Neurodegenerative MRI brain (an approach)

Imaging of the brain in patients with suspected neurodegenerative conditions is common and challenging, as in patients with subtle and equivocal signs and symptoms, the imaging findings are also subtle and equivocal. In many instances, by the time imaging findings are clear cut, then the patient has declared themselves clinically, and the diagnosis is already established or at least strongly suggested. 

As such the true role of imaging is often to push clinicians towards or away particular differential rather than making a firm diagnosis. 

Main conditions

Although there are a great many conditions which fall under the neurodegenerative umbrella, and even more which can result in cognitive impairment, the majority of patients with significant cognitive impairment will have one of a relatively small group, and familiarity with them is crucial. These include: 

• Alzheimer's disease
• vascular dementia
• Lewy body disease
• frontotemporal lobar degeneration

In addition there are a number of 'classic' albeit uncommon to rare conditions with specific imaging findings: 

• Creutzfeldt-Jakob disease
• progressive supranuclear palsy (PSP)
• multiple system atrophy (MSA) 
• Huntington disease
• corticobasal degeneration
• CADASIL

A further group of conditions, beyond the scope of this article, are conditions which can present with neurodegenerative-like signs and symptoms, such as: 

• anterior cranial fossa meningioma
• chronic subdural hematomas
• normal pressure hydrocephalus

Importance of the clinical history

A good clinical history is paramount if the importance of subtle findings is to be appreciated. Unfortunately all too often requests contain only vague details such as "dementia?". If possible, further history should be obtained including:

• patient demographics
  • age, gender, ethnicity, occupation
• main presenting complaint
• characterisation of cognitive symptoms
  • attentional problems
  • memory problems (e.g. short term / long term / ante-grade / retrograde)
  • language problems (e.g. receptive, expressive) 
  • visual/constructional / constructional problems
  • apraxia / acalculia
  • personality change (e.g. disinhibition, aggression) 
• characterisation of physical symptoms
  • tremor
  • rigidity
  • hyperkinesis
  • falls
  • dysphagia
  • incontinence
  • eye signs
• time course
  • onset, duration, progression
• any relevant family history
  • e.g. parent with Huntington disease
• any risk factors for differential diagnosis
  • e.g. smoking, hypertension, diabetes, stroke
• any toxic exposures
  • e.g. medications, alcohol, illicit substances, radiation, environmental poisons
• clearly stated differential diagnosis or study question
  • e.g. ?caudate atrophy

Protocol

There are many variations on a 'neurodegenerative protocol' and much will depend upon local preferences and equipment. What is essential is that good quality three plane imaging (sagittal, coronal and axial is obtained, preferably with the coronal images angled at right angles to the hippocampus) with T1, T2, FLAIR, DWI and T2* sequences. A fairly standard protocol may include: 

• T1
  • sequence: ​volumetric gradient echo e.g. MPRAGE, preferably isometric e.g. 0.9mm.9 mm reformatted in three planes
  • purpose: anatomical, best for assessing regional volume loss
• T2
  • ​sequence: fast spin echo, whole brain or limited to basal ganglia and posterior fossa (thins e.g. 3mm3 mm)
  • purpose: signal intensity of basal ganglia, and posterior fossa structures (often less well seen on FLAIR due to flow artefactartifact)
• FLAIR
  • ​​sequence: whole brain axial or volumetric
  • purpose: white matter signal abnormality such as small vessel ischaemia resulting in multi-infarct dementia and abnormal sulcal signal in leptomeningeal processes (e.g. leptomeningeal carcinomatosis)
• DWI / ADC (or isometric images from optional DTI acquisition)
  • purpose: cortical or deep grey matter restricted diffusion in Creutzfeldt Jakob disease (CJD) and restriction in demyelination of infarction (e.g. cerebral vasculitis) 
• SWI
  • ​​sequence: SWI including phase and magnitude images
  • purpose: microhaemorrhages (e.g. cerebral amyloid angiopathy (CAA), hypertensive encephalopathy). Mineral deposition in cortex (e.g. Alzheimer's disease, amyotrophic lateral sclerosis (ALS)). Loss of low signal in substantia nigra (Parkinson disease)
• Optional additional sequences
  • DTI (optional): for tractography
  • MR Perfusionperfusion: arterial spin labelling or preferably contrast perfusion
  • MR spectroscopy 

Scoring systems and measurements 

Although in most instances individual scoring systems are not reported, they are useful to know even if only as guides on which features have been found useful and reliable. Some of the more common scoring systems include: 

• Fazekas scale for white matter lesions: the deep white matter component is used in assessing the amount of chronic small vessel ischaemic change
• posterior atrophy score of parietal atrophy (PA or PCA or Koedam score): useful in atypical (posterior cortical atrophy) or early onset Alzheimer's disease. 
• medial temporal lobe atrophy score (MTA score)
• global cortical atrophy scale (GCA scale) 

A number of measurements / ratios are also useful: 

• midbrain to pons area ratio (for PSP)
• magnetic resonance parkinsonism index (MRPI) (for PSP)

Signs

In addition to systematically going through each scan, it is worth specifically looking for some signs, which will ensure you do not miss a diagnosis which will in retrospect be obvious. These include: 

• hummingbird sign of PSP
• Mickey Mouse sign of PSP
• morning glory sign of PSP
• hot cross bun sign of MSA-C
• reversal of normal T2 signal of putamen vs globus pallidus of MSA-P
• atrophic caudate heads of Huntington's disease
• mammillary high T2 signal of Wernicke-Korsakoff syndrome
• hockey stick sign or pulvinar sign of CJD

Systematic approach

It should be self evident that no single approach is the 'correct one'. What is certain is that in assessing an MRI brain for neurodegenerative diseases, perhaps more so than for other indications, a careful systematic approach is needed. What that approach is does not matter so much, as long as all pertinent features are sought. What is presented here is the approach used by the author.

1. T1 sagittal

Begin by looking at the midline sagittal image and assess the following: 

• corpus callosum
  • ​the anterior half of the body should be thicker, and certainly not thinner than the posterior half. If thinner a degree of frontal lobe atrophy should be immediately suspected. ​
  • upward bowing may suggest hydrocephalus, including normal pressure hydrocephalus
• midbrain shape, size and midbrain to pons area ratio
  • it is often easier to note abnormalities of the midbrain in sagittal plane
  • roughly the area of the midbrain should be about a quarter of the pons, and with a little practice this can be easily eyeballed
  • look for the hummingbird sign of PSP
• pons shape
  • the pons should be plump and rounded and about 4 times as large as the midbrain. Be prepared to look for pontine atrophy if it looks small or flattened (e.g. multiple system atrophy) 
• general morphology of the rest of the brain: many congenital anomalies have midline changes

Next move slightly to the left and right of the midline to asses the following:

• medial surfaces of the frontal, parietal and occipital lobes
  • all the sulci should be about the same size
  • significant parietal sulcal widening with atrophy of the precuneus and posterior cingulate suggests Alzheimer's disease (AD)
  • anterior to posterior gradient of sulcal size (bigger anteriorly) seen in frontotemporal lobar degeneration
  • mamillary bodies
    • should be about the same size. Atrophic or asymmetrical mammillary bodies may imply hippocampal pathology or Wernicke-Korsakoff syndrome 
  • hippocampal volume: sagittal is not a great plane for the hippocampi but have a look. You should see them to be plump and gradually taper as you progress from anterior to posterior. Reversal of this pattern is seen in FTLD and general atrophy is seen particularly in AD

Finally move all the way to the lateral surfaces of the brain and examine the following:

• sylvian fissure and cistern size
  • out of keeping with the rest of the brain? 
  • left > right?
• general sulcal and gyral size looking for regional atrophy

Don't forget to look at everything else too. Sagittal T1 is often your largest field of view sequence and will be the only one to image the oral cavity, TMJ and upper cervical spine and cord. 

2. Axial FLAIR & T2

Start with the FLAIR axial sequences and examine: 

• gyral atrophy, particularly useful for the frontal lobes
• widening of the sylvian fissures
  • in FTLD typically left > right 
  • normal pressure hydrocephalus in excess of gyral widening and expect to see crowding of the gyri at the vertex
• hippocampal volume and signal
• posterior fossa morphology
  • midbrain
    • Mickey Mouse sign of PSP
    • morning glory sign of PSP
  • pons
    • pontine hot cross bun sign of MSA-C
  • medulla
    • olivary atrophy of MSA-C
  • cerebellum 
    • atrophy and high signal in middle cerebellar peduncles (e.g. MSA-C)
    • atrophy of the vermis (e.g. in alcohol abuse and antiepilepsy medication) 
• Wernicke pattern high T2 signal (ventromedial thalamus, mammillary bodies, periaqueductal grey matter) 
• degree of white matter signal and pattern
  • subcortical / deep white matter in chronic small vessel ischaemia (common); consider mulit-infarct dementia
  • periventricular in demyelination (uncommon in this setting) 
• ventricular size: is it commensurate with sulcal widening?
• evidence of old cortical infarcts
  • especially of cognitively important areas, for example ¹:
    • bilateral thalamic infarcts
    • inferomedial temporal lobe (especially dominant side) 
    • association areas (parietotemporal, temporo-occipital and angular gyrus)
    • borderzone (watershed) infarcts (superior frontal and parietal)

T2 axial imaging is often better for basal ganglia structures and posterior fossa. Assess for: 

• reversal of normal T2 signal of putamen vs globus pallidus of MSA-P
• atrophic caudate heads of Huntington's disease
• size and flow void in aqueduct (usually prominent in NPH) 

Don't forget that T2 sequences usually give you the best look at the intracranial arteries, so make sure you look for aneurysms or vascular malformations. 

3. Coronal sequences

Coronal sequences are essential in the assessment of the hippocampi and careful attention must be paid not only to their size, but also the distribution of change. On these sequences assess: 

• hippocampal, choroidal fissure and temporal horn size (see medial temporal lobe atrophy score)
• symmetry
  • left > right atrophy favours FTLD
  • equal involvement favours Alzheimer's disease
• anterior to posterior gradient
  • anterior atrophy > posterior atrophy favours FTLD
• involvement of the temporal lobe generally favours FTLD
• atrophy largely restricted to the hippocampus and parahippocampal gyrus favours Alzheimer's disease
• mammillary body size, signal and symmetry

4. T2* sequences

Sequences susceptible to blood products are particularly useful in assessing:

• microhaemorrhages
  • peripherally distributed in cerebral amyloid angiopathy which in turn is associate with Alzheimer's disease
  • centrally distributed (basal ganglia / pons / cerebellum) in chronic hypertensive encephalophathy

5. DWI 

DWI has a limited role in the assessment of a patient with a suspected neurodegenerative disease, but is crucial particularly for Creutzfeldt-Jakob disease: look for cortical, basal ganglia and thalamic restricted diffusion. 

Always look carefully for evidence of acute ischaemia, although this is uncommonly seen in elective outpatient scans. 

Putting it all together

Having gone through the scan systematically hopefully a definite pattern conforming to one of the suspected pathologies has become evident. In such cases your conclusion should state which entity is most likely.

If findings are subtle or contradictory then one should convey this and try, if possible, indicate which condition is most likely taking into account the clinical differential. 

If adequate clinical information is absent an attempt to obtain it should be made and the author of the request card gently chastised :)

In either case it is important to not appear to be overly certain, as shrugging off an incorrect label is very difficult. It is best to state that findings are non-specific and not strongly indicative of any single entity and recommend repeat imaging in 12 months at which time both the clinical and imaging features may be more convincing.