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Volumetric MRI quantification in the diagnosis of Alzheimer's disease

  • Writer: Milan Walraevens
    Milan Walraevens
  • Apr 7, 2021
  • 6 min read

Updated: 3 days ago

Apr 7, 2021

A definite diagnosis of Alzheimer’s disease (AD) can only be confirmed on an autopsy examination of brain tissue. However, the 2018 National Institute on Aging - Alzheimer’s Association (NIA-AA) research framework suggests investigating AD in vivo across its entire spectrum, from preclinical to dementia stages.1 Within this framework, amyloid (A), tau (T), and neurodegeneration (N) biomarkers (ATN) can be utilized to support the AD diagnosis, in conjunction with clinical and neurocognitive information. Today, cognitive testing, cerebrospinal fluid (CSF) testing, genetic testing, magnetic resonance imaging (MRI), and positron emission tomography (PET) are used at different stages of the care pathway for AD, while the development of new tools, such as diagnostic blood tests is ongoing.2


MRI in the diagnosis of AD

Conventional brain MRI is regularly used in the diagnosis of dementia patients. MRI helps investigate co-pathologies and exclude alternative pathologies and offers sensitive markers for the detection of dementia in addition to specific markers to support the differential diagnosis of dementia. AD is characterized by macroscopic structural brain changes of moderate to severe atrophy in the frontal and temporal cortices and limbic structures (including the hippocampus). These macroscopic changes are assessed with conventional MRI in clinical practice and have shown potential as a marker for diagnosis and disease progression, correlating with tangle deposition and downstream neuropsychological deficits.3, 4


Visual rating

Radiologists visually inspect MRIs to exclude structural pathologies and assess the degree of brain atrophy with the help of established rating scales (Figure 1). Based on a survey conducted across 193 centers in 38 countries, visual rating scales are used in 75% of centers. The most frequently used scales are the MTA scale (81.3%), other scales such as the global cortical atrophy (GCA) scale (53.4%), and the Koedam scale for posterior atrophy (32.6%) were less often applied. 5



Figure 1. Most frequently used visual rating scales in the assessment of structural MRI for dementia.


Visual rating scales are designed to categorize patients quickly and can be reliably used in current practice. However, these scales remain too coarse to track individual atrophy progression over short periods6, require a certain level of experience, and lack age-matched cut-off values.5


Figure 2. Volumes for the whole brain (WH), lateral ventricle (LV), and their ratio, with reference to age-and sex-matched control population and coronal view of corresponding segmentation. Left: Healthy person (78 y/o) presenting with values within normal range. Right: Patient (70 y/o) presenting with values in the abnormal range, in line with dementia.

Whole-brain volume and ventricular enlargement

Whole-brain volume and ventricular enlargement are considered sensitive biomarkers of dementia due to their early and consistent involvement in neurodegeneration, supporting their utility for the timely diagnosis of AD.3 The relation between the whole brain and the ventricles can also be indicative of diseases such as normal pressure hydrocephalus (NPH). A high correlation is reported between the whole brain and ventricular volume and changes in cognitive performance in AD and MCI, and an even more robust correlation with their ratio.7 By using the ratio of measures, potential errors introduced by normalization methods are omitted, producing more statistically significant results for discriminating pathological subjects from normal controls. (Figure 2) 


Hippocampal volume

Hippocampal volume loss is a supportive feature for the diagnosis of Alzheimer’s disease. However, visually disentangling age-related changes from pathological variations is challenging.8 Accordingly, the use of automated quantification software can help introduce hippocampal volume loss in the clinic.9-13 Neurodegeneration of the hippocampus (HC) typically co-occurs with the enlargement of the inferior lateral ventricle (ILV). This enlargement differentiates individuals with congenitally small hippocampi from those due to neurodegeneration and can act as an indicator for volume loss.14 The combination of hippocampal and inferior lateral ventricle volumes indicated the highest correlation with visual rating scales.15 Whereby the ILV/HC ratio has shown to have a small measurement error, which is crucial for detecting abnormalities during the radiological interpretation of MCI and AD.16 (Figure 3.)



Figure 3. Volumes for the hippocampus (HC), inferior lateral ventricle (ILV), and their ratio, with reference to age-and sex-matched control population and coronal view of corresponding segmentation. Left: Healthy person (78 y/o) presenting with values within normal range. Right: Patient (70 y/o) presenting with values in the abnormal range, suggestive of Alzheimer’s disease.

Cortical atrophy patterns

An important step in the diagnosis of AD is the exclusion of other causes accounting for up to 40% of dementia cases. However, the differential diagnosis of dementia or predementia subtypes can be challenging due to mixed etiologies.17,18 The most common forms of dementia are characterized by a particular pattern of atrophy. (Figure 4) AD initially involves medial temporal lobe structures (e.g., hippocampus) and subsequently extends to the temporal, parietal, and frontal lobe as the disease progresses (Figure 5).



Figure 4. Typical MRI findings in most common dementia types.

Patients with an atypical presentation of AD show more frequent parietal atrophy.  Patients with semantic dementia represent distinct behavioral-cognitive profiles based on left and right-dominated asymmetry. Furthermore, frontotemporal dementia (FTD) is typically associated with frontal and/or temporal atrophy. Patients with behavioral variant FTD (bvFTD) may have symmetrical or asymmetrical frontal atrophy with or without additional temporal lobe atrophy.19 Longitudinal quantification of atrophy rates in these structures have been useful in predicting the conversion of MCI subjects, with differences detected well before clinical AD diagnosis.20



Figure 5. Ratios of the whole brain (WB) and lateral ventricle (LV) volumes, and hippocampal (HC) and inferior lateral ventricle (ILV) volumes, with reference to age-and sex-matched control population, and corresponding segmentation and volume signature. Patient (81 y/o) presenting with values in the abnormal range for the LV/WB and ILV/HC ratios and a volume signature indicating low percentiles for hippocampal and temporal cortical volumes, suggestive of Alzheimer’s disease.

Toward a timely and confident diagnosis

The use of automated quantification software can improve diagnostic sensitivity and accuracy while reducing the inter-and intra-rater variability for the detection of brain volume loss in clinical practice.9-13 Adding a volumetric quantitative analysis to standard brain MRIs, which are regularly used in diagnosing dementia patients, can therefore be a low-cost improvement toward a more timely and accurate diagnosis of Alzheimer’s disease. 



Additional online educational resources: 


References:


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