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KEY FACTS

Terminology
- Alzheimer disease (AD) - Slowly progressive neurodegenerative disease
Imaging
- Current role of imaging in AD - Exclude other causes of dementia - Identify region-specific patterns of brain volume loss - Identify imaging markers of coexistent disease, such as amyloid angiopathy - Identify early AD for possible innovative therapy
- Best imaging = volumetric MR, F-18 FDG PET
- Thinned gyri, widened sulci, and enlarged ventricles
- Medial temporal lobe particularly hippocampus and entorhinal cortex disproportionately affected
- F-18 FDG PET - Early-stage AD: ↓ metabolism in parietotemporal association cortices, posterior cingulate, and precuneus regions - Moderate to severe AD: Additional frontal lobe involvement
- Amyloid PET imaging: High sensitivity in detecting amyloid plaques and vascular amyloid in vivo
Top Differential Diagnoses
- Normal aging
- Vascular dementia
- Normal-pressure hydrocephalus
- Frontotemporal lobar degeneration
- Dementia with Lewy bodies
Clinical Issues
- Most common cause of dementia > age 65
- Age is biggest risk factor - 1-2% prevalence at age 65 - Incidence doubles every 5 years after age of 60
Diagnostic Checklist
- Look for reversible causes of dementia

TERMINOLOGY

Abbreviations
- Alzheimer disease (AD)
Synonyms
- Senile/presenile dementia of Alzheimer type
Definitions
- AD dementia is progressive neurodegenerative condition characterized by progressive cognitive decline, memory impairment, and adverse impact on activities of daily living
- National Institute on Aging and Alzheimer's Association (NIA-AA) 2011 workgroup recommendations - Phases of AD pathophysiological processes - Preclinical AD - Mild cognitive impairment (MCI) in AD - AD dementia
- AD is pathologic process reflected in specific postmortem histopathologic criteria, which is frequently but not necessarily associated with characteristic dementia syndrome
- Probable AD dementia: Clinical syndrome meeting core clinical criteria specified in NIA-AA workgroup report
- Possible AD dementia: Clinical syndrome meeting core clinical criteria for AD dementia in terms of nature of cognitive deficits for AD dementia, but either 1) has sudden onset of impairment or demonstrates insufficient historical detail or objective documentation of progression, or 2) has mixed etiological presentation due to evidence of vascular or Lewy body pathology
- MCI: Clinical syndrome meeting published core clinical criteria for MCI; generally agreed core features include 1) concern for change in cognition, 2) impairment in one or more cognitive domains, and 3) preservation of independence in functional activities, but 4) not demented

IMAGING

General Features
- Best diagnostic clue
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- MR: Temporal/parietal cortical atrophy
        - Disproportionate hippocampal volume loss
- FDG PET: Regional ↓ glucose metabolism
        - Temporoparietal lobes, posterior cingulum
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- Current role of imaging in AD - Exclude other structural abnormalities - Evaluate degree and location of atrophic changes - Evaluate for metabolic abnormalities - When structural abnormalities absent/uncharacteristic (i.e., early in disease course) - Identify preclinical and MCI in AD for possible innovative therapy

CT Findings

NECT

- Screening to exclude potentially reversible or treatable causes of dementia
- Medial temporal lobe atrophy in early disease and generalized atrophy in late stages

MR Findings
- Current role of MR - Exclude other causes of dementia - Identify region-specific patterns of brain volume loss - Identify imaging markers of coexistent disease, such as amyloid angiopathy
- T1 to assess medial temporal atrophy score and atrophy patterns - High resolution (MPRAGE/SPGR) for volumetric analysis - Thinned gyri, widened sulci, and enlarged ventricles - Medial temporal lobe disproportionately affected - May help distinguish patients with MCI from normal elderly - Average hippocampal volume reduction 20-25% in AD and 10-15% in MCI
- T2* GRE/SWI for microhemorrhages, amyloid angiopathy
- MRS - ↓ NAA and ↑ mI in AD, even in early stage - NAA:mI ratio relatively sensitive and highly specific in differentiating AD from normal elderly - NAA:Cr ratio in posterior cingulate gyri and left occipital cortex predicts conversion of MCI to probable AD
- DTI: ↓ FA in multiple regions, especially superior longitudinal fasciculus and splenium
- Perfusion MR: ↓ rCBV in temporal, parietal regions
Nuclear Medicine Findings
- F-18 FDG PET - Early-stage AD - ↓ metabolism in parietotemporal association cortices, posterior cingulate, and precuneus regions - Most reliable early changes in posterior cingulate - Moderate to severe AD - Additional frontal lobe involvement - MCI in AD - Same pattern of ↓ metabolism as AD - Higher accuracy than MR for diagnosing early AD
- Amyloid (Aβ) PET imaging - Specifically bind to Aβ plaques and retention of tracer is specific for Aβ neuritic plaque pathology - F-18 florbetapir, F-18 florbetaben, and F-18 flutemetamol FDA approved for clinical use - Positive scan shows loss of gray/white matter distinction due to tracer uptake in neocortex - Negative scan retains gray/white matter distinction - Criteria for appropriate use (AUC) of amyloid PET - Persistent/progressive unexplained MCI - Possible AD with unclear presentation - Atypical early-onset progressive dementia - In patients with MCI fulfilling clinical AUC, Aβ-PET is associated with - Significant improvement in diagnostic confidence - High impact on therapeutic management
- Tau PET imaging - Currently under development - Signal matches anatomic distribution of neurofibrillary tangles - Earliest detection in entorhinal cortex and hippocampus, later inferior and lateral temporal, followed by parietal and occipital, and finally frontal cortices

Imaging Recommendations

Best imaging tool

- Volumetric MR (MPRAGE/SPGR sequences)
- F-18 FDG PET
- Aβ PET for patients who meet AUC

Protocol advice

- MPRAGE or SPGR for volumetric measurement

DIFFERENTIAL DIAGNOSIS

Causes of Reversible Dementia
- Thiamine deficiency, vitamin B12 deficiency, hypothyroidism
- Depression ("pseudodementia")
- Normal-pressure hydrocephalus
- Mass lesions (chronic subdural hematoma, tumor, etc.)
Vascular Dementia
- 2nd most common dementia (15-30%)
- Parenchymal hyperintensities, focal atrophy (infarcts)
Frontotemporal Lobar Degeneration
- Frontal &/or anterior temporal atrophy
Dementia With Lewy Bodies
- Hypometabolism of entire brain
Corticobasal Degeneration
- Prominent extrapyramidal, cortical symptoms
- Asymmetric severe frontoparietal atrophy
Creutzfeldt-Jakob Disease
- Dementia with myoclonus, EEG abnormalities
- Hyperintensity in anterior basal ganglia, cortex
Cerebral Amyloid Angiopathy
- Often coexists with AD
- Microhemorrhages on T2* GRE/SWI

PATHOLOGY

General Features

Etiology

- Extracellular β-amyloid plaques
        - Located in cerebral cortex
- Intracellular accumulation of neurofibrillary tangles (NTs)
        - Initially around hippocampus, later spread to other cortical areas

Genetics

- Most cases late-onset sporadic AD
        - Deterministic genetic mutation not found
        - Apolipoprotein E (*ApoE*) ε4 allele is major genetic risk factor
- Rare early-onset AD
        - Mutations in 1 of 3 genes
                  - Amyloid precursor protein gene on chromosome 21
                  - Presenilin-1 (*PSEN1*) gene on chromosome 14
                  - Presenilin-2 (*PSEN2*) gene on chromosome 1

Staging, Grading, & Classification
- Consortium to Establish a Registry for Alzheimer Disease (CERAD) - Semiquantitative approach counting plaques/tangles - Frequent, moderate, or infrequent
- Braak and Braak (B&B) - 6 levels of staging - Transentorhinal stage (1-2): NTs develop in parahippocampal gyrus (clinically asymptomatic) - Limbic stage (3-4): NTs dramatically increase in parahippocampal gyrus, begin to develop in hippocampus (mild cognitive impairment) - Neocortical stage (5-6): NTs develop in temporal and parietal cortex, eventually spread to entire neocortex (severe dementia)
- NIA-Reagan - Likelihood high - CERAD frequent, B&B 5/6 - Likelihood intermediate - CERAD moderate, B&B 3/4 - Likelihood low - CERAD infrequent, B&B 1/2
Gross Pathologic & Surgical Features
- Shrunken gyri, widened sulci
Microscopic Features
- 2 abnormal protein aggregates characterize AD pathologically - Neurofibrillary tangles - Intracellular aggregates in neurons due to hyperphosphorylation of tau protein - Begins in entorhinal cortex, progresses to hippocampus, paralimbic system, and adjacent medial-basal temporal lobe - Aβ deposition - Hallmark of Aβ peptide deposit in AD is neuritic plaque - Dense Aβ core with inflammatory cells and dystrophic neurites in its periphery
- Neurodegeneration: Synapse and neuron loss

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Slowly progressive neurodegenerative disease
- Initially affects episodic memory
        - Then, at least 1 other area of cognition

Clinical profile

- Clinical subtypes
        - MCI: Early, mild memory impairment; no deficits in cognitive domains other than memory, not impairing daily function
        - Possible AD: Dementia features in presence of 2nd disease that could cause memory deficit but is not likely cause
        - Probable AD: Memory deficits on neuropsychological testing, progressive worsening of memory and ≥ 2 cognitive functions
        - Definite AD: Pathologic diagnosis

5 major biomarkers for AD - Amyloid accumulation: CSF Aβ 42, Aβ-PET imaging - Neurogeneration or neuronal injury: CSF tau (total and phosphorylated), structural MR, and FDG PET

Demographics

Age

- Biggest risk factor
        - 1-2% prevalence at age 65
        - Incidence doubles every 5 years after age of 60

Sex
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- Women more commonly affected
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Epidemiology

- AD most common neurodegenerative dementia
- 5-7 million new AD dementia cases every year
- Currently ~ 5.3 million in USA
        - 13% of individuals > 65 years and > 50% of individuals > 85 years

Other risk factors - Family history (20%) - Head trauma, metabolic syndrome

Natural History & Prognosis
- Chronic, progressive
- Patients live average 8-10 years after diagnosis
Treatment
- No established treatments
- May transiently improve cognitive function - Cholinesterase inhibitors, NMDA receptor antagonists
- Many current disease-modifying drugs to reduce Aβ

DIAGNOSTIC CHECKLIST

Consider
- Look for - Reversible causes of dementia - Ventricular enlargement, sulcal widening proportionate - ↑ temporal horns of lateral ventricle - Hippocampal, entorhinal cortex volume loss
Image Interpretation Pearls
- MR volumetric analysis helps distinguish MCI in AD from normal elderly subjects, measure change hippocampus/parahippocampal gyri over time
- F-18 FDG PET - Helps distinguish AD from frontotemporal dementia - May identify early AD when MR normal

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References

Selected References

Images

Selected Images

Clinical examination of a 72-year-old woman with AD shows typical findings for long history of memory deficit. FDG PET raw data and 3D SSP show preservation of the primary sensorimotor cortex . There is hypometabolism involving the bilateral parietotemporal association cortices and mild hypometabolism within the right greater than left posterior cingulate regions and, to a lesser extent, the precuneus regions . There is no hypometabolism in the primary visual cortices or frontal lobes. (Courtesy M. Matesan MD.)

Volumetric MR in a patient FDG PET positive for hypometabolic areas in bilateral temporoparietal lobes, posterior cingulate, and precuneus regions is shown. Bilateral hippocampi and lateral ventricle volumes are in normal range, indicating that FDG PET is more specific than quantitative MR in early AD. (Courtesy M. Matesan, MD.)

Axial T2 MR in a patient with AD shows enlarged temporal horns and disproportionate volume loss in the temporal lobes as compared to the normal-appearing occipital lobes .

F-18 AV-45 (florbetapir) PET in a healthy control (left) shows nonspecific white matter uptake and preserved gray matter-white matter differentiation. In a patient with AD (right), there is marked cerebral gray matter uptake (Aβ deposition) with loss of gray matter-white matter differentiation. (Courtesy A. Ali, MD.)

Tc-99m HMPAO SPECT in a 67-year-old woman with suspected AD shows decreased perfusion in bilateral parietal lobes . (Courtesy J. Singh, MD.)

Coronal FDG PET in a 45 year old with slowly progressive dementia shows decreased metabolic activity in bilateral medial temporal lobes , slightly greater on the right.

Axial FDG PET in the same patient shows decreased metabolic activity in the left parietal lobe . Also note mild decreased metabolic activity in bilateral frontal lobes , indicating possible advanced disease. (Courtesy J. Singh, MD.)

Additional Images

Axial T2WI MR through the lateral ventricles depicts atrophy of the superior aspect of the temporal lobes and parietal lobe atrophy. (Courtesy J. Norfray, MD.)

Coronal T2WI MR through the temporal lobes depicts marked atrophy of the hippocampi. (Courtesy J. Norfray, MD.)

Axial T1WI MR through the inferior temporal lobes shows marked atrophy of the temporal lobes and enlargement of the lateral ventricles.

Axial FLAIR MR shows marked atrophy of the temporal lobes and enlargement of the sylvian fissures.

Axial T2WI MR through the inferior temporal lobes shows marked atrophy of the temporal lobes and enlargement of the parahippocampal fissures. (Courtesy J. Norfray, MD.)

MRS spectrum in the parietal lobe of a patient with probable AD shows decreased N-acetyl aspartate level (neuronal loss) and elevated myoinositol level (gliosis). (Courtesy J. Norfray, MD.)

FDG PET in a patient with dementia depicts hypometabolism (green and blue regions in cortex) in both parietal lobes, typical of AD. (Courtesy N. Foster, MD.)

FDG PET in the same patient shows a decreased rate of glucose metabolism in the posterior aspects of both temporal lobes, typical of AD. (Courtesy N. Foster, MD.)

Stereotaxic surface projection in AD shows mild hypometabolism in the temporal lobes and especially diminished in the parietal lobes . The Z-score map demonstrates the hypometabolism very well. (Courtesy N. Foster, MD.)

Axial NECT in a 59 year old with AD shows hippocampal atrophy is present, as evidenced by temporal horn enlargement . Both sylvian fissures are also very prominent. There was no evidence for intracranial mass lesion or ischemia/infarction.

Axial amyloid β PET using florbetapir in a 63-year-old man with slowly progressive dementia shows moderate amyloid neuritic plaque burden indicating AD.

Sagittal PET in early AD shows a classic pattern of hypometabolism in the posterior cingulate gyrus and precuneus . (Courtesy S. Nayak, MD.)

Axial graphic illustrates the presence of amyloid plaques in the cerebral gray matter .

Axial FDG PET in a patient with AD shows decreased glucose metabolism in both medial temporal lobes . Note the preserved glucose metabolism in the cerebellum and frontal lobes.

Axial FDG PET in the same patient shows decreased metabolism in both parietal lobes . Hypometabolism within both the temporal and parietal cortices is typical of AD.

Sagittal T1WI MR in a 72-year-old patient with suspected AD shows marked enlargement of the sylvian fissure compared to the other subarachnoid spaces. Cortical atrophy of structures around the sylvian fissures can be striking, as in this case.

Axial T1WI MR in the same patient 3 years later shows more prominent medial temporal lobe atrophy as well as enlargement of parahippocampal fissures. In addition, diffuse cerebral atrophy has progressed further. The patient was diagnosed as probable AD.

40 KiB Raw Blame History

KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Clinical Issues

Diagnostic Checklist

TERMINOLOGY

Abbreviations

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

CT Findings

NECT

MR Findings

Nuclear Medicine Findings

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Causes of Reversible Dementia

PATHOLOGY

General Features

Etiology

Genetics

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Clinical profile

Demographics

Age

Sex

Epidemiology

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Images

Selected Images

Additional Images

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