neuroimaging in alzheimer’s disease emily altmananthony grigas sue kotchgeorgine pindar elizabeth...

Neuroimaging in Alzheimer’s Disease

Emily Altman•Anthony Grigas

Sue Kotch•Georgine Pindar

Elizabeth Thompson

Alzheimer’s DiseaseDefined

Alois Alzheimer 100 years ago41

Chronic neurodegenerative disorder characterized by the pathological accumulation of insoluble intraneuronal and extraneuronal proteins in the brain and neuronal degeneration

The most common cause of degenerative dementia in individuals over 6511

Alzheimer’s DiseaseAppearance

Progressive alterations in functional status secondary to cognitive deficits42

Warning signs Progression beginning with short-term

memory deficits or “forgetfulness.”

Alzheimer’s DiseaseThe Facts12

One of the principal causes of disability and decreased Quality of Life among older adults

4th leading cause of death due to disease in people over 65

In 2000: 4.5 million people with AD in the US Barring a cure: 13.2 million people will have

AD in 2050 Cost of treatment in US is $100 billion/year


Prognosis: inexorable decline and eventual death

Primary risk factors: age, family hx, genetic markers, female gender after 80, HTN, diabetes, obesity, ↑cholesterol

Possible risk factors: head injury, depression, low TSH, folate deficiency, low educational attainments


Possible protective factors: Homozygous APOE2, fish consumption, omega-3 fatty acid, high educational level, regular exercise, NSAID therapy, moderate ETOH intake, vitamins C, E, B6, B12, folate

Alzheimer’s DiseaseHistology 101

Pathology located in the entorhinal cortex, hippocampus, frontal and temporal cortices13

– Neuronal loss (atrophy/shrinking of brain tissue volume)

– Synaptic loss– Accumulation of insoluble proteins

Extracellular: Amyloid β protein or senile plaques Intracellular: Neurofibrillary tangles composed of

hyperphosphorylated tau protein

Neuritic Degeneration

Tau & Neurofibrillary Tangles

Synaptic degenerationNeuronal Death

Amyloid & Senile Plaques

Alzheimer’s Disease

Pathogenesis of Alzheimer’s Disease

Unknown– Amyloid cascade hypothesis– Tau hypothesis– Apoptosis hypothesis– Pathologic return to cell cycle– Attrition hypothesis– Genetic influences– Vascular theory

Current Pharmacological Interventions

Currently two classes of compounds– Cholinesterase inhibitors

Aricept

– A Partial NMDA receptor antagonist Memantine

Symptom management

Diagnosing Alzheimer’s Disease

Clinical Diagnosis Autopsy Neuroimaging

- Description

- New horizons

- Prognostic value?

Diagnosing Alzheimer’s DiseaseClinical Diagnosis

Clinical diagnosis requires 3 elements43:- Insidious onset of anterograde memory loss- Progressive decline in memory and mental functions as measured by neurocognitive tests- Cognitive and laboratory tests exclude all other differential diagnoses


Laboratory tests to rule out other possible sources of symptoms

- Reversible dementia: nutritional deficiencies, normal-pressure hydrocephalus, subdural hematoma, hypothyroidism, brain tumor, hyponatremia, drug toxicity, alcoholism, infection12

- Non-reversible dementia: Parkinson’s Disease, HIV/AIDS, organic brain disease, cerebrovascular disease53


Clinically diagnosed Alzheimer’s may be preceded by a stage of “mild cognitive impairment” (MCI), in which loss of memory and function does not yet meet the criteria for an Alzheimer’s diagnosis43,26

Post-mortem examination

- Autopsy is the only way to definitively identify Alzheimer’s pathology (plaques and tangles)12

- Examiners track the incidence and locations of neuritic plaques and neurofibrillary tangles53

- Disease process is considered more advanced if there are more plaques and tangles, and if they have spread out of the limbic/thalamic regions into the cortex27

Diagnosing Alzheimer’s DiseaseAutopsy

Diagnosing Alzheimer’s DiseaseAutopsy

Post-mortem examination- Uses CERAD scale and Braak staging to quantify

tangles and plaques27

- Sample taken in coronal sections around temporal lobe, hippocampus, entorhinal cortex53

Clinical diagnosis correlates well with autopsy diagnosis (74-90%)43

Diagnosing Alzheimer’s DiseaseNeuroimaging - Description

PET scan:

- F-18 isotope attached to fluorodeoxyglucose (FDG)

- studies brain metabolism of glucose

- provides good test to distinguish Alzheimer’s pathology from vascular dementia

(sensitivity 95%, specificity 71%)26

- H215O used to measure “regional cerebral blood

flow”26, an indirect measure of oxygen usage.


MRI- Structural MRI used to detect brain atrophy, especially in the entorhinal cortex, hippocampal region, medial temporal lobe, and posterior cingulate gyrus.

- Functional (fMRI) tracks blood flow during a task with better spatial resolution than PET, as well as no ionizing radiation. However, it is much more expensive.


MRI- MRI to study cerebral perfusion

- contrast media- arterial spin-labeled

SPECT- Provides perfusion info using tracer chemicals- Most useful in early stages of Alzheimer’s

Diagnosing Alzheimer’s DiseaseNeuroimaging – New horizons

Synchrotron X-ray fluorescence of metals

- Fe and Zn more concentrated in

plaques than normal tissue

- can be detected in very small amounts16

Diagnosing Alzheimer’s DiseaseNeuroimaging – Prognostic value

When combined with genetic testing (for APOE4 allele), FDG PET and fMRI can identify atypical activation patterns in high-risk, asymptomatic persons14,27.

In some cases, onset of symptoms may be predicted up to 3 years in advance.26

But with these research areas so new, and the tests so expensive, is neuroimaging really a good tool to fight Alzheimer’s?...

Use of Neuroimaging in Alzheimer’s Disease

The use of neuroimaging in AD is limited for many reasons including:

– Limited research– Existence of reliable cognitive exams– Once clinical signs present, already irreversible brain

damage– MRI is a costly test– Unable to see plaques and tangles on imaging– Common to see some imaging results with AD that also are

present with different types of dementia


Limited Research

No neuroimaging or lab markers now exist for reliable presymptomatic diagnosis of AD12.

The exact mechanism by which brain degeneration results from neurofibrillary tangles and amyloid plaques remain incompletely understood41.


Reliable Cognitive Exams

A probable diagnosis of AD can be established pre mortem with a confidence interval of ~80% based on the following clinical criteria:– Medical history– Physical exam– Lab tests– Radiology– Neuropsychological evaluation16


Irreversible Brain Damage

By the time individuals show signs of cognitive impairment due to AD or MCI as a precursor to AD, they already have irreversible brain pathology.

The prodromal (preclinical) phase of AD includes a period of disease pathology that is clinically undetectable or uncertain43.


Similar Imaging Results

Neurofibrillary tangles can be found in AD and other forms of dementia. They can be seen in the absence of plaques, while the same amount of plaques can be found in both people with AD and non-pathologic elderly. Plaques are specific to AD but may also occur in the absence of dementia36.

Diagnostic Imaging ForDifferential Diagnosis

COMMON TYPES OF DEMENTIA Alzheimer's Disease Vascular Dementia Dementia with Lewy Bodies

Neuroimaging Forthe

Diagnosis of Alzheimer’s Disease

Alzheimer's Disease– Structural MRI

Greater atrophy of hippocampus and parahippocampus than in DLB3

Atrophy of the entorhinal cortex is present in MCI27

Volume change of entorhinal cortex27

– Normal aging <1%– Early AD 4%

Neuroimaging Forthe


Alzheimer's Disease– Functional Studies

Cerebral metabolism– PET

Cerebral perfusion– SPECT– PET– MRI

Neuroimaging Forthe


Alzheimer's Disease– Activation Studies27

PET– Water marked with radioactive oxygen measures cerebral

regional blood flow (rCBF).– The rCBF increases paralled to the increase in oxygen

need, which corresponds to the increase in synaptic activity in the part of the brain being activated.

MRI– Greater spatial and temporal resolution than PET– No ionizing radiation

Neuroimaging Forthe


Alzheimer's Disease– Regional density as measured by PET27

Compounds being developed that detect amyloid deposition and neurofibrillary tangles

Not readily available yet Further studies need to be done

Neuroimaging for the

Diagnosis of Vascular Dementia

Vascular Dementia– Initially thought to be caused by recurrent strokes– No pathological criteria exist for the diagnosis– “Cerebrovascular disease resulting in dementia”– MRI or CT Scan

Subcortical infarcts Ischemic changes Leukoaraiosis

Diagnostic Imaging forthe

Diagnosis of Dementia with Lewy Bodies

Dementia with Lewy Bodies (DBL)– Protein lumps found in the nuclei

Cortical or subcortical

– PET Hypometabolism29

Diagnostic Imaging forthe

Diagnosis of Dementia with Lewy Bodies

DLB– Supportive Features29

MRI or CT Scan– Preservation of medial temporal lobe structures– Hippocampal and parahippocampal volumes are significantly

larger when compared to AD SPECT

– Atrophy of putamen and occipiatl hypoperfusion PET

– Hypometabolism Low uptake on MIBG myocardial scintigraphy Prominent slow wave activity on EEG with temporal lobe

transient sharp waves

Neuroimaging forthe

Diagnosis of “Mixed Dementia”

Mixed Dementia– AD vs VaD

Combined pathology very common Autopsy final determination

Use of Neuroimaging Results Prognosis

Prognosis = very difficult to predict/evaluate on an individual level– Density of amyloid plaques: poor correlation with

severity of dementia– Vague trend toward ↓medial temporal lobe

volume as severity of dementia increases– ↑NF tangles seems to correlate with ↓cognitive

skills, but very late in disease progression

Use of Neuroimaging Results Selection of Intervention/Management

fMRI (Functional MRI)– Has been used in research to measure changes in brain

function as it is related to cognition.– Used as an indirect measure of neural activity as it

examines changes in blood oxygenation signal intensity.– Treatment strategies may be considered based on results

found on the group level, however clinicians will need to identify neurotransmitter system dysfunction in each individual.

– Currently not used frequently in clinical setting due to cost, unable to detect all plaques and tangles in AD, unable to detect pre-symptomatic AD, and damage already done.

Use of Neuroimaging Results Selection of

Intervention/Management

Pharmacological Intervention Current pharmacological treatment

approaches are based upon staging of AD.– Mild to Moderate AD

Acetylcholinesterase Inhibitors (Donepezil, Galantamine, Rivastigmine, Tacrine)

– Moderate to Severe AD NMDA antagonists (Memantine)


Acetylcholinesterase Inhibitors– Helps to delay the disease process in terms of

cognitive function and improves activities of daily living.

– Enhances cholinergic activity by inhibiting the enzyme acetylcholinesterase which metabolizes the neurotransmitter acetylcholine rapidly and improves cognitive function.


NMDA Antagonists– Improves functional capacity, global clinical status, and

cognitive domains in advanced stages of AD.– Attaches to NMDA receptors in the brain and regulates

glutamate allowing for the appropriate chemical environment for the brain to process, store, and retrieve information for learning and memory.

– Regulates glutamate to control the balance of calcium and prevent further nerve cell death.

Limitations Seen in MRI Studies

Small sample sizes No effective disease stage classification used for experimental group “MRI protocol” varies widely

– No uniformity/standardization of imaging acquisition and processing– Variety of choice of structures are used– Tracing methods vary, are often done by hand and are very labor

intensive and complex – +/- head size corrections– +/- establishment of interrater reliability for methods– Lack rater-independent objective measures of brain anatomy and

function Often lack post-mortem confirmation of “probable AD” diagnosis of

the experimental group What is the MCID for volume change?

Points to Ponder

We are treating this disease totally in the dark Think complement, not compete Biases of neuropsychological (cognitive) tests

used in the diagnosis of AD Need a preclinical diagnosis…then what? The pathologic burden of AD begins decades

before diagnosis

Discussion Questions

1. We are in an era of “pre-emptive” medical testing. Especially as clients age, they are advised to get early-detection tests even in the absence of any clinical symptoms (i.e. mammograms.) Do you think pre-emptive MRIs (or other imaging) are warranted to look for signs of Alzheimer’s?

2. Clinically speaking, would you treat a client with stroke differently if they manifest no symptoms, but their MRI also shows changes suggestive of Alzheimer’s? A client with hip fracture (and a positive MRI)? A client with elective knee replacement and “no health problems” (but a positive MRI)?

3. Despite an abundance of research on the use of MRI in the diagnosis of AD, in “real life” medical clinics, the use of MRI imaging is not the standard of care. Knowing the definition of Alzheimer’s disease (on a histological/tissue level), knowing how it is currently diagnosed in neurology clinics, and understanding a little about MR imaging, discuss why MR imaging is not yet the standard of care or routinely used in diagnosing patients with Alzheimer’s disease.

Thank You

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53 www.alzforum.org

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