Using visual scales to determine brain atrophy subtypes in Alzheimer’s Disease

AD subtypes based on patterns of brain atrophy. Regional atrophy was measured with the MTA, PA, and GCA-F visual rating scales based only on T1-weighted images. In the 3 visual rating scales, a score of zero denotes no atrophy, whereas scores from 1 to 3 (PA and GCA-F) or 4 (MTA) indicate an increasing degree of atrophy. The typical AD subtype was defined as abnormal MTA together with abnormal PA and/or abnormal GCA-F. The limbic-predominant subtype was defined as abnormal MTA alone with normal PA and GCA-F. The hippocampal-sparing subtype included abnormal PA and/or abnormal GCA-F but normal MTA. The minimal atrophy subtype was defined as normal scores in MTA, PA, and GCA-F. The figure shows examples of each subtype in axial and coronal sections of the brain. AD, Alzheimer’s disease; MTA, medial temporal atrophy scale; PA, posterior atrophy scale; GCA-F, global cortical atrophy scale – frontal subscale; A, anterior part of the brain; P, posterior part of the brain; R, right; L, left.

Reference: https://doi.org/10.1159/000515322

Medial temporal atrophy in preclinical dementia: visual and automated assessment during six year follow-up

Medial temporal lobe (MTL) atrophy is an important morphological marker of many dementias and is closely related to cognitive decline. In this study we aimed to characterize longitudinal progression of MTL atrophy in 93 individuals with subjective cognitive decline and mild cognitive impairment followed up over six years, and to assess if clinical rating scales are able to detect these changes. All MRI images were visually rated according to Scheltens' scale of medial temporal atrophy (MTA) by two neuroradiologists and AVRA, a software for automated MTA ratings. The images were also segmented using FreeSurfer's longitudinal pipeline in order to compare the MTA ratings to volumes of the hippocampi and inferior lateral ventricles. We found that MTL atrophy rates increased with CSF biomarker abnormality, used to define preclinical stages of Alzheimer's Disease. Both AVRA's and the radiologists' MTA ratings showed a similar longitudinal trajectory as the subcortical volumes, suggesting that visual rating scales provide a valid alternative to automatic segmentations. While the MTA scores from each radiologist showed strong correlations to subcortical volumes, the inter-rater agreement was low. We conclude that the main limitation of quantifying MTL atrophy with visual ratings in clinics is the subjectiveness of the assessment.

Full text

Brain volumes and their ratios in Alzheimer´s disease on magnetic resonance imaging segmented using Freesurfer 6.0

• Study shows 44 brain regions volume changes with Alzheimer's disease. 
• Volumes were calculated both in absolute values and ratios to the whole brain volume. 
• The hippocampo-horn proportion is effective for hippocampal atrophy evaluation. 
• This method can be simplified for visual assessment.

Abstract

A ‘Comprehensive Visual Rating Scale’ for predicting progression to dementia in patients with mild cognitive impairment

Background Numerous efforts have been made to identify biomarkers for predicting the progression of dementia in patients with mild cognitive impairment (MCI), and recently, a comprehensive visual rating scale (CVRS) based on magnetic resonance imaging (MRI) has been validated to assess structural changes in the brain of elderly patients. Based on this, the present study investigated the use of CVRS for predicting dementia and elucidated its association with cognitive change in patients with MCI over a three-year follow-up. Methods We included 340 patients with MCI with more than one follow-up visit. Data were obtained from the Alzheimer’s disease Neuroimaging Initiative study. We assessed all the patients using CVRS and determined their progression to dementia during a follow-up period of over 3 years. The cox proportional hazards model was used to analyze hazard ratios (HRs) of CVRS for disease progression. Further, multiple cognitive measures of the patients over time were fitted using the random effect model to assess the effect of initial CVRS score on subsequent cognitive changes. Results Of 340 patients, 69 (20.2%) progressed to dementia and the median baseline score (interquartile range) of CVRS significantly differed between stable MCI and progressive MCI (9 (5–13) vs 13 (8–17), p<0.001). The initial CVRS score was independently associated with an increased risk of progression to dementia (HR 1.123, 95% confidence interval [CI] 1.059–1.192). From 12 to 24 months, the effect of the interaction between CVRS and interval of follow-up visit on cognitive performance achieved significance (p<0.001). Conclusions Baseline CVRS predicted the progression to dementia in patients with MCI, and was independently associated with longitudinal cognitive decline.

Reference: Jang J-W, Park JH, Kim S, Park YH, Pyun J-M, Lim J-S, et al. (2018) A ‘Comprehensive Visual Rating Scale’ for predicting progression to dementia in patients with mild cognitive impairment. PLoS ONE 13(8): e0201852. https://doi.org/10.1371/journal.pone.0201852

New MRI visual rating scales

Six visual rating scales, three alreary described: medial temporal, posterior, anterior temporal and three new/addapted: orbito-frontal, anterior cingulate and fronto-insula) were assessed in this study

Time to perform visual rating
Mean time to perform and record all six visual rating scales based on three raters assessing the subset study population ( n = 80) was 2.9 ± 1.3 min. Individual rater means and standard deviations were 2.7 ± 1.1, 2.4 ± 1.0 and 3.6 ± 1.6 min.

Inter-rater reliability of visual rating scores
Single measure and average measure ICC results for each scale are shown in Supplementary Table 1 . For the single measures ICC values, representing the reliability of each scale at the level of the individual rater, the MTA scale performed best overall, with very similar results achieved with two raters assessing all 257 scans, and four raters scoring 80 scans [ICC(2,1) ≥ 0.79]. The PA, OF and FI scales also demonstrated good reliability [ICC(2,1) ≥0.71] based on two raters assessing the total study population; reliability was slightly reduced when performed by four raters in the subset population [ICC(2,1) ≥ 0.58]. The reliability of the AC scale was lowest overall [ICC(2,1) range = 0.49–0.62]. As expected, the reliability based on mean rater scores was consistently greater for all scales [ICC(2,k) ≥ 0.73]. There were no material differences in reliability based on the larger or smaller population samples for any scale with the exception of the AT and AC scales, which were less reliable in the larger population sample.

Correlation of grey matter volume with visual rating scores
Voxel-based morphometry analysis revealed a negative partial correlation of higher visual rating score with lower grey matter density for all visual rating scales. 

Reference:

Lorna Harper, Giorgio G. Fumagalli, Frederik Barkhof, Philip Scheltens, John T. O’Brien, Femke Bouwman, Emma J. Burton, Jonathan D. Rohrer, Nick C. Fox, Gerard R. Ridgway, Jonathan M. Schott; MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases. Brain 2016; 139 (4): 1211-1225. doi: 10.1093/brain/aww005https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aww005

Related publications: BALI: An MRI-Based Semiquantitative Index for the Evaluation of Brain Atrophy and Lesions

Categorizing and grading criteria of the BALI

Categories Criteria
GM-SV (gray matter lesions and small vessels) 0 = absence; 1 = punctuate foci in gray matter or multiple small vessels in subcortical area; 2 = beginning confluence of foci in gray matter or diffuse small vessels in subcortical area; 3 = large confluent lesions in gray matter (rare, evidence for stroke-related malacia foci)
PV (periventricular lesions) 0 = absence; 1 = ‘caps’ or pencil-thin lining; 2 = smooth ‘halo’; 3 = irregular periventricular abnormal signal intensities extending into the deep white matter
DWM (deep white matter lesions) 0 = absence; 1 = punctuate foci; 2 = beginning of confluence foci; 3 = large confluent areas; 4 = large confluent white matter areas involving all cerebral lobes; 5 = complete confluent white matter disease
BG (basal ganglia and surrounding area lesions) 0 = absence; 1 = 1 focal lesion; 2 = >1 focal lesion; 3 = large confluent lesions IT (infratentorial region lesions) 0 = absence; 1 = 1 focal lesion; 2 = >1 focal lesion; 3 = large confluent lesions
GA (global atrophy) 0 = no obvious atrophy; 1 = mild atrophy; 2 = moderate atrophy; 3 = severe atrophy
Other lesions 0 = no other kind of disease; 1 = any 1 kind of brain neoplasm, deformation or trauma; 2 = any 2 kinds of brain neoplasm, deformation or trauma; 3 = simultaneous presence of brain neoplasm, deformation and trauma

Full text

Related publications: Brain volume/cerebrospinal fluid index (BV/CSF index) in the diagnosis of Alzheimer's disease

BV/CSF index= (Total WM + Total GM) / Total spaces containing CSF

The BV/CSF index may also be named as yrRA-WB(I-II-III-IV-sulci) using the standarized terminology

Background: Global brain atrophy is present in normal aging and different neurodegenerative disorders such as Alzheimer's disease (AD) and is becoming widely used to monitor disease progression. Summary: The brain volume/cerebrospinal fluid index (BV/CSF index) is validated in this study as a measurement of global brain atrophy. We tested the ability of the BV/CSF index to detect global brain atrophy, investigated the influence of confounders, provided normative values and cut-offs for mild, moderate and severe brain atrophy, and studied associations with different outcome variables. A total of 1,009 individuals were included [324 healthy controls, 408 patients with mild cognitive impairment (MCI) and 277 patients with AD]. Magnetic resonance images were segmented using FreeSurfer, and the BV/CSF index was calculated and studied both cross-sectionally and longitudinally (1-year follow-up). Both AD patients and MCI patients who progressed to AD showed greater global brain atrophy compared to stable MCI patients and controls. Atrophy was associated with older age, larger intracranial volume, less education and presence of the ApoE ε4 allele. Significant correlations were found with clinical variables, CSF biomarkers and several cognitive tests. Key Messages: The BV/CSF index may be useful for staging individuals according to the degree of global brain atrophy, and for monitoring disease progression. It also shows potential for predicting clinical changes and for being used in the clinical routine.

Reference: Camila Orellana, Daniel Ferreira, J.-Sebastian Muehlboeck, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kłoszewska, Hilkka Soininen, Simon Lovestone, Andrew Simmons, Lars-Olof Wahlund, Eric WestmanMeasuring Global Brain Atrophy with the Brain Volume/Cerebrospinal Fluid Index: Normative Values, Cut-Offs and Clinical Associations. Neurodegener Dis (DOI: 10.1159/000442443)

Free Supplementary Material

Medial Temporal Lobe indices: Concept & Description

The recent focus on biomarkers in the diagnosis of Alzheimer's disease (AD) and its prodromal stage have created a need to translate research findings into tools for use in everyday clinical practice. Although AD and mild cognitive impairment (MCI) are commonly diagnosed using sets of clinical criteria, MRI findings may aid the clinical diagnosis, and may predict clinical progression. In AD, the medial temporal lobe (MTL) gets atrophied out of proportion to other brain areas in comparison to healthy age-matched controls and this fact may be used to ease the diagnosis. Indeed, the new research criteria have recently been proposed for AD, and MCI that incorporate (disproportionate) medial temporal lobe or hippocampal atrophy on MRI as one of the supportive features.

Age-associated differences are detected in the  MTL with an acceleration of Medial Temporal Lobe Atrophy (MTA) starting around 72 years of age in healthy people (read more). However, these changes are modest and their rate of progression over time is relatively slow with a mean rate of about 1.6% per year. Accelerated MTA is a consistent finding in AD and MCI with rates of about 2.8% in stable MCI, 3.7% in MCI transitioning to AD (MCI progressors), and up to 4.0% in AD. Frontotemporal dementia may also lead to MTA, but in a different pattern: frontotemporal dementia and semantic dementia show atrophy in the anterior portion of the hippocampus, and in semantic dementia the atrophy is asymmetrical, with the left hippocampus being affected more severely. No significant hippocampal atrophy is detected in non-fluent progressive aphasia. Other diseases such as dementia with Lewy bodies do not show MTA or it is much milder.

In contrast to MTA, ventricular enlargement (body of lateral ventricles) in old people lacks specificity, representing a measure of global brain atrophy due to aging or any neurodegenerative disorder. Ventricular enlargement  correlates with decline in cognitive performance and with cerebrospinal fluid pathologic markers of AD and several studied have assessed different methods based on the lateral ventricles measurements as AD biomarkers. However, it is well known that ventricular enlargement is a measure of global brain atrophy and is strongly associated with aging both in healthy and diseased people. In addition, almost any neurodegenerative disorder affecting the brain hemispheres leads to some degree of ventricular enlargement, including Parkinson’s disease, Frontotemporal Dementia, Lewy-Bodies Dementia and Corticobasal Degeneration and so do some psychiatric conditions. Thus, it is interesting to compare measures indicative of atrophy in the MTL with measures indicative of global brain atrophy. I propose the next indices, that allow us to interpret result of atrophy measures easier:

Planimetry methods consist in measuring the area of regions of interest (ROI). The areas of several ROI can be compared using ratios and indices. The Medial Temporal-Lobe Atrophy index (MTAi), is a simple method for measuring the relative extent of atrophy in the MTL in relation to the global brain atrophy. This 2D-method consists on calculating a ratio using the area of 3 regions traced manually on one single coronal MRI slide at the level of the interpeduncular fossa: 1. the medial temporal lobe region (A); 2. the parenchyma within the medial temporal region, that includes the hippocampus and the parahippocampal gyrus -the fimbria taenia and plexus choroideus were excluded- (B); and 3. the body of the ipsilateral lateral ventricle (C). Therefrom we can compute the “2D-Medial Temporal Atrophy” (2D-MTA=A-B) that represents absolute atrophy of the MTL; and the ratio “Medial Temporal Atrophy index”  (MTAi = (A-B) x10 / C) that represents relative atrophy of the MTL. The MTAi is suitable to assess the asymmetry of relative MTA within a subject. High asymmetry is typical of some types of FTLD. However, as there is important interindividual variability in the size of the lateral ventricles, this index is not recommended for comparing subjects but to track the progression in a given subject over time. Indeed, if we have 2 MRI studies from different times (1= first one, 2=second one), we can also compute the yearly rate of MTA (yrMTA)  as follows: yrMTA=(A2-B2)-(A1-B1) x 1200 / (#months between MRI studies) and the yearly rate of relative MTA (yrRMTA) as follows: yrRMTA=(A2-B2)-(A1-B1) x 1200 / (C2-C1) x (#months between MRI studies). High values are suggestive of "disproportionated" MTA in relation to the extent of global brain atrophy, and therefore the pattern of atrophy matches the expected in typical AD.

Volumetric methods are more sophisticated. The Medial Temporal-Lobe ratio (MTLr) compares the volume of the MTL with the whole hemispheric volume. To find out the MTLr we need 1. the volume of the hippocampus (A); the volume of the parahippocampal gyrus (B); 3. the volume of the whole brain hemisphere (C). We can compute the ratio “Medial Temporal Lobe ratio” as follows: MTLr = (A+B)^2 / C.  Low values are suggestive of MTL atrophy, and therefore the pattern of atrophy matches the expected in typical AD.

If we have 2 MRI studies from different times (1= first one, 2=second one), we can also compute the yearly rate of MTL atrophy (yrMTL) =(A1+B1)-(A2+B2) x 1200 / (#months between MRI studies) and the yearly rate of relative MTL atrophy as follows: (yrMTLr) =(A1+B1)-(A2+B2) x 1200 / (C2-C1) x (#months between MRI studies).

The Hippocampus ratio (Hr) compares the volume of the hippocampus with the whole hemispheric volume. To find out the HAr we need 1. the volume of the hippocampus (A); 2. the volume of the ipsilateral brain hemisphere (B). We can compute the ratio “Hippocampus ratio” as follows: HAr= A^2 / B. Low values are suggestive of hippocampus atrophy, and therefore the pattern of atrophy matches the expected in typical AD.

If we have 2 MRI studies from different times (1= first one, 2=second one), we can also compute the yearly rate of Hippocampus Atrophy as follows: (yrHA)= (A1-A2) x 1200 / (#months between MRI studies) and the yearly rate of relative Hippocampus atrophy as follows: (yrHAr)=(A1-A2) x 1200 / (B1-B2) x (#months between MRI studies).

The Hippocampus-Ventricle index (HVi) is the addition of the volume of the hippocampus plus the tenth part of the volume of the the lateral ventricle. Then, to find out the HVi we need  1. the  normalized volume of the hippocampus (A); 2. the normalized volume of the the lateral ventricle (B). We can compute the ratio “Hippocampus-Ventricle index” as follows: HVi = A+(B/10). Low HVi values are suggestive of AD pathology in incipient stages, while high HVi values are suggestive of global brain atrophy due to aging or any neurodegenerative disease other than AD. Intermediate values are not informative.

	Compares	Parameters needed to calculate it	Computing	Interpretation
Temporal horn index (Ti)	Volume of the temporal horn with the volume of the lateral ventricles	Temporal horn volume (A) and the lateral ventricular volume (B)	THi= A / B	Low values are suggestive of MTL atrophy, and therefore the pattern of atrophy matches the pattern expected in typical AD
Medial Temporal-Lobe ratio (MTLr)	Volume of the MTL with the ipsilateral hemispheric volume	The volume of the hippocampus (A); the volume of the parahippocampal gyrus (B); the volume of the whole brain hemisphere (C)	MTLr = (A+B)2 / C	Low values are suggestive of MTL atrophy, and therefore the pattern of atrophy matches the pattern expected in typical AD
Yearly rate of MTL atrophy (yrMTLA)	Not an index	A and B as in MTLr in 2 different MRI studies	(yrMTL) = (A1+B1) - (A2+B2) × 1200 / (# mo between MRI studies)	High values are expected in typical AD
Yearly rate of relative MTL atrophy (yrRMTLA)	Rate of atrophy of the MTL with the rate of enlargement of the ipsilateral lateral ventricles	A, B and C as in MTLr in 2 different MRI studies	yrRMTA = (A1+B1)-(A2+B2) × 1200 / (C2-C1) × (# mo between MRI studies)	High values are expected in early typical AD
Hippocampus ratio (Hr)	Volume of the hippocampus with the ipsilateral hemispheric volume	The volume of the hippocampus (A); the volume of the ipsilateral brain hemisphere (B)	Hr = A2 / B	Low values are suggestive of hippocampus atrophy, and therefore the pattern of atrophy matches the pattern expected in typical AD
Yearly rate of Hippocampus Atrophy (yrHA)	Not an index	A as in Hr in 2 different MRI studies	(yrHA) = (A1-A2) × 1200 / (# mo between MRI studies)	High values are expected in typical AD
Yearly rate of relative Hippocampus Atrophy (yrRHA)	Rate of atrophy of the hippocampus with the rate of atrophy of the ipsilateral hemisphere	A and B as in Hr in 2 different MRI studies	yrRHA = (A1-A2) × 1200 / (B1-B2) × (# mo between MRI studies)	High values are expected in early typical AD
Hippocampus-Ventricle index (HVi)	Addition of the volume of the hippocampus plus the 10th part of the volume of the lateral ventricle	Normalized volume of the hippocampus (A); normalized volume of the lateral ventricle (B)	HVi = A + (B/10)	Low HVi values are suggestive of AD pathology in incipient stages; high HVi values are suggestive of global brain atrophy due to aging or any neurodegenerative disease other than AD

Volumetric indices for comparing the extent/rate of atrophy in the medial temporal lobe with the extent/rate of global brain atrophy (full text).

Linear measures for assessing gray matter atrophy in Multiple Sclerosis

The the bicaudate ratio (BCR) is increased in MS and is more closely associated with cognitive dysfunction than are other magnetic resonance imaging surrogate markers including whole-brain atrophy. Increased BCR is best explained by frontal horn ventricular enlargement due to atrophy of deep frontal subcortical white matter. This highlights the close relationship between subcortical atrophy and cognitive impairment in patients with MS (read more) and AD (read more).

Fluid-attenuated inversion-recovery magnetic resonance imaging scan of a patient with multiple sclerosis showing the technique of determining the bicaudate ratio (BCR). The BCR is the minimum intercaudate distance (solid line) divided by brain width along the same line (dashed line).

Bicaudate ratio. The yellow represents the distance between the two apices of the caudate nuclei. The inner skull dimension is shown in turquoise. The bicaudate ratio is derived by dividing the ventricular dimension (yellow) by the inner skull dimension

However, although the bicaudate ratio is a fairly good measure of caudate atrophy, seems to be poor measures of caudate size when no atrophy is present (read more). 

Figures 2D-MTAi

Figure showing the areas needed to calculate the MTAi: (A-B) x10 / C
A: the medial temporal lobe region
B: the parenchima within the medial temporal region, that includes the hippocampus and the parahippocampal girus

C: the body of the ipsilateral lateral ventricle

Example of the Medial Temporal Atrophy index (MTAi) in a patient with mild AD. A. The coronal TIR MRI at the interpeduncular fosa is taken. B. Areas traced according to Figure 1. The data needed to compute the index are underlined in colors as in the previous figure. Note how the right MTAi is clearly higher than the left MTAi in this patient.