Images

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