Clinical Significance of the Plasma Biomarker Panels in Amyloid-Negative and Tau PET-Positive Amnestic Patients: Comparisons with Alzheimer's Disease and Unimpaired Cognitive Controls.

The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma Aß42/Aß40, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and Aß42/Aß40 (rho = -0.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized ß = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging.

Episodic memory network characteristics in patients with amnestic mild cognitive impairment accompanied by executive function impairment.

OBJECTIVE: To explore the functional connectivity (FC) characteristics of the episodic memory network (EMN) in amnestic mild cognitive impairment (aMCI) patients with different levels of executive function (EF). METHODS: This study included 76 participants from the Alzheimer's Disease Neuroimaging Initiative database, comprising 23 healthy controls (HCs) and 53 aMCI patients. Based on EF levels, aMCI patients were categorized into aMCI-highEF and aMCI-lowEF groups. Cognitive function scores, pathological markers (cerebrospinal fluid ß-amyloid, total tau protein, phosphorylated tau protein, AV45-PET, and FDG-PET), and functional magnetic resonance imaging were collected and compared among the three groups. Seed-based FC analysis was used to examine differences in the EMN among the groups, and partial correlation analysis was employed to investigate the relationship between changes in FC and cognitive function scores as well as pathological markers. RESULTS: Compared to the aMCI-highEF group, the aMCI-lowEF group exhibited more severe cognitive impairment, decreased cerebral glucose metabolism, and elevated AV45 levels. Significant FC differences in the left superior temporal gyrus (STG) of the EMN were observed among the three groups. Post hoc analysis revealed that the aMCI-lowEF group had increased FC in the left STG compared to the HCs and aMCI-highEF groups, with statistically significant differences. Correlation analysis showed a significant negative correlation between the differences in FC in the left STG of aMCI-highEF and aMCI-lowEF groups and Rey Auditory Verbal Learning Test forgetting scores. Receiver operator characteristic curve analysis indicated an area under the curve of 0.741 for distinguishing between aMCI-highEF and aMCI-lowEF groups based on FC of left STG, with a sensitivity of 0.808 and a specificity of 0.667. CONCLUSION: aMCI-lowEF exhibits characteristic changes in FC within the EMN, providing theoretical support for the role of EF in mediating EMN alterations and, consequently, impacting episodic memory function.

Tongue coating-dependent superior temporal sulcus remodeling in amnestic mild cognitive impairment.

Tongue coating affects cognition, and cognitive decline at early stage also showed relations to functional and structural remodeling of superior temporal sulcus (STS) in amnestic mild cognitive impairment (aMCI). The potential correlation between disparate cognitive manifestations in aMCI patients with different tongue coatings, and corresponding mechanisms of STS remodeling remains uncharted. In this case-control study, aMCI patients were divided into thin coating (n = 18) and thick coating (n = 21) groups. All participants underwent neuropsychological evaluations and multimodal magnetic resonance imaging. Group comparisons were conducted in clinical assessments and neuroimaging measures of banks of the STS (bankssts). Generalized linear models were constructed to explore relationships between neuroimaging measures and cognition. aMCI patients in the thick coating group exhibited significantly poorer immediate and delayed recall and slower information processing speed (IPS) (P < 0.05), and decreased functional connectivity (FC) of bilateral bankssts with frontoparietal cortices (P < 0.05, AlphaSim corrected) compared to the thin coating group. It was found notable correlations between cognition encompassing recall and IPS, and FC of bilateral bankssts with frontoparietal cortices (P < 0.05, Bonferroni's correction), as well as interaction effects of group × regional homogeneity (ReHo) of right bankssts on the first immediate recall (P < 0.05, Bonferroni's correction). aMCI patients with thick coating exhibited poor cognitive performance, which might be attributed to decreased FC seeding from bankssts. Our findings strengthen the understanding of brain reorganization of STS via which tongue coating status impacts cognition in patients with aMCI.

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

The diagnostic and prognostic value of tau-PET in amnestic MCI with different FDG-PET subtypes.

OBJECTIVES: Mild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, including brain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow-up. METHODS: We included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG-PET, tau-PET, amyloid-PET, and clinical follow-up (2.3 years ± 1.2). A data-driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel-wise comparisons were performed both with FDG-PET and tau-PET data. RESULTS: The algorithm classified three metabolic subtypes, namely "Hippocampal-sparing with cortical hypometabolism" (Type1; N = 27), "Hippocampal and cortical hypometabolism" (Type 2; N = 23), and "Medial temporal hypometabolism" (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow-up. All tau-positive patients, independently of the FDG-based subtype, showed faster cognitive decline. INTERPRETATION: aMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline.

Network Localization of Spontaneous Confabulation.

OBJECTIVE: Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia. METHODS: Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53). RESULTS: Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05). CONCLUSIONS: Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.

Keeping track of who knows what in multiparty conversation despite severe memory impairment.

Language use has long been understood to be tailored to the intended addressee, a process termed audience design. Audience design is reflected in multiple aspects of language use, including adjustments based on the addressee's knowledge about the topic at hand. In group settings, audience design depends on representations of multiple individuals, each of whom may have different knowledge about the conversational topic. A central question, then, concerns how these representations are encoded and retrieved in multiparty conversation where successful conversation requires keeping track of who knows what. In the present research, we probe the biological memory systems that are involved in this process of multiparty audience design. We present the results of two experiments that compare language use in persons with bilateral hippocampal damage and severe declarative memory impairment (amnesia), and demographically matched neurotypical comparison participants. Participants played a game in which they discussed abstract images with one partner in conversation, and then discussed the images again with the same partner or with a new partner in a three-party conversation. Neurotypical participants' language use reflected newly formed representations of which partner was familiar with which images. Participants with amnesia showed evidence of partner-specific audience design in multiparty conversation but it was attenuated, especially when success required rapid alternations between representations of common ground. The findings suggest partial independence of the formation and use of partner-specific representations from the hippocampal-dependent declarative memory system and highlight the unique contributions of the declarative memory system to flexible and dynamic language use.

Converging diencephalic and hippocampal supports for episodic memory.

To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.

Characteristics and Potential Neural Substrates of Encoding and Retrieval During Memory Binding in Amnestic Mild Cognitive Impairment.

BACKGROUND: Whether encoding or retrieval failure contributes to memory binding deficit in amnestic mild cognitive impairment (aMCI) has not been elucidated. Also, the potential brain structural substrates of memory binding remained undiscovered. OBJECTIVE: To investigate the characteristics and brain atrophy pattern of encoding and retrieval performance during memory binding in aMCI. METHODS: Forty-three individuals with aMCI and 37 cognitively normal controls were recruited. The Memory Binding Test (MBT) was used to measure memory binding performance. The immediate and delayed memory binding indices were computed by using the free and cued paired recall scores. Partial correlation analysis was performed to map the relationship between regional gray matter volume and memory binding performance. RESULTS: The memory binding performance in the learning and retrieval phases was worse in the aMCI group than in the control group (F = 22.33 to 52.16, all p < 0.001). The immediate and delayed memory binding index in the aMCI group was lower than that in the control group (p < 0.05). The gray matter volume of the left inferior temporal gyrus was positively correlated with memory binding test scores (r = 0.49 to 0.61, p < 0.05) as well as the immediate (r = 0.39, p < 0.05) and delayed memory binding index (r = 0.42, p < 0.05) in the aMCI group. CONCLUSION: aMCI may be primarily characterized by a deficit in encoding phase during the controlled learning process. Volumetric losses in the left inferior temporal gyrus may contribute to encoding failure.

Using image reconstruction to investigate face perception in amnesia.

Damage to the medial temporal lobe (MTL), which is traditionally considered to subserve memory exclusively, has been reported to contribute to impaired face perception. However, it remains unknown how exactly such brain lesions may impact face representations and in particular facial shape and surface information, both of which are crucial for face perception. The present study employed a behavioral-based image reconstruction approach to reveal the pictorial representations of face perception in two amnesic patients: DA, who has an extensive bilateral MTL lesion that extends beyond the MTL in the right hemisphere, and BL, who has damage to the hippocampal dentate gyrus (DG). Both patients and their respective matched controls completed similarity judgments for pairs of faces, from which facial shape and surface features were subsequently derived and synthesized to create images of reconstructed facial appearance. Participants also completed a face oddity judgment task (FOJT) that has previously been shown to be sensitive to MTL cortical damage. While BL exhibited an impaired pattern of performance on the FOJT, DA demonstrated intact performance accuracy. Notably, the recovered pictorial content of faces was comparable between both patients and controls, although there was evidence for atypical face representations in BL particularly with regards to color. Our work provides novel insight into the face representations underlying face perception in two well-studied amnesic patients in the literature and demonstrates the applicability of the image reconstruction approach to individuals with brain damage.

How May a Brief Seizure Lead to Prolonged Epileptic Amnesia?

Pure amnestic seizures are defined as self-limited episodes with isolated, anterograde memory loss and have been attributed to bilateral dysfunction of mesial temporal structures. This type of seizure can occur in patients with different forms of temporal lobe epilepsy and has been more recently associated with a late-onset epileptic syndrome, called transient epileptic amnesia (TEA). The mechanisms of such prolonged manifestations are not well known and notably its ictal or post-ictal origin remains poorly understood. We report a case of prolonged anterograde amnesia (lasting several hours) following a brief seizure induced by stimulation of the left entorhinal cortex, recorded during stereo-EEG (SEEG). This episode was associated with prolonged changes in the intracerebral EEG signal complexity (entropy) within bilateral mesial temporal structures, particularly the entorhinal cortices, with a progressive normalization paralleling the clinical recovery. Our case shows that long-lasting (hours) memory impairment may follow brief seizure that led to prolonged electrophysiological signals alterations in bilateral mesial temporal structures.

A neurostructural biomarker of dissociative amnesia: a hippocampal study in dissociative identity disorder.

BACKGROUND: Little is known about the neural correlates of dissociative amnesia, a transdiagnostic symptom mostly present in the dissociative disorders and core characteristic of dissociative identity disorder (DID). Given the vital role of the hippocampus in memory, a prime candidate for investigation is whether total and/or subfield hippocampal volume can serve as biological markers of dissociative amnesia. METHODS: A total of 75 women, 32 with DID and 43 matched healthy controls (HC), underwent structural magnetic resonance imaging (MRI). Using Freesurfer (version 6.0), volumes were extracted for bilateral global hippocampus, cornu ammonis (CA) 1-4, the granule cell molecular layer of the dentate gyrus (GC-ML-DG), fimbria, hippocampal-amygdaloid transition area (HATA), parasubiculum, presubiculum and subiculum. Analyses of covariance showed volumetric differences between DID and HC. Partial correlations exhibited relationships between the three factors of the dissociative experience scale scores (dissociative amnesia, absorption, depersonalisation/derealisation) and traumatisation measures with hippocampal global and subfield volumes. RESULTS: Hippocampal volumes were found to be smaller in DID as compared with HC in bilateral global hippocampus and bilateral CA1, right CA4, right GC-ML-DG, and left presubiculum. Dissociative amnesia was the only dissociative symptom that correlated uniquely and significantly with reduced bilateral hippocampal CA1 subfield volumes. Regarding traumatisation, only emotional neglect correlated negatively with bilateral global hippocampus, bilateral CA1, CA4 and GC-ML-DG, and right CA3. CONCLUSION: We propose decreased CA1 volume as a biomarker for dissociative amnesia. We also propose that traumatisation, specifically emotional neglect, is interlinked with dissociative amnesia in having a detrimental effect on hippocampal volume.

Relationship between cognitive reserve, brain volume, and neuropsychological performance in amnestic and nonamnestic MCI.

Cognitive Reserve (CR) is a theoretical construct that influences the onset and course of cognitive and structural changes that occur with aging and mild cognitive impairment (MCI). There is a paucity of research that examines the relationship of CR and brain volumes in amnestic (aMCI) and nonamnestic (naMCI) separately. This study is a retrospective chart review of MCI patients who underwent neuropsychological evaluation and brain MRI with NeuroReader™ (NR). NR is an FDA-cleared software that standardizes MRI volumes to a control sample. Classifications of aMCI and naMCI were based on Petersen criteria. CR was measured as education, occupation, and word reading. Data analysis included bivariate correlations between CR, neuropsychological test scores, and NR-brain volumes by MCI subtype. The Benjamini-Hochberg method corrected for multiple comparisons. The sample included 91 participants with aMCI and 41 with naMCI. Within naMCI, positive correlations were observed between CR and whole brain volume, total gray matter, bifrontal, left parietal, left occipital, and bilateral cerebellum. Within aMCI, no significant correlations were observed between CR and brain volumes. Positive correlations with CR were observed in language, attention, and visual learning in both aMCI and naMCI groups. The current study adds to the minimal literature on CR and naMCI. Results revealed that CR is associated with volumetrics in naMCI only, though cognitive findings were similar in both MCI groups. Possible explanations include heterogeneous disease pathologies, disease stage, or a differential influence of CR on volumetrics in MCI. Additional longitudinal and biomarker studies will better elucidate this relationship.

Isolated bilateral fornix anterior columns infarction with acute amnesia and fiber tracts damage, a case report.

Isolated fornix anterior column infarction has rarely been described and is difficult to assess accurately using conventional magnetic resonance imaging (MRI). We report the case of a 75-year-old female who experienced acute anterograde amnesia. MRI performed within 24 h after amnesia onset showed an isolated infarction of the bilateral anterior columns of the fornix on diffusion-weighted imaging (DWI). Her symptoms persisted for up to 50 days, and diffusion tensor imaging (DTI) showed disruption of the fiber tracts of the fornix. when acute amnesia syndrome onset, fornix anterior column infarction should be considered, and optimized DWI and DTI methods are needed to study the fornix in vivo in future research.

Intact high-resolution working memory binding in a patient with developmental amnesia and selective hippocampal damage.

Debate continues regarding the possible role of the hippocampus across short-term and working memory tasks. The current study examined the possibility of a hippocampal contribution to precise, high-resolution cognition and conjunctive memory. We administered visual working memory tasks featuring a continuous response component to a well-established developmental amnesic patient with relatively selective bilateral hippocampal damage (Jon) and healthy controls. The patient was able to produce highly accurate response judgments regarding conjunctions of color and orientation or color and location, using simultaneous or sequential presentation of stimuli, with no evidence of any impairment in working memory binding, categorical accuracy, or continuous precision. These findings indicate that hippocampal damage does not necessarily lead to deficits in high-resolution cognitive performance, even when the damage is severe and bilateral.

Structural Alteration of Medial Temporal Lobe Subfield in the Amnestic Mild Cognitive Impairment Stage of Alzheimer's Disease.

Objective: Volume reduction and structural abnormality is the most replicated finding in neuroimaging studies of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is the early stage of AD development. Thus, it is necessary to investigate the link between atrophy of regions of interest (ROIs) in medial temporal lobe, the variation trend of ROI densities and volumes among patients with cognitive impairment, and the distribution characteristics of ROIs in the aMCI group, Alzheimer's disease (AD) group, and normal control (NC) group. Methods: 30 patients with aMCI, 16 patients with AD, and 30 NC are recruited; magnetic resonance imaging (MRI) brain scans are conducted. Voxel-based morphometry was employed to conduct the quantitative measurement of gray matter densities of the hippocampus, amygdala, entorhinal cortex, and mammillary body (MB). FreeSurfer was utilized to automatically segment the hippocampus into 21 subregions and the amygdala into 9 subregions. Then, their subregion volumes and total volume were calculated. Finally, the ANOVA and multiple comparisons were performed on the above-mentioned data from these three groups. Results: AD had lower GM densities than MCI, and MCI had lower GM densities than NC, but not all of the differences were statistically significant. In the comparisons of AD-aMCI-NC, AD-aMCI, and AD-NC, the hippocampus, amygdala, and entorhinal cortex showed differences in the gray matter densities (p < 0.05); the differences of mammillary body densities were not significant in the random comparison between these three groups (p > 0.05). The hippocampus densities and volumes of the subjects from the aMCI group and the AD group were bilaterally symmetric. The gray matter densities of the right side of the entorhinal cortex inside each group and the hippocampus from the NC group were higher than those of the left side (p < 0.05), and the gray matter densities of the amygdala and mammillary body were bilaterally symmetric in the three groups (p > 0.05). There were no gender differences of four ROIs in the AD, aMCI, and NC groups (p > 0.05). The volume differences of the hippocampus presubiculum-body and parasubiculum manifest no statistical significance (p > 0.05) in the random comparison between these three groups. Volume differences of the left amygdala basal nucleus, the left lateral nucleus, the left cortical amygdala transitional area, the left paravamnion nucleus, and bilateral hippocampal amygdala transition area (HATA) had statistical differences only between the AD group and the NC group (p < 0.05). Conclusion: Structural defects of medial temporal lobe subfields were revealed in the aMCI and AD groups. Decreased gray matter densities of the hippocampus, entorhinal cortex, and amygdala could distinguish patients with early stage of AD between aMCI and NC. Volume decline of the hippocampus and amygdala subfields could only distinguish AD between NC.

Bilateral fornix infarction presented with acute amnesia: case report.

Acute episodes of amnestic syndrome can be a challenging diagnostic problem. Except for nonvascular etiology, thalamic strokes or infarction involving several temporal lobe structures has been reported in earlier cases. The authors report a patient who suddenly developed memory loss without any other focal neurologic deficits. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) performed 1 day after onset revealed acute infarction involving the bilateral fornix column and the genu of corpus callosum. Because simple fornix infarcts often have no obvious positive neurological signs, most of the related manifestations were provided by family members, are easy to be diagnosed falsely, and missed in clinical areas, we suggest that bilateral fornix infarction should be considered in the diagnosis of an acute onset amnestic syndrome.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. OBJECTIVE: Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. METHODS: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. RESULTS: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. CONCLUSION: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Neuroprotective Potential of Synthetic Mono-Carbonyl Curcumin Analogs Assessed by Molecular Docking Studies.

Cognitive decline in dementia is associated with deficiency of the cholinergic system. In this study, five mono-carbonyl curcumin analogs were synthesized, and on the basis of their promising in vitro anticholinesterase activities, they were further investigated for in vivo neuroprotective and memory enhancing effects in scopolamine-induced amnesia using elevated plus maze (EPM) and novel object recognition (NOR) behavioral mice models. The effects of the synthesized compounds on the cholinergic system involvement in the brain hippocampus and their binding mode in the active site of cholinesterases were also determined. Compound h2 (p < 0.001) and h3 (p < 0.001) significantly inhibited the cholinesterases and reversed the effects of scopolamine by significantly reducing TLT (p < 0.001) in EPM, while (p < 0.001) increased the time exploring the novel object. The % discrimination index (DI) was significantly increased (p < 0.001) in the novel object recognition test. The mechanism of cholinesterase inhibition was further validated through molecular docking study using MOE software. The results obtained from the in vitro, in vivo and ex vivo studies showed that the synthesized curcumin analogs exhibited significantly higher memory-enhancing potential, and h3 could be an effective neuroprotective agent. However, more study is suggested to explore its exact mechanism of action.