Identifying a subtype of Alzheimer’s disease characterised by predominant right focal cortical atrophy

We aimed to identify an Alzheimer’s disease (AD) subtype with right predominant focal atrophy. We recruited 17 amyloid PET positive logopenic variant primary progressive aphasia (lvPPA) and 226 amyloid PET positive AD patients. To identify AD with right focal atrophy (Rt-AD), we selected cortical areas that showed more atrophy in lvPPA than in AD and calculated an asymmetry index (AI) for this area in each individual. Using a receiver operating characteristic curve, we found that the optimal AI cut-off to discriminate lvPPA from AD was −3.1 (mean AI – 1.00 standard deviation) (sensitivity 88.2, specificity 89.8). We identified 32 Rt-AD patients whose AI was above mean AI + 1.00 standard deviation, 38 Lt-AD patients whose AI was lower than mean AI − 1.00 standard deviation, and 173 Symmetric-AD patients whose AI was within mean AI ± 1.00 standard deviation. We characterized clinical and cognitive profiles of Rt-AD patients by comparing with those of Lt-AD and Symmetric-AD patients. Compared to Symmetric-AD patients, Rt-AD patients had asymmetric focal atrophy in the right temporoparietal area and showed poor performance on visuospatial function testing (p = 0.009). Our findings suggested that there is an AD variant characterized by right focal atrophy and visuospatial dysfunction.

Neuropsychological test. Rt-AD patients showed poor performance on visuospatial function testing compared to Sym-AD patients (p = 0.013). Rt-AD patients showed poor performance on visual memory testing compared to Sym-AD (p = 0.032) and Lt-AD patients (p = 0.008). Lt-AD patients showed poor performance on language testing (p = 0.002), calculation testing (p = 0.024), and frontal/executive function testing (COWAT animal, p = 0.004) compared to Sym-AD (Table 2).

Discussion
In this study, we identified AD patients with right focal atrophy, so called Rt-AD, based on the hypothesis that this subtype might be the counterpart to lvPPA. Additionally, we investigated the overall cortical atrophy pattern and neuropsychological characteristics of Rt-AD patients. Our main findings were that there are AD patients who have asymmetric right focal atrophy in the temporoparietal area, and these patients had worse visuospatial function compared to Sym-AD patients.
We identified 32 (14.2%) Rt-AD patients among 226 amyloid-positive AD patients. The Rt-AD patients had asymmetric focal atrophy in the right temporoparietal area. AD is a heterogeneous disease with various subtypes. Each subtype has its unique regions that are vulnerable to neurodegeneration 8,12 . Recent neuroimaging studies clustered AD into 3-5 anatomical subtypes based on cortical atrophy patterns 13,14 . However, a clustering approach might be weak for capturing a specific subtype. Therefore, we searched for Rt-AD patients by using AI of cortical thickness based on the hypothesis that AD with right focal atrophy might be the counterpart of lvPPA.
Our finding that Rt-AD patients had focal atrophy in the temporoparietal area was supported by additional analysis. Instead of calculating AI in the atrophied area of lvPPA, we used the whole hemisphere to calculate AI hemi and defined Rt hemi -AD patients based on AI hemi which is strictly anatomical approach. Compared to Sym hemi -AD patients, Rt hemi -AD patients showed asymmetric focal atrophy in the right temporoparietal area,  Table 1. Participant demographics. AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; Lt-AD, AD with left focal atrophy; Rt-AD, AD with right focal atrophy; Sym-AD, AD with symmetric atrophy the same area we found in Rt-AD patients. Furthermore, the atrophied area of lvPPA patients (the left superior temporal area) mirrored that of Rt hemi -AD or Rt-AD patients (the right superior temporal area). This suggests that the temporoparietal area might be a unique region vulnerable to neurodegeneration in AD patients with asymmetric focal atrophy. AD with right focal atrophy may not have been recognized as a clinical syndrome for several reasons. Right hemisphere function involves a diffuse area. The non-dominant hemisphere (right hemisphere in 95% of right   www.nature.com/scientificreports www.nature.com/scientificreports/ handed people and 70% of left handed people 15 ) is responsible for visuospatial function, attention, and emotion while the dominant hemisphere is responsible for language and praxis. Because visuospatial function, attention, and emotion are processed by a diffuse bilateral area, a focal defect in the right hemisphere may be partially compensated by the left hemisphere or other areas in the right hemisphere 9,10 . On the other hand, focal lesions in the left hemisphere may cause a profound deficit in language since language is almost exclusively localized to the left inferior frontal, perisylvian, and posterior temporal areas. This is why invasive procedures (ex. ventricular shunts) are more likely to be done on the right hemisphere 16 . Additionally, a subtle language deficit may well be recognized as it causes inconvenience in daily life whereas subtle deficit in visuospatial function, attention, or emotion may not be easily recognized. The most common initial symptom of our Rt-AD patients was episodic memory impairment 50.0% (16/32), followed by both visuospatial dysfunction and episodic memory impairment 28.1% (9/32). We speculate that a focal defect in the right hemisphere in Rt-AD patients might have been compensated by other areas or that a subtle deficit might have been unrecognized.

Rt-AD Sym-AD Lt-AD
Although the Rt-AD subtype has not been recognized as a clinical subtype, a group-wise comparison showed that the Rt-AD group had more severe dysfunction in right hemisphere activities, including visuospatial dysfunction and visual memory impairment, compared to Sym-AD patients. Consistent with our study, a previous study showed that visuospatial dysfunction was associated with predominant pathologic changes in the right hemisphere and right dominant atrophy 8 . Clinically defined, rare AD variants such as frontal variant AD, PCA, and lvPPA each have unique focal atrophy in the frontal, posterior, and left cortex, respectively, that matches clinical symptoms 2,3 . Likewise, anatomically defined Rt-AD patients also had visuospatial dysfunction and visual memory impairment that corresponded to cortical thinning in the right temporoparietal area.
Our study has several limitations. First, we searched for the Rt-AD subtype among amyloid-positive AD patients and did not include other amyloid-positive dementia syndromes. Corticobasal syndrome (CBS) or behavioral variant frontotemporal dementia (bvFTD) may also have right asymmetric atrophy with AD as the underlying pathology 17 . Further studies that include other dementia syndromes with AD biomarkers are needed to find the true clinical characteristics of Rt-AD. Second, although our patients were all amyloid PET-positive, we needed pathologic confirmation. Finally, our results need to be replicated with a larger sample.
In conclusion, our study is noteworthy in that we identified an AD variant with right focal atrophy among well-characterized amyloid-positive AD patients. Our findings suggest that there is an AD variant characterized by right focal atrophy and visuospatial dysfunction. Identifying the distinct patterns of structural and neuropsychological characteristics of Rt-AD could provide new insights into regions vulnerable to neurodegeneration in the AD spectrum.

Participants.
We retrospectively collected data from 226 patients with amyloid PET-positive AD and 17 patients with amyloid PET-positive lvPPA. Experienced neurologists evaluated the participants based on their clinical symptoms and reviewed medical histories, neuropsychological test results, MRI, amyloid PET, and laboratory tests. AD patients met the research criteria for probable AD dementia with evidence of the AD pathophysiological process proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) 1 . lvPPA patients met current consensus criteria for lvPPA 18 . Participants with other structural lesions, such as territorial infarction, intracranial hemorrhage, brain tumor, hydrocephalus, or severe white matter hyperintensities (WMH), observed on brain MRI were excluded. Severe WMH was defined as a periventricular WMH ≥ 10 mm or a deep WMH ≥ 25 mm as modified from the Fazekas ischemia criteria 19 .

Standard protocol approvals, registrations, and patient consents. The Institutional Review Board
at Samsung Medical Center approved our study and waived the need for informed consent as part of our study approval since we used retrospective de-identified data collected during health exam visits. In addition, all methods were carried out in accordance with the approved guidelines.
Neuropsychological assessments. All patients underwent a standardized neuropsychological battery called the Seoul Neuropsychological Screening Battery (SNSB) 20,21 . The SNSB consists of tests for attention, language, calculation, visuospatial, memory, frontal-executive function, and tests for general cognition such as the Mini-mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Attention was assessed with the backward digit span and letter cancellation tests; language was assessed with the Korean version of the Boston Naming Test (K-BNT); calculation was assessed with addition, subtraction, multiplication, and division; visuospatial function was assessed with the Rey-Osterrieth Complex Figure Test (RCFT); memory function was assessed with delayed recall of the Seoul Verbal Learning Test (SVLT) and RCFT; and frontal-executive function was assessed with the Controlled Oral Word Association Test (COWAT) phonemic fluency test and the Stroop color reading test. Each score was converted into a standardized Z-score based on age-and education-adjusted norms.

Brain MRI scans. All patients underwent brain MRI including fluid-attenuated inversion recovery (FLAIR)
and three-dimensional (3D) T1 imaging at Samsung Medical Center in a 3.0 T MRI scanner (Philips 3.0 T Achieva; Best, the Netherlands).
Amyloid PET scan. Amyloid accumulation in the brain was assessed with amyloid PET scans: 11  www.nature.com/scientificreports www.nature.com/scientificreports/ Milwaukee, WI, USA) at Samsung Medical Center. Amyloid PET positivity was interpreted based on previously reported guidelines for each ligand. PiB PET positivity was defined as a global 11 C-PiB uptake ratio more than two SD from the mean of normal controls (PiB retention ratio ≥ 1.5) 22 . 18  Cortical thickness analysis. The standard Montreal Neurological Institute (MNI) anatomical pipeline was used to extract cortical thickness. Native MRI images were registered to a standardized stereotaxic space with a linear transformation 26 . The N3 algorithm was used to correct intensity nonuniformities due to inhomogeneities in the magnetic field 27 . The registered and corrected images were classified into white matter, gray matter, cerebrospinal fluid, and background with a 3D stereotaxic brain mask and the Intensity-Normalized Stereotaxic Environment for Classification of Tissues (INSECT) algorithm 28 . The inner and outer cortical surfaces were automatically extracted with the Constrained Laplacian-based Automated Segmentation with Proximities (CLASP) algorithm 29 .
The cortical thickness was defined as the Euclidean distance between the linked vertices of the inner and outer surfaces, after applying an inverse transformation matrix to cortical surfaces and reconstructing them in the native space 29,30 . Identifying AD variants with right focal atrophy. Rt-AD patients were identified based on the assumption that the Rt-AD cortical atrophy pattern would be the counterpart of lvPPA. In other words, we selected patients whose cortical atrophy pattern mirrored that of lvPPA. To identify Rt-AD patients, we began by selecting a cortical area that showed more atrophy in lvPPA compared to AD. That area, the left superior temporal area, was defined as the region of interest (ROI) (Fig. 2A). We then calculated an asymmetry index (AI) 31 for the ROI in each participant as follows: R and L represent mean cortical thicknesses of corresponding voxels from the right and left ROI, respectively. The optimal AI cut-off to discriminate lvPPA from AD was identified by using a receiver operating characteristic curve (sensitivity 88.2, specificity 89.8) (Fig. 2B). This cut-off value (−3.1377) corresponds to the mean AI -1.00 SD. Finally, we identified 32 Rt-AD patients by selecting patients who had an AI value greater than the mean AI + 1.00 standard deviation (1.8112) (Fig. 2C). To make a fair comparison, we identified 38 Lt-AD patients by selecting patients who had an AI value lower than the mean AI − 1.00 SD (−3.1377) and identified 173 Sym-AD patients whose AI was within mean AI ± 1.00 SD (between −3.1377 and 1.8112). We performed additional analysis to identify AD patients with right focal atrophy using strictly anatomical method. Instead of using ROI that was defined based on the atrophied area of lvPPA, we used the whole hemisphere to calculate AI hemi .  We selected the cortical area that showed more atrophy in lvPPA compared to AD and defined that area as the region of interest (ROI) (q < 0.05 FDR corrected). (B) We calculated an asymmetry index (AI) for the ROI in each participant. The optimal AI cut-off to discriminate lvPPA from AD was identified by using a receiver operating characteristic curve (sensitivity 88.2, specificity 89.8, area under curve 0.921, p < 0.001). This cut-off value (−3.1377) corresponds to the mean AI -1.00 SD.
(C) Finally, we identified 32 Rt-AD patients by selecting patients who had an AI value greater than the mean AI + 1.00 SD (1.8112). We also identified 38 Lt-AD patients by selecting patients who had an AI value lower than the mean AI − 1.00 SD (−3.1377) and identified 173 Sym-AD patients who had an AI value within mean AI ± 1.00 SD (between −3.1377 and 1.8112). Red box indicates lvPPA and gray box indicates AD. AD, Alzheimer's disease; AI, Asymmetry index; lvPPA, logopenic variant primary progressive aphasia; Lt-AD, AD with left focal atrophy; Rt-AD, AD with right focal atrophy; Sym-AD, AD with symmetric atrophy; SD, standard deviation.