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Ross
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---
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title: "Alzheimer Disease"
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docid: "2aad3ac4-44fd-43e5-8e50-a86987483af3"
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breadcrumbs:
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- "Nuclear Medicine"
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- "Central Nervous System"
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- "Neurodegeneration"
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- "Alzheimer Disease"
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---
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# KEY FACTS
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- ## Terminology
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- Alzheimer disease (AD)
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- Progressive neurodegenerative brain disease related to build up of (Aβ) neuritic plaques and subsequent tau neurofibrillary tangles (NFTs)
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- ## Imaging
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- Amyloid PET
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- Cortical amyloid deposition on PET is early biomarker in AD and appears prior to clinical symptoms
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- Absence of amyloid plaque rules out AD in patients with dementia
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- ↓ gray-white matter differentiation in at least 2 regions or single area of focally ↑ gray matter uptake are signs of positive florbetapir study
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- F-18 FDG PET
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- Glucose hypometabolism in parietotemporal, posterior cingulate, and precuneus regions; usually symmetric
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- Glucose hypometabolism continues to worsen with disease progression
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- Atypical AD variants can show hypometabolism in occipital lobes, frontal lobes, or with marked bilateral asymmetry
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- SPECT
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- 2nd-line study if PET is not available/reimbursed
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- Tau PET
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- Cortical deposition of tau NFTs in posterolateral temporal lobes, parietal lobes, occipital lobes, and cingulate gyrus can stage disease severity
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- Negative to early disease stage by tau PET can predict better response to amyloid targeting therapies (ATTs) with 50% of patients showing improved memory function at 3 years of treatment
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# TERMINOLOGY
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- ## Definitions
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- Alzheimer disease (AD)
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- Progressive neurodegenerative brain disease generally characterized by impairments in episodic memory and other cognitive domains
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- Likely related to β-amyloid (Aβ) neuritic plaques and tau neurofibrillary tangles (NFTs) leading to synaptic dysfunction, neuronal/glial cell death
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- ATN(C) classification defines patient status according to amyloid (A), tau (T), neurodegeneration (N), and clinical (C) status
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- Amyloid determined by PET &/or certain cerebrospinal fluid (CSF) biomarkers with plasma biomarkers on horizon
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- Tau determined by PET &/or CSF markers with plasma biomarkers on horizon
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- Neurodegeneration typical for AD via MR, FDG PET, or CSF biomarkers
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- Clinical status by formal neurocognitive evaluation/screening with MMSE or MoCA
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- Role of imaging
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- Early detection of AD neuropathologic changes (ADNCs) prior to symptom onset
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- Diagnosis of AD with clinical presentation and other biomarkers
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- Differential diagnosis between AD and other causes of dementia
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- Preclinical AD or asymptomatic ADNC
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- Stage of disease process where pathologic Aβ plaque or tau NFT deposition has occurred but prior to onset of significant clinically detectable symptoms
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- Amyloid PET positive; positive CSF Aβ42 or p-tau181/217
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- Mild cognitive impairment (MCI)
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- Clinical symptoms of memory &/or other cognitive problems greater than normal for age and education
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- ↑ risk of conversion to AD but not all progress to full dementia
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- Annual conversion rate from MCI to dementia ~ 5-10%
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# IMAGING
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- ## General Features
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- ### Best diagnostic clue
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- ADNC (A+T+/-N+/-C-)
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- Amyloid PET positive (or CSF biomarker positive)
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- May or may not show changes on tau PET or FDG PET/MR
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- ↑ risk of developing AD symptoms
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- MCI and early AD (A+T+/-N+/-C+) clinically meeting criteria for MCI
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- Amyloid PET positive
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- F-18 FDG PET, tau PET, and MR abnormalities become more evident and can help stage disease severity, risk for symptomatic conversion of ADNC, and help assess likelihood that symptoms are related to AD
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- Mild clinical symptoms
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- Late AD (A+T+/-N+/-C+) clinically meeting criteria for dementia
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- Amyloid and F-18 FDG PET grossly positive
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- FDG PET hypometabolism and cortical tau PET accumulation can become more extensive or involve atypical areas
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- More extensive atrophy present (CT/MR)
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- ## Nuclear Medicine Findings
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- Amyloid PET imaging
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- F-18 florbetapir, flutemetamol, and florbetaben tracers are FDA approved
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- ↑ brain amyloid in gray matter on PET, normal off-target white matter binding to myelin proteins
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- Earliest imaging biomarker in AD
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- Absence of amyloid plaque rules out AD in patients with dementia
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- Interpretation of amyloid PET images
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- View in black-on-white background at high contrast levels (flutemetamol can be read in color)
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- View axial images 1st
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- Coronal and sagittal views for confirmation
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- Cerebellum gray-white differentiation is baseline for discerning normal gray matter from physiologic tracer retained in white matter
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- Positive scan (moderate or frequent Aβ deposition in cerebral cortex)
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- Blurring of gray/white matter junction due to radiotracer uptake in gray matter
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- ↑ gray matter uptake in temporal, parietal, and frontal cortices
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- Uptake in posterior cingulate gyrus and precuneus (may be early deposition sign)
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- F-18 florbetapir: ↓ gray-white matter differentiation in at least 2 regions or single area of focally ↑ gray matter uptake ≥ adjacent white matter = positive
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- Extent of amyloid deposition does not correlate with severity of AD
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- Negative scan (no evidence of significant Aβ deposition)
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- Symptoms unlikely due to AD
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- Does not exclude non-AD dementia
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- Artifacts and pitfalls
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- Severely diminished gray matter volume in AD patients may make abnormal exam appear normal due to contoured cortex
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- View fused PET/CT or PET/MR images as supplement to evaluate uptake relative to white and gray matter
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- Highest transaxial images above orbits often have diminished gray-white matter differentiation, even in normal patients
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- F-18 FDG PET
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- General F-18 FDG uptake patterns
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- MCI: Medial temporal lobe hypometabolism
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- Early AD
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- Relative reduction in activity in parietal, temporal lobes and posterior cingulate gyri and precuneus, usually symmetric
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- Advanced AD
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- Progression of findings present in early AD
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- Usually symmetric
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- Frontal lobe hypometabolism can develop later in disease course
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- Moderate to severe atrophy
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- Atypical AD patterns
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- Posterior cortical atrophy: Similar hypometabolism to typical AD + asymmetric occipital hypometabolism
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- Logopenic variant primary progressive aphasia (lvPPA): Similar to typical AD though with strong left-sided predominance (language dominant hemisphere)
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- Behavioral or dysexecutive AD: 50% similar to typical AD + extensive frontal hypometabolism; 50% indistinguishable from frontotemporal dementia (FTD) without parietal involvement
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- F-18 FDG PET most accurate when read in conjunction with quantitative software that compares F-18 FDG uptake to age-matched normal database
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- Surface projections also ↑ sensitivity for AD detection
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- SPECT perfusion with Tc-99m HMPAO or Tc-99m ethyl cystine dimer (ECD) has similar appearance as PET but ↓ resolution and sensitivity
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- Tau PET
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- Flortaucipir: Only FDA-approved tau PET tracer
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- Compare uptake to reference region [1.65 x mean standardized uptake value ratio (SUV) cerebellum], which acts as internal negative control during interpretation
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- Negative if cortical binding is limited to mesial and anteromedial temporal lobes or isolated frontal lobes, off-target binding to choroid plexus
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- Mild/early AD may be indistinguishable from normal study
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- Moderate AD if cortical binding extends to posterolateral temporal lobes and temporooccipital regions
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- Advanced AD if cortical binding extends beyond to parietal, occipital, and cingulate regions
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- Negative to early disease stage by tau PET can predict better response to amyloid targeting therapies (ATTs) with 50% of patients showing improved memory function at 3 years of treatment
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- ## MR Findings
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- T1WI, T2WI
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- Atrophy of medial temporal lobe structures (entorhinal cortex, hippocampus); visible as early as MCI and posterior structures (precuneus and parietal convexities)
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- Rates of whole-brain and hippocampal atrophy may be used to monitor progression of neurodegeneration and help stage AD severity
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- Can use volumetrix to quantitatively assess volume loss
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- ## Imaging Recommendations
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- ### Best imaging tool
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- Amyloid PET best for ruling out AD
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- Appropriate Use Criteria (AUC) for amyloid PET (SNMMI and AA joint task force)
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- Objectively confirmed persistent or progressive unexplained cognitive impairment
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- May satisfy core clinical criteria for AD but unclear presentation, such as atypical or mixed
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- Progressive dementia and atypically early age of onset (< 65 years)
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- Candidacy for ATTs
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- If considering amyloid PET, knowledge of Aβ pathology should ↑ diagnostic certainty &/or patient management
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- Amyloid and F-18 FDG PET can help to differentiate between AD and other causes of dementia (FTD, Lewy body dementia)
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- PET may be used in early diagnosis of ADNC
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- Correlate imaging results with clinical picture and other biomarkers of AD
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- ### Protocol advice
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- Amyloid PET
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- Patient preparation
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- Patient needs to lie still for 20-30 min; thus, immobilization techniques may be necessary
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- Radiopharmaceutical, dose, and time of scan post injection
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- F-18 florbetapir (Amyvid), 10 mCi, 30-50 min
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- F-18 flutemetamol (Vizamyl), 5 mCi, 90 min
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- F-18 florbetaben (Neuraceq), 8 mCi, 45-130 min
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- Dosimetry: Gallbladder wall receives highest dose, followed by intestines
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- Image acquisition
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- Depends largely on available PET scanner
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- CT typically used for attenuation correction; older PET scanners may use separate source (e.g., Ge-68/68-Ga) for transmission scan
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- Imaging begins 30-130 min after injection
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- 20-min acquisition
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- Matrix: Transaxial 128 x 128 or 256 x 256
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- Pixel size: 2-3 mm
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- Slice thickness: 2-4 mm
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- Filtered back projection or iterative reconstruction
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- F-18 FDG PET
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- Patient preparation
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- Patient should fast, stop IV fluids containing dextrose, and stop parenteral feeding for 4-6 hours
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- Blood sugar should be < 150-200 mg/dL
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- Patient should be placed in quiet, dimly lit room prior to and after injection for 30 min
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- Radiopharmaceutical: F-18 FDG
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- Dose: 5-20 mCi (185-740 MBq)
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- Dosimetry: Urinary bladder receives largest dose
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- Image acquisition: 30-60 min after injection
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- Perfusion SPECT
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- 2nd-line study if PET is not available
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- Patient preparation
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- Place patient in quiet, dimly lit room prior to and after injection for 30 min
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- Radiopharmaceutical
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- Tc-99m exametazime (HMPAO)
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- Tc-99m bicisate (ECD)
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- Dose: 15-30 mCi (555 MBq to 1.1 GBq)
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- Dosimetry
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- Tc-99m HMPAO: Kidneys receive highest dose
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- Tc-99m ECD: Bladder wall receives highest dose
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- Image acquisition
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- Optimal imaging time for Tc-99m HMPAO: 90 min post injection
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- Optimal imaging time for Tc-99m ECD: 45 min post injection
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- Tau PET
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- Dose: 10 mCi flortaucipir
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- Image acquisition: ~ 80 min after injection, 20-min acquisition
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- Dosimetry: Intestines and liver are critical organs
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# DIFFERENTIAL DIAGNOSIS
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- ## Vascular Dementia (Multiinfarct Dementia)
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- Impaired blood supply to brain regions
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- 2nd most common cause of dementia
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- Global atrophy with diffuse white matter lesions/infarcts that generally correlate with cognitive symptoms
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- ## Alzheimer Disease Mixed Dementia
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- AD and other dementia
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- ## Dementia With Lewy Bodies
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- Commonly presents with hallucinations, sleep disturbances, and parkinsonian motor features
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- F-18 FDG PET hypometabolism in occipital cortex distinguishes from typical amnestic AD
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- Consider DaT SPECT or FDOPA PET to help exclude posterior cortical atrophy if clinically uncertain
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- Can consider cardiac MIBG scan (reduced cardiac sympathetic activity in dementia with Lewy bodies, see on MIBG)
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- Skin biopsy for α-synuclein
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- ## Frontotemporal Dementia
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- Commonly presents with personality and behavioral changes, which can also be seen with behavioral/dysexecutive AD variants
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- Atrophy of frontal and anterior temporal lobes
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- Language variant FTDs (semantic and nonfluent agrammatic PPA) can mimic lvPPA
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- F-18 FDG PET hypometabolism primarily in frontal and anterior temporal lobes
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- Negative amyloid PET; helps exclude AD in favor of FTD
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- ## Creutzfeldt-Jakob Disease
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- Rapidly fatal, prion-related disease with impairments in cognition and behavioral changes
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- MR DWI: Hyperintensity in striatum, cingulum, neocortex
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- ## Causes of Reversible Dementia
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- [Normal-pressure hydrocephalus](/document/normal-pressure-hydrocephalus/834ccc3e-2116-4295-8408-0ac9a06bd2ff)
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- Hypothyroidism
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- Infections: Neurosyphilis, HIV
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- Trauma (e.g., chronic subdural hematoma)
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- Tumor, other mass lesions
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- Depression
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- Vitamin B12 deficiency
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- ## Other Neurodegenerative Disease
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- Parkinson disease
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- Huntington disease
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- ## Cerebral Amyloid Angiopathy
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- Abnormal accumulation of amyloid in leptomeningeal and cortical vessels, leading to intracranial hemorrhage
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- Can present with cognitive decline concerning for AD
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- Amyloid positive scan
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- MR is most helpful for finding lobar predominant microhemorrhages and superficial siderosis
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- Can have inflammatory variants and even amyloidomas (mimicking intracranial mass)
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- ## Primary Age-Related Tauopathy (A-T+N+/-C+)
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- Tau-related NFTs limited to temporal lobes without amyloid deposition on PET
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- Patients are typically much older than AD, and cognitive decline rate is typically slower
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- ## Limbic-Predominant Age-Related TDP-43 Encephalopathy
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- Amyloid negative (unless associated with AD copathology)
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- Typically in older patients (> 80 years)
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- Extensive temporal lobe FDG hypometabolism with less involvement of parietal structures
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- MR may show marked hippocampal sclerosis
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# PATHOLOGY
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- ## General Features
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- ### Etiology
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- Most likely combination of genetic, lifestyle, and environmental factors
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- Pathologic deposition of Aβ neuritic plaques and subsequent tau NFTs in pathogenesis
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- Accumulation of extracellular amyloid plaques contribute to disrupted synaptic communication and neuronal death
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- Accumulation of intracellular tau NFTs contribute to disruption of nutrient and molecular transfer and neuronal death
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- ### Genetics
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- Early-onset, familial AD
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- Single-gene mutation
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- βA precursor protein (*APP*) gene on chromosome 21
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- Presenilin 1 (*PSEN1*) gene on chromosome 14
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- Presenilin 2 (*PSEN2*) gene on chromosome 1
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- Results in formation of abnormal proteins involved in APP
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- May contribute to production of harmful forms of βA and βA-related pathology
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- Late-onset, sporadic AD
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- Significant risk is related to apolipoprotein E (*APOE*) gene on chromosome 19
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- ApoE plays role in cholesterol transport and βA maintenance
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- ApoE exists as 3 alleles (e2, e3, e4) with each individual carrying 2 copies
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- ApoE-e4 allele is present in 20-30% of USA population and confers ↑ risk for AD development
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- 40-65% of individuals with AD carry at least 1 copy of e4 allele
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# CLINICAL ISSUES
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- ## Presentation
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- ### Most common signs/symptoms
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- Significant impairment in memory and cognition with typical AD
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- Mood and personality changes with behavioral/dysexecutive AD variant
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- Language impairment, including sentence repetition, preserved single-word meaning with lvPPA
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- Visuospatial and visuoperceptual impairment with posterior cortical atrophy
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- ### Clinical profile
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- Preclinical AD
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- Amyloid PET turns positive during this period
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- No noticeable symptoms of AD with early AD brain changes (up to 20 years before symptoms)
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- MCI
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- Change in cognition within ≥ 1 cognitive domains with functional independence intact
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- Possible AD
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- Significant cognitive/behavioral symptoms
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- Must represent change from prior status
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- Must interfere with functional ability
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- In presence of sudden onset &/or another disorder that could cause similar symptoms, e.g., cerebrovascular disease
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- Probable AD
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- Insidious change of cognitive/behavioral symptoms that interferes with functional ability
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- Not in presence of another disorder that could cause similar symptoms
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- ## Demographics
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- ### Epidemiology
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- ~ 5.2 million in USA affected by AD
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- Most common cause of dementia (60-80% of cases)
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- Prevalence
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- ~ 11% of adults ≥ 65 years
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- ~ 32% of adults ≥ 85 years
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- ## Treatment
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- Novel amyloid-targeting antibody therapies slow decline and may improve mental status if started early
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- Requires initial baseline MR to exclude cerebral amyloid and preexisting risk for hemorrhage
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- Requires surveillance for development of amyloid-related imaging abnormalities (ARIA)
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- Cholinesterase inhibitors may delay worsening of cognitive symptoms for 6-12 months
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- NMDA inhibitors may temporarily delay worsening of symptoms
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# DIAGNOSTIC CHECKLIST
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- ## Key Imaging Findings
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- AD neuropathic change
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- Amyloid PET positive or positive key CSF biomarkers
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- AD
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- FDG hypometabolism develops in parietal lobes, precuneus, posterior cingulate gyrus, posterior temporal lobes, and frontal lobes in advanced cases
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- Tau PET shows NFTs in posterolateral temporal neocortex, temporooccipital regions, and, eventually, parietal and cingulate regions
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