Effects of the APOEɛ4 Allele on the Relationship Between Tau and Amyloid-ß in Early- and Late-Onset Alzheimer's Disease.

BACKGROUND: Little is known regarding the differential effects of the apolipoprotein E (APOE) ɛ4 on the regional topography of amyloid and tau in patients with both early-onset (EOAD) and late-onset Alzheimer's disease (LOAD). OBJECTIVE: To compare the distribution and association of tau, amyloid, and cortical thickness among groups classified by the presence of APOEɛ4 allele and onset age. METHODS: A total of 165 participants including 54 EOAD patients (29 ɛ4-; 25 ɛ4+), 45 LOAD patients (21 ɛ4-; 24 ɛ4+), and 66 age-matched controls underwent 3T MRI, 18F-THK5351 (THK) and 18F-flutemetamol (FLUTE) PET scans, APOE genotyping, and neuropsychological tests. Data for voxel-wise and standardized uptake values from PET scans were analyzed in the context of APOE and age at onset. RESULTS: EOAD ɛ4- patients showed greater THK retention in the association cortices, whereas their EOAD ɛ4+ counterparts had more retention in medial temporal areas. THK topography of LOAD ɛ4+ was similar to EOAD ɛ4 + . THK correlated positively with FLUTE and conversely with mean cortical thickness, being lowest in EOAD ɛ4-, highest in LOAD ɛ4-, and modest in ɛ4+ groups. Even in the APOEɛ4+ groups, THK tended to correlate with FLUTE and mean cortical thickness in the inferior parietal region in EOAD and in the medial temporal region in LOAD. LOAD ɛ4- manifested with prevalent small vessel disease markers and the lowest correlation between THK retention and cognition. CONCLUSION: Our observations suggest the differential effects of the APOEɛ4 on the relationship between tau and amyloid in EOAD and LOAD.

[18F]THK-5351 PET Patterns in Patients With Alzheimer's Disease and Negative Amyloid PET Findings.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) does not always mean amyloid positivity. [18F]THK-5351 has been shown to be able to detect reactive astrogliosis as well as tau accompanied by neurodegenerative changes. We evaluated the [18F]THK-5351 retention patterns in positron-emission tomography (PET) and the clinical characteristics of patients clinically diagnosed with AD dementia who had negative amyloid PET findings. METHODS: We performed 3.0-T magnetic resonance imaging, [18F]THK-5351 PET, and amyloid PET in 164 patients with AD dementia. Amyloid PET was visually scored as positive or negative. [18F]THK-5351 PET were visually classified as having an intratemporal or extratemporal spread pattern. RESULTS: The 164 patients included 23 (14.0%) who were amyloid-negative (age 74.9±8.3 years, mean±standard deviation; 9 males, 14 females). Amyloid-negative patients were older, had a higher prevalence of diabetes mellitus, and had better visuospatial and memory functions. The frequency of the apolipoprotein E ε4 allele was higher and the hippocampal volume was smaller in amyloid-positive patients. [18F]THK-5351 uptake patterns of the amyloid-negative patients were classified into intratemporal spread (n=10) and extratemporal spread (n=13). Neuropsychological test results did not differ significantly between these two groups. The standardized uptake value ratio of [18F]THK-5351 was higher in the extratemporal spread group (2.01±0.26 vs. 1.61±0.15, p=0.001). After 1 year, Mini Mental State Examination (MMSE) scores decreased significantly in the extratemporal spread group (-3.5±3.2, p=0.006) but not in the intratemporal spread group (-0.5±2.8, p=0.916). The diagnosis remained as AD (n=5, 50%) or changed to other diagnoses (n=5, 50%) in the intratemporal group, whereas it remained as AD (n=8, 61.5%) or changed to frontotemporal dementia (n=4, 30.8%) and other diagnoses (n=1, 7.7%) in the extratemporal spread group. CONCLUSIONS: Approximately 70% of the patients with amyloid-negative AD showed abnormal [18F]THK-5351 retention. MMSE scores deteriorated rapidly in the patients with an extratemporal spread pattern.

Translocator Protein (18 kDa) Polymorphism (rs6971) in the Korean Population.

Background and Purpose: The expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population. Methods: We performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer's disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively. Results: We found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex. Conclusions: The majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.

Association of Subcortical Structural Shapes With Tau, Amyloid, and Cortical Atrophy in Early-Onset and Late-Onset Alzheimer's Disease.

The objectives of this study were to compare the topographical subcortical shape and to investigate the effects of tau or amyloid burden on atrophic patterns in early onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). One hundred and sixty-one participants (53 EOAD, 44 LOAD, 33 young controls, and 31 older controls) underwent [18F]THK5351 positron emission tomography (PET), [18F]flutemetamol (FLUTE) PET, and 3T MRI scans. We used surface-based analysis to evaluate subcortical structural shape, permutation-based statistics for group comparisons, and Spearman's correlations to determine associations with THK, FLUTE, cortical thickness, and neuropsychological test results. When compared to their age-matched controls, EOAD patients exhibited shape reduction in the bilateral amygdala, hippocampus, caudate, and putamen, while in LOAD patients, the bilateral amygdala and hippocampus showed decreased shapes. In EOAD, widespread subcortical shrinkage, with less association of the hippocampus, correlated with THK retention and cortical thinning, while in LOAD patients, subcortical structures were limited which had significant correlation with THK or mean cortical thickness. Subcortical structural shape showed less correlation with FLUTE global retention in both EOAD and LOAD. Multiple cognitive domains, except memory function, correlated with the bilateral amygdala, caudate, and putamen in EOAD patients, while more restricted regions in the subcortical structures were correlated with neuropsychological test results in LOAD patients. Subcortical structures were associated with AD hallmarks in EOAD. However, the correlation was limited in LOAD. Moreover, relationship between subcortical structural atrophy and cognitive decline were quite different between EOAD and LOAD. These findings suggest that the effects of Alzheimer's pathologies on subcortical structural changes in EOAD and LOAD and they may have different courses of pathomechanism.

Identification of Heterogeneous Subtypes of Mild Cognitive Impairment Using Cluster Analyses Based on PET Imaging of Tau and Astrogliosis.

Background: Mild cognitive impairment (MCI) is a condition with diverse causes and clinical outcomes that can be categorized into subtypes. [18F]THK5351 has been known to detect reactive astrogliosis as well as tau which is accompanied by neurodegenerative changes. Here, we identified heterogeneous groups of MCI patients using THK retention patterns and a graph theory approach, allowing for the comparison of risk of progression to dementia in these MCI subgroups. Methods: Ninety-seven participants including 60 MCI patients and individuals with normal cognition (NC, n = 37) were included and undertook 3T MRI, [18F]THK5351 PET, and detailed neuropsychological tests. [18F]Flutemetamol PET was also performed in 62 participants. We calculated similarities between MCI patients using their regional standardized uptake value ratio of THK retention in 75 ROIs, and clustered subjects with similar retention patterns using the Louvain method based on the modularity of the graph. The clusters of patients identified were compared with an age-matched control group using a general linear model. Dementia conversion was evaluated after a median follow-up duration of 34.6 months. Results: MCI patients were categorized into four groups according to their THK retention patterns: (1) limbic type; (2) diffuse type; (3) sparse type; and (4) AD type (retention pattern as in AD). Subjects of the limbic type were characterized by older age, small hippocampal volumes, and reduced verbal memory and frontal/executive functions. Patients of the diffuse type had relatively large vascular burden, reduced memory capacity and some frontal/executive functions. Co-morbidity and mortality were more frequent in this subgroup. Subjects of the sparse type were younger and declined only in terms of visual memory and attention. No individuals in this subgroup converted to dementia. Patients in the AD type group exhibited the poorest cognitive function. They also had the smallest hippocampal volumes and the highest risk of progression to dementia (90.9%). Conclusion: Using cluster analyses with [18F]THK5351 retention patterns, it is possible to identify clinically-distinct subgroups of MCI patients and those at greater risk of progression to dementia.

18F-THK5351 PET Imaging in the Behavioral Variant of Frontotemporal Dementia.

BACKGROUND AND PURPOSE: Behavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD. METHODS: Forty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients. RESULTS: In the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem. CONCLUSIONS: The distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.