The role of neuroimaging in dementia nowadays extends beyond its traditional role of excluding neurosurgical lesions.
Radiological findings may support diagnosis of specific neurodegenerative disorders and sometimes radiological confirmation of these findings is obligatory for the diagnosis.
It is a challenge for neuroimaging to contribute to the early diagnosis of neurodegenerative diseases, such as Alzheimer's disease.
Early diagnosis includes recognition of pre-demented conditions, such as mild cognitive impairment (MCI).
In addition, early diagnosis allows early treatment using currently available therapies or new therapies in the future.
Secondly, neuroimaging can be used to assess disease progression and is adopted in current trials in MCI and AD.

On the left a coronal image of the hippocampus, which is the most important structure involved in many forms of dementia.

T1-weighted images are used for the assessment of medial temporal lobe and hippocampal atrophy.
They are obtained in a plane orthogonal to the long axis of the hippocampus, which is parallel to the brainstem.
It should be thin-section images.

FLAIR images are used to assess global cortical atrophy (GCA), vascular white matter hyperintensities and infarctions.

T2-weighted images are used to assess infarctions, in particular lacunar infarctions in basal ganglia, that can be missed on FLAIR images.

T2*-weighted images can be used for the detection of microbleeds in amyloid angiopathy. These images can be added to a routine protocol.

CT protocol

CT can be used in case of contraindications for MRI or when the only interest is to rule out surgically treatable causes of cognitive decline.
In the transverse plane the scan angle should be parallel to the long axis of the temporal lobe.

Even better is to perform a spiral CT and to make coronally reformatted images perpendicular to the long axis of the temporal lobe for best visualisation of the hippocampus.

The MR-study of a patient, who is suspected of having dementia, should be assessed in a standardised way.
First we must exclude treatable diseases like subdural hematomas, tumors and hydrocephalus.

Secondly we should look for signs of specific dementias like:

• Alzheimer disease (AD): medial temporal lobe atrophy (MTA) and parietal atrophy.
• Frontotemporal Lobar Degeneration (FTLD): Frontal lobe atrophy and asymmetric temporal pole atrophy.
• Vascular Dementia (VD): Global atrophy, diffuse white matter lesions, lacunes and 'strategic infarcts' (infarcts in regions that are involved in cognitive function).
• Lewi bodies Dementia: In contrast to the other forms of dementia usually no specific abnormalities.

So when we study the MR images we should score in a systematic way for global atrophy, focal atrophy and for vascular disease (i.e. infarcts, white matter lesions, lacunes).

When we perform this standardised assessment of the MR findings in a patient suspected of having a cognitive disorder, we use:

1. GCA-scale for Global Cortical Atrophy
2. MTA-scale for Medial Temporal lobe Atrophy
3. Fazekas scale for WM lesions
4. Look for strategic infarcts

GCA-scale for Global Cortical Atrophy

GCA scale is the mean score for cortical atrophy throughout the complete cerebrum:

• 0: no cortical atrophy
• 1: mild atrophy: opening of sulci
• 2: moderate atrophy: volume loss of gyri
• 3: severe (end stage) atrophy: 'knife blade' atrophy.

Cortical atrophy is best scored on FLAIR images.
In some neurodegenerative disorders the atrophy is asymmetric and presents in specific regions.
Notification of asymmetry and regions with atrophy should be part of the radiological report of a dementia scan.
When we specify the atrophy for different regions, we should realise that cranially the central sulcus is more posteriorly than you would expect (figure).

MTA-scale for Medial Temporal lobe Atrophy

MTA score should be rated on coronal T1-weighted images at a consequent slice position.
Select a slice through the corpus of the hippocampus, at the level of the anterior part of the pons.

< 75 years : MTA score 2 or more is abnormal (i.e. 1 can be still normal)
> 75 years : MTA score 3 or more is abnormal (i.e. 2 can still be normal at this age)

Data from a study with 222 controls and patients with various forms of dementia in which this visual rating scale was used to assess temporal lobe atrophy suggest that sensitivities and specificities of 85% can be obtained for patients with AD.

The score is based on visual rating of the width of the choroid fissure, width of the temporal horn, and height of the hippocampal formation.

• score 0: no atrophy
• score 1: only widening of choroid fissure
• score 2: also widening of temporal horn of lateral ventricle
• score 3: moderate loss of hippocampal volume (decrease in heigt)
• score 4: severe volume loss of hippocampus

Scroll through the images on the left for examples of MTA score 0-4.

A high MTA-score is very sensitive for the diagnosis of Alzheimer disease and it is present in 100% of patients with AD, while in controls a positive score is almost always absent (Table on the left).
So it is a good test to disciminate controls from patients with AD.
However this test is not very specific for AD as it can also be positive in other forms of dementias (7).
On the other hand, if there is a patient with mild cognitive impairment (MCI), which can be a predromal state of AD, and the MTA score is negative, than you can be quite sure that this patient will not develop AD (high sensitivity yields high negative predictive value).

If there is a strong suspicion of Alzheimers disease, it can be usefull to repeat the examination to see if there is any progress of the medial temporal lobe atrophy.
On the left a follow up examination at 18 and 36 months in a patient, who was at risk for familial AD, demonstrating the progression of the disease.
An alternative approach would be to perform a SPECT or PET-scan to look for changes in metabolism of the tempero-parietal cortex as these changes precede development of atrophy.

Fazekas scale for WM lesions

On MR white matter hyperintensities (WMH) and lacunes, both of which are frequently observed in the elderly, are generally viewed as evidence of small vessel disease.

The Fazekas scale provides an overall impression on the occurence of WMH for the complete brain.
It is best scored on transverse FLAIR or T2-weighted images.

Score:

• Fazekas 0: No or a single punctate WMH lesion
• Fazekas 1: Multiple punctate lesions
• Fazekas 2: Beginning confluency of lesions.
• Fazekas 3: Large confluent lesions.

Fazekas 1 is normal in elderly.
Fazekas 2 and 3 are pathologic, but can sometimes be seen in normal functioning people. They are however at high risk for disability.

In 600 normal functioning elderly the Fazekas score predicted disability within one year (table).
In the Fazekas 3 group 25% was disabled within one year (10).

Strategic infarctions

Strategic infarctions are infarctions in areas that are crucial for normal cognitive functioning of the brain.
In the table on the left these areas are summarized.

Strategic infarctions are best seen on transverse FAIR and T2W sequences.
On the left bilateral thalamic infarctions which are often associated with cognitive dysfunction.

Study the images on the left of two different patients.
Then continue reading.

The image on the far left shows an infarction in Posterior Cerebral Artery territory, with involvement of the inferior medial temporal lobe which includes the hippocampus.
This is a strategic infarction, and since it is in the dominant hemisphere, will result in cognitive dysfunction.

The image next to it is a transverse FLAIR image showing infarction in the Posterior Cerebral Artery territory, with involvement of temporo-occipital association area.
Also a strategic infarction, that can result in cognitive dysfunction.

The prevalence of specific forms of dementia is age-dependent.
In patients < 65 years there are more cases of family-related and presenile progressive forms of AD and more cases of FTLD.
In patients > 65 years there are more cases of senile AD and vascular dementia.
In many older patients with manifest AD there is co-existing vascular disease, that contributes to the demented state.

Alzheimers Disease

AD accounts for 50%-70% of all cases of dementia in the elderly.
Age is a strong risk factor, with the disease affecting approximately 8% of individuals over the age of 65 years and 30% over the age of 85 years.
The progression of AD is gradual and the average patient lives 10 years after the onset of symptoms.
With the growth of the older population, the prevalence of AD is expected to triple over the next 50 years.

In end-stage AD there is widespread atrophy, which is not different from other end-stage dementias.
So in imaging we have to try to identify AD in an earlier stage and we have to concentrate on the hippocampus and the medial temporal lobe, because that is where AD starts.
The role of MRI in the diagnostic process of AD is twofold:

• Rule out other causes of cognitive impairment.
• Identify early onset AD for possible innovative therapy and counseling

Study the image on the left, then continue reading.

The image on the left is consitent with the diagnosis of end stage AD, because there is:

• Extreme hippocampal and medial temporal lobe atrophy (MTA score: 4)
• Severe global atrophy (GCA scale: 3)

However, it is not specific for AD, since severe GCA occurs in other end-stage disorders as well

Presenile AD

Presenile AD ( < 65 y) has a different presentation.
Although there usually is some mild hippocampal atrophy, the most striking finding is parietal atrophy with atrophy of the posterior cingulum and the precuneus.
Only in senile AD you can rely on imaging of the hippocampus.

Mild Cognitive Impairment (MCI)

Mild cognitive impairment is a relatively recent term, used to describe people who have some problems with their memory, but do not actually have dementia, since dementia is defined as having problems in two or more cognitive domains.
Some of these patients will be in the early stages of Alzheimer's disease or another dementia, so it is important to identify them.

Vascular Dementia (VaD)

Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer's disease.
VaD can be distinguished from AD by its more sudden onset and association with vascular risk factors.
It can be characterized by a stepwise course with periods of stability followed by sudden decline in cognitive function &#8211; however, most patients have small vessel disease, with a more subtle deterioration pattern.
Control of vascular risk factors is the treatment of choice, but cholinesterase inhibitors. that are being used in AD, are also increasingly being used to treat vascular dementia.

On the left a patient with a strategic PCA infarction involving the hippocampus.
If this infarction is located in the dominant hemisphere, it can result in sudden dementia.
In the non-dominant hemisphere it will usually not result in dementia.

In most patients with VaD there is diffuse white matter disease graded as Fazekas 3 with large confluent lesions.
In some of these patients there can also be dilatation of the ventricles due to global atrophy and some will also have medial temporal lobe atrophy.
The patient on the left had VaD, but the medial temporal lobe was normal.

Strategic infarcts and small vessel disease

Cognitive dysfunction in VaD can be the result of (2):

• Large vessel infarctions:
  • Bilateral in territory of anterior cerebral artery.
  • Parietotemporal- and temporo-occipital association areas of the dominant hemisphere (angular gyrus included)
  • Posterior cerebral artery occlusion with infarction of the paramedian thalamic region and inferior medial temporal lobe of dominant hemispere
• Watershed infarctions in the dominant hemisphere (superior frontal and parietal)
• Small vessel disease:
• Multiple lacunar infactions in frontal white matter (>2) and basal ganglia (>2)
• WMLs (at least more than 25% of WM)
• bilateral thalamic lesions

There is increasing attention for the importance of small vessel disease as a predictor of cognitive decline and dementia.
Moreover, it seems to amplify the effects of pathologic changes of Alzheimer disease.
On the left we see a patient who was diagnosed as having VaD.
White matter disease is seen as severe WMH (hypointense on T1) in the periventricular regions.
In addition to these vascular chages, there is also medial temporal lobe atrophy (MTA).
So presumably this patient has both VaD and AD, a finding that is seen in many elderly patients.
These findings should be described separately as it may have therapeutic consequences.

The problem however is, that white matter hyperintensities and lacunes are also frequently observed in non-demented elderly and at some level can be regarded as normal findings in aging.
To overcome this problem the NINDS-AIREN International Work Group has formulated criteria for the history and physical, radiological, and pathological examination to classify patients as having possible, probable and definite VaD.
However considerable interobserver variability exists for the assessment of the radiological part of these NINDS-AIREN criteria and some level of training is mandatory (2).

The medial nuclei of the thalamus play an important role in memory and learning.
A large unilateral infarction or bilateral infarctions in this region can cause dementia.
You have to pay special attention to these areas to find these small infarctions.

On FLAIR images you will easily miss these infarctions, because they can be isointens to the surrounding structures (8).
A high resolution T2WI is needed to detect these thalamic infarcts. FLAIR in the infratentorial region and in the spinal cord is of limited value as it suppresses not only the signal of water, but also of pathology with long T1 relaxation time.
This phenomenon can also be seen in the detection of Multiple Sclerosis, where FLAIR is of limited value in the infratentorial region and of no use in the spinal cord.

Frontotemporal Lobar Degeneration (FTLD )

FTLD, formerly called Pick's disease, is a progressive dementia, that accounts for 5-10% of cases of dementia.
FTLD is clinically characterized by behavioral and language disturbances that may precede or overshadow memory deficits.
There currently is no treatment for this condition.

Imaging plays an important role in the diagnosis as the findings are easy to recognize.
Radiological findings are pronounced atrophy of frontal and / or temporal lobes.
In some forms of FTLD the atrophy might occur strikingly asymmetric, as in Semantic Dementia, a disease with progressive aphasia and left-sided temporal lobe degeneration.

On the left a patient with progressive afasia.
The most prominent finding is the striking asymmetric atrophy of the temporal lobe on the left side with not only atrophy of the hippocampus, but also the temporal poles.
The atrophy has resulted in gyri that appear as sharp as knives ('knife blade atrophy').
There is also some increased signal intensity seen on the FLAIR image probably due to gliosis.
These findings are very typical for the diagnosis of FTLD.

Patients with left sided temporal atrophy are usually clinically obvious. Right sided atrophy mostly is not clinically evident as these patients only present with subtle disturbances in recognition of faces.

Dementia with Lewy bodies

Dementia with Lewy bodies is responsible for approximately 25% of dementias and belongs to the atypical Parkinson syndromes together with progressive supranuclear palsy (PSP) and multi-system atrophy (MSA).
The clinical manifestation can be similar to that of AD or dementia associated with Parkinson disease.
Patients typically present with one of three symptom complexes: detailed visual hallucinations, Parkinson-like symptoms and fluctuations in alertness and attention.
Pathologically, the disease is characterized by the presence of Lewy bodies in various regions of the hippocampal complex, subcortical nuclei and neocortex with a variable number of diffuse amyloid plaques.
Cholinesterase inhibitors are currently the treatment of choice for this condition.

The role of imaging is limited in Lewi body dementia.
Usually the MR of the brain is normal including the hippocampus.
This finding is important as it enables us to differentiate this disease from Alzheimer, which is the main differential diagnosis.

Progressive supranuclear palsy (PSP)

PSP is also one of the atypical parkinsonian syndromes.
In PSP there is pronounced atrophy of the midbrain (mesencephalon), which accounts for the typical upward gaze paralysis.

Normally the upper border of the midbrain is convex.
The atrophy of the midbrain in PSP results in a concave upper border of the midbrain with the typical 'humming bird sign' (figure).

Multi System Atrophy (MSA)

MSA is also one of the atypical parkinsonian syndromes.
Multiple system atrophy is a rare neurological disorder characterized by a combination of parkinsonism, cerebellar and pyramidal signs, and autonomic dysfunction.

Usually there is pronounced cerebellar atrophy and severe atrophy of the pons.
In contrast to PSP, we don't see the humming bird sign, because the midbrain has a normal convex upper border.
The so-called 'hot cross bun sign', which is a result of pontine hyperintensity, is typical for MSA.

Creutzfeldt-Jakob disease

CJD is a very rare and incurable neurodegenerative disease, caused by a unique type of infectious agent called a prion.
The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes and hallucinations.
The disease is characterized by spongiform changes in the cortical and subcortical gray matter, with loss of neurons and replacement by gliosis.

On T2WI and FLAIR the changes in the cortex can be difficult to detect.
Diffusion weighted imaging are very helpfull in depicting these changes.

New variant CJD
Nowadays there is a new variant of CJD, also known as the 'mad cow disease' (12).
In this variant the changes are seen in the posterior part of the thalamus, which is called the pulvinar.

In the book on the left you can find more information about the role of MR in dementia (9).