Neuroimaging in Alzheimer disease

Florence GOMBERT Biomedical engineering, U.T.C,

Overview
Alzheimer disease Signs 

Diagnostic Imagery Scanner Structural imagery : vMRI Functional imagery : fMRI SPECT / PET Magneto encephalography


AD images


Perspectives

Introduction
5–10% of people over 65 years old, 50% at age 95


AD will become an increasingly important public health issue.
Progressive decline of higher cognitive functions, memory, attention, planning, language..
Preserve motor function
Due to plaques, lesions and tangled bundles of fibers in the brain
Imagery explorations are used to: — eliminate curable cause of madness; — give argues to eliminate madness from vascular origin; — find argues in favor of AD diagnosis.

Introduction Main Signs of AD are:
Bilateral metabolic reduction in the parietotemporal association cortex,
Glucose metabolism reduction in the frontal association cortex, mainly in advanced disease,
Metabolic reduction in the medial temporal cortex
Most prominent Cortical atrophy in temporal, hippocampus and parahippocampal structures
Loss of white matter in late AD

Diagnostic imagery Scanner :
Eliminate tumor or subdural haematoma, haematoma
Detect an aspect of bilateral temporal atrophy
Prominent in hippocampus structures
Essential to detect past cerebrals vessels accidents
Scanner appears normal in AD
Not specific to AD

Diagnostic imagery Structural imagery (MRI) : Significant and early reduction and atrophy of the hippocampus and Para hippocampus region in AD



Good imaging of this atrophy (better than Scanner)  3D visualization
Early visualization of atrophy, early diagnosis
Exists also in Parkinson disease, vascular madness
Can't diagnostic AD. Predictive diagnosis. Volumetric MRI

 DWI

 Functional MRI

 MTI

Diagnostic imagery Structural imagery

MRI scan of patient with early-stage Alzheimer’s disease. Hippocampochoroidal fissure on right side is dilated (arrow), demonstrating hippocampal atrophy.

Diagnostic imagery Structural imagery  Volumetric MRI: Evaluation of white matter in AD patients – significantly smaller mean cerebral brain

matter and temporal volumes in AD – significantly greater mean ventricular and temporal lobe peripheral cerebrospinal fluid volumes compared to controls

Diagnostic imagery Structural imagery Volumetric

MRI:

Subcortical areas of study H: Hippocampus Anterior Posterior A: Amygdala PHC:Parahippocampal Cortex

Diagnostic imagery Structural imagery  Volumetric MRI : Results
Volume of Medial temporal lobe decline with

advancing severity of AD
Significant decrease in volume of amygdale in very mild AD
Amygdale is more likely to atrophy than hippocampus More atrophy = less cognitive function

Diagnostic imagery Structural imagery  Volumetric MRI : Results

Cut level

Hypocampus atrophy

Amygdala atrophy

These structures subserve memory function, and are the sites of major damage in Alzheimer's disease

Diagnostic imagery Functional imagery  Functional MRI:
Visualize normal brain function and abnormalities
Rapid acquisition data
Without radiotracer
Measure regional cerebral blood flow and volume
Use more the BOLD technique
Based on the blood oxygenation dependent effect  BOLD technique : study brain in action during Cognitive tasks in AD. Functional activation study.

Diagnostic imagery Functional imagery  Functional MRI:
Into MRI : magnetic field near deoxyhemoglobin is different from this of oxyhemoglobin.
Deoxyhemoglobin is like a magnetic heterogeneity.
Cerebral activity = enhance in oxygen in activated regions
This increasing reduces the heterogeneity due to desoxyhemoglobin
So, the signal increase

Diagnostic imagery Functional imagery  Functional MRI:
Oxyhemoglobine : diamagnetic.
Deoxyhemoglobine : paramagnetic

Diagnostic imagery Functional imagery  Functional MRI: BOLD effect, principle
BOLD effect = local variation of magnetic susceptibility by desoxyhemoglobin concentration variation (Contrast agent intrinsic)  T2* variation  variation of signal RMN amplitude
Ultra-speed imagery sequence sensitive to T2*  sequence EPI (Echo Planar Imaging).
Non invasive technique of cerebral activation indirect measurement
Very good spatial resolution (3 . 4 mm).
Temporal Resolution : around 1 s.

Diagnostic imagery Functional imagery  Functional MRI:
Applied and repeated easily, widely available
Combined with other functional, metabolic and structural techniques
Require a high degree of patient cooperation  Can use contrast agent gadolinium-DTPA
Clinical benefits lie in the earliest stages of AD

Diagnostic imagery Functional imagery fMRI images: Difference in brain activation during a memory test between two groups. One carries the apolipoprotein Eε4 allele ( known risk factor for Alzheimer's disease). This increase in activation may reflect a need to compensate for minor defects in memory - even though both groups appear normal.

Diagnostic imagery Functional imagery/Cerebral Scintigraphy
Reflects cerebral metabolism level cerebral blood flow or glucose consumption
Indirect measure. Good index of cellular activity
Whole brain functional activity is reduced in AD patients (results of PET et SPECT)
More tempo-parietal associative cortex
Diagnosis depend more on analysis methods than radiotracer or camera

Diagnostic imagery Functional imagery/Cerebral Scintigraphy SPECT:
Evaluate cerebral blood flow.
More a cerebral region is activated, more it needs blood
Observe hypo perfusion in the 2 temporo-parietal regions, prefrontal cortex, posterior cingulum
Neither sensitive nor specific
Not systematically recommended examination

Diagnostic imagery Functional imagery/Cerebral Scintigraphy SPECT:

SPECT in Alzheimer, phase state. Look at the bilateral hypo perfusion but quiet asymmetrical.

Diagnostic imagery Functional imagery/Cerebral Scintigraphy PET :
Determine cerebral glucose metabolism in ageing and dementia.
PET fluorodeoxyglucose (FDG) detects very early neocortical hypometabolism before neuropsychological testing.
Meanly parietal , frontal and posterior temporal cortex associative
Also, FDG cortical global reduction of cerebral glucose metabolism in parietotemporal associative cortex  Diagnostic AD

Diagnostic imagery Functional imagery/Cerebral Scintigraphy  PET :
Visualize local dysfunction in cortex as soon as the first symptoms appear
Quantify and localize brain deficits in AD
Few clinical applications, more used in research
Very important for early diagnosis
Good superposition with SPECT studies
FDG PET may provide a methodology to subdivide types of neurodegenerative progression.

Diagnostic imagery Functional imagery/Cerebral Scintigraphy

FDG-PET by normal subjects (left), and by patients with AD (right). There is an hypometobolism in the posterior tempo-parietal associative cortex.

Diagnostic imagery Functional imagery/Cerebral Scintigraphy [18F]Fluorodeoxyglucose PET Brain Scan ( 52-Year-Old Woman With Cognitive Complaintsa)

Lower metabolism in midparietal lobes bilaterally

In left cortex inferiorly

Diagnostic imagery Magneto encephalography  MEG : Principles
Give temporal informations
Excellent time resolution (msec), although poor spatial resolution at the moment
Measures the magnetic field generated by neuron activity in the brain,
Reconstruct the electric current from this measurement.
Shows spatial and temporal activity together
Has established different brain activation profiles for AD and controls

Diagnostic imagery Magnetoencephalography MEG: Results
Low frequency magnetic power is significantly and rather diffusely, increased relative to controls with a fronto-central maximum.
High frequency power values significantly decrease over the occipital and temporal areas.
Reactivity to eye-opening and mental tasks reduced
Relative to controls, a general decrease of MEG coherence values, in AD patients.

Diagnostic imagery Magnetoencephalography Control

AD
AD patients  fewer activity

sources in left parietal and temporal lobes during 400-700 ms after stimulus onset,  had more activation in left than in right parietal and temporal
Controls

Diagnostic imagery MRI stage in AD Shrink of the central sulcus AD

Control Cut Level

Diagnostic imagery MRI stage in AD At this lower level,we can see severe widening of the intraparietal sulci, and atrophy of the inferior parietal lobules, in the face of relative sparing of the frontal gyri.

Cut Level

Diagnostic imagery MRI stage in AD The third ventricle is enlarged and contains a barely visible massa intermedia.

Cut Level

Diagnostic imagery MRI stage in AD Mid-ventricular slice. SPECT image. Dark blue regions in parietal lobes represent areas of decreased blood flow or perfusion, due to - the underlying atrophy, - the presence of diseased brain, - the functional "disconnection"

Cut Level

Diagnostic imagery Perspectives 1_fusion IRMF (very good spatial resolution /MEG (very good temporal resolution) 2_fusion SPECT/IRMF

Diagnostic imagery Perspectives 3_use imagery for monitoring treatment response 4_develop fMRI 5_develop MEG 6_achieve high specificity and sensitivity in the very early disease stages. 7_speculate the probability to develop AD 8_Pursue PET study to link the presence of apolipoproteine (APOE)e4 allele on chr 19 to late AD.

Main Bibliography


Mizuno K, WakaiM, Takeda A, SobueG. 1 Feb. 2002. "Medial temporal atrophy and

memory impairment in early stage of Alzheimer's disease: an MRI volumetric and memory assessment study." Journal of the Neurological Sciences, Volume 173, Issue 1, Pages 18-24.
Konrad Maurera, David Prvulovica, Friedhelm E. Zanellac, David E.J. Lindena,b, Functional neuroimaging in psychiatry, International Congress Series 1247 (2002) 651– 661.


Andreas K. Demetriades, Functional neuroimaging in Alzheimer’s type dementia, Journal of the Neurological Sciences 203– 204 (2002) 247–251.
Keith A. Johnson, M.D, Neuroimaging of Alzheimer disease,.
Daniel H.S. Silverman, M.D., Ph.D.Gary W. Small, M.D,Prompt Identification of

Alzheimer’s Disease With Brain PET Imaging of a Woman With Multiple Previous Diagnoses of Other Neuropsychiatric Conditions,

Sitography
Alzheimer Disease Image adress: http://www.med.harvard.edu/AANLIB/cases/case3/case.html


Papers : Pubmed /Medline http://www.pubmedcentral.nih.gov/redirect.cgi?&&reftype=other&art id=33991&&http://www.pnas.org/cgi/doi/10.1073/pnas.090106797


MEG documentation:

CNRS UPR 640 website: http://www.ccr.jussieu.fr/cnrs-upr640lena/Fra/home.html

Thanks and Questions…

Diagnostic imagery MRI stage in AD At this level one can appreciate that the parietal regions are somewhat more atrophic than frontal regions.

Cut Level

Diagnostic imagery Functional imagery/Cerebral Scintigraphy PET :
hypometabolism in association cortical areas and subcortical structures
Early reduction, more extensive in primary cortices
Frontal involvement more prominent in advanced disease
FDG PET correlates with AD neuropathology and is able to indicate disease progression or severity, meeting both functional neuroimaging prerequisites in diagnosing AD , measurements of cerebral glucose metabolism (rCMRGlc) by Fluoro-DeoxyGlucose PET and of rCBF by single photon emission tomography (SPECT) in AD patients revealed a characteristic pattern of diminished rCMRGlc and rCBF during rest in temporoparietal and, to a lesser extent, frontal areas, while primary visual and sensorimotor cortices showed normal patterns until very late stages [31,36,40,51,70]. Impaired temporoparietal resting rCMRGlc could