Saccades, Alzheimer’s disease and ASL-MR

  

Introduction: ASL-MR is an MRI technique enabling the non-invasive quantification of cerebral blood flow (CBF). ASL-MR in Alzheimer's disease (AD) demonstrates a hypo-perfusion pattern of frontal, parietal, temporal, posterior cingulate cortices and thalami1,2,3, a pattern consistent with PET data4. Antisaccade error rates have previously correlated with neuropsychological measures of AD severity5,6,7,8. To date, the use of ASL in AD has been limited and it has not been determined whether hypo-perfusion correlates with saccadic measures and a more comprehensive battery of neuropsychological tests.

Methods: Pseudo-continuous ASL was used on a 3T HDx Signa GE scanner to investigate CBF perfusion. Six subjects (of a planned 16) with probable Alzheimer's disease (average age=73.2±8.3 years, MMSE=19.5±5.1, range 13-26) and eleven age and sex matched controls (average age=71.5± 7.1 years, MMSE=29.0±1.0, range 27-30) had MRI scans including T1-weighted structural images and ASL-MR images. All subjects completed a battery of saccadic paradigms including standard reflexive, predictive and the antisaccade task. All subjects completed neuropsychological tests of global cognition including the Mini Mental Status Examination (MMSE), Montreal Cognitive Assessment scale (MoCA) and Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Whole brain CBF maps were obtained and transformed to a standard anatomical template for analysis. Principal Component Analysis (PCA), a method of multivariate analysis, detailed perfusion patterns of the data set as principal component images. The first component was used from every subject to examine differences between the two groups and relationships to the saccadic and neuropsychological measures. Saccadic measures included latency (ms) and the antisaccade directional error rates, both corrected and uncorrected.

Results: The average antisaccade uncorrected error rate was 61.7% compared with 24.1% for the healthy elder controls (p=0.002). The first principal component captured 24.4% of between group variation and demonstrated a perfusion pattern in which the AD group showed regional hypo-perfusion relative to the control group in the parieto-occipital cortices, frontal cortices, posterior cingulate cortices and thalami (p=0.005).

 

Fig 1. Receiver operating curves of the ASL-MR, neuropsychological tests and saccadic measures. The global cognitive tests of MMSE,
MoCA and ADAS-cog clearly distinguished the AD group from the healthy elder controls. The ASL-MR and the error rate of uncorrected
antisaccades also differentiated the groups (refer Fig 3 and 4). In comparison, the other saccadic measures did not appear to differentiate the
groups as well.

 

 

Fig 2. PCA demonstrated regional hypo-perfusion in the AD group relative to the control group in the parieto-occipital cortices, posterior cingulate cortices, frontal cortices and thalami (p=0.005, see Fig 3). 

 

 

Fig 3. Each point indicates the expression of the first ASL-MR principal component in each subject. Blue
diamonds represent the AD group (n=6, mean=0.21,ci=0.03, 0.4) and red circles indicate the control group
(n=11, mean=-0.12, ci=-0.25, 0.02). This difference was significant t(15)=3.31, p=0.005.

 

 

Fig 4. Each point indicates the percent antisaccade error uncorrected in each subject. Blue diamonds represent
the AD group (n=6, mean=61.7%, ci=37.0,86.4) and orange circles indicate the control group

(n=11,mean=24.1%, ci=12.0,36.2). This difference was significant t(15)=3.7, p=0.002.

 

Conclusions: Arterial spin-labelled MRI is a technique to investigate perfusion that is useful in the discrimination of AD and control groups. The saccadic measures, with the exception of erroneous uncorrected antisaccade rates, were unable to discriminate AD from controls well. There was no correlation between the erroneous uncorrected antisaccade rates measure and that of cerebral perfusion. These preliminary results from a larger ongoing study demonstrated the ability to detect differing patterns of perfusion and differing performance of the antisaccade task, even with a small sample size. In AD, the antisaccade task appears to be the most informative saccadic task, as previously found5,6,7,8. The ability to non-invasively acquire high quality images
and a quantitative measure of CBF, give ASL promise as a biomarker and in the study of future therapeutics in AD.

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S.L Wright1, 2, M.R MacAskill1, 2, R. Watts1, 3, T.R Melzer1, 2, R. Keenan4, A. Shankaranarayanan5, D.C Alsop6, B. Deavoll7, J.C Dalrymple-Alford1, 8, and T.J Anderson1, 2 1Van der Veer Institute for Parkinson's and Brain Research, Christchurch, New Zealand,
2Medicine, University of Otago, Christchurch, New Zealand, 3Physics and Astronomy, University of Canterbury, Christchurch, New Zealand, 4Christchurch Radiology Group, Christchurch, New Zealand, 5GE Healthcare, Menlo Park, CA, United States, 6Beth Israel
Deaconess Medical Centre, Boston, MA, United States, 7Canterbury District Health Board, Christchurch, New Zealand, 8Psychology, University of Canterbury, Christchurch, New Zealand.

This research is funded by the Neurological Foundation of New Zealand. The assistance of Dr Matthew Croucher in patient
recruitment is gratefully acknowledged. The author is supported by the University of Otago, New Zealand.