Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases.

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.

In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Investigating neural dysfunction with abnormal protein deposition in Alzheimer's disease through magnetic resonance spectroscopic imaging, plasma biomarkers, and positron emission tomography.

In Alzheimer's disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-ß depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and 11C-PiB for amyloid-ß positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = -0.50) and NAA/Cr ratios (P = 0.003, r = -0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD's pathological context.

Association of Tooth Loss with Alzheimer's Disease Tau Pathologies Assessed by Positron Emission Tomography.

BACKGROUND: Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC). OBJECTIVE: To elucidate the relevance of oral conditions and amyloid-ß (Aß) and tau pathologies in human participants. METHODS: We examined the number of remaining teeth and the biofilm-gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aß and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aß-positive, and all HCs were Aß-negative. We analyzed the correlation between the oral parameters and radiotracer retention. RESULTS: No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status. CONCLUSIONS: Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.

Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease.

OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD. METHODS: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11 C]PiB and [18 F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography. RESULTS: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05). INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2023.

Assessing late-life anxiety in Japanese older adults: psychometric evaluation of the Japanese version of the Geriatric Anxiety Scale.

BACKGROUND: This study developed a Japanese version of the Geriatric Anxiety Scale (GAS-J) and its short form (GAS-10-J) to evaluate anxiety in Japanese older adults and assess its psychometric properties using a cross-sectional design. METHODS: A total of 331 community-dwelling older adult participants (208 men, 116 women, seven unknowns; mean age = 73.47 ± 5.17 years, range = 60-88 years) recruited from two Silver Human Resources Centres in the Kanto region, Japan, answered a set of self-report questionnaires. Of these respondents, 120 participated in a follow-up survey to evaluate test-retest reliability. RESULTS: Confirmatory factor analysis suggested that, as with the original GAS, the GAS-J had a three-factor structure and the GAS-10-J had a unifactor structure with high standardised factor loadings. Test-retest correlations and internal consistency analyses indicated that these scales were reliable. Correlations between the GAS-J/GAS-10-J with the Geriatric Anxiety Inventory, Generalised Anxiety Disorder-7, Geriatric Depression Scale-15, World Health Organization-Five Well-Being Index, and Kihon Checklist were mostly consistent with our hypotheses, thereby supporting the construct validity of the GAS-J/GAS-10-J. CONCLUSIONS: The findings indicate that the GAS-J and GAS-10-J have robust psychometric properties for assessing late-life anxiety in Japanese older adults. Further GAS-J studies are required for clinical groups.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A new device-aided cognitive function test, User eXperience-Trail Making Test (UX-TMT), sensitively detects neuropsychological performance in patients with dementia and Parkinson's disease.

BACKGROUND: A newer generation neuropsychological tests can take advantage of touch screen and mobile technology. We have developed a new Android application termed "User eXperience-Trail Making Test (UX-TMT)" for neurocognitive assessment and training. This study investigated the utility, including the reliability and the validity, of the UX-TMT as a screening test for cognitive decline in adults. METHODS: A total of 84 individuals aged 27-86 years were divided into three groups; healthy controls ([HC] n = 29), people with Parkinson's disease (PD; n = 28), and people with mild cognitive impairment (MCI) and dementia (MCI&D; n = 27). We examined the distributions of the scores and the time required, and the effects of age and group on these distributions. We analyzed internal consistency and convergent validity in all samples and applied receiver operator characteristic (ROC) analysis to determine a cutoff score that could differentiate the MCI & D group from the HC group. RESULTS: 97.6% of the participants completed all of the tasks, and the average total test time required for UX-TMT was 428.8 (± 109.1) s in the HC, 542.0 (± 168.7) s in the PD, and 777.5 (± 256.1) s in the MCI&D groups, respectively. The MCI&D group showed significantly lower UX-TMT scores and longer total time in completing the task than the HC group. In an ROC analysis, a score of 21 showed high sensitivity (.83) and specificity (.92), and the UX-TMT score plus age improved sensitivity to .96. Additionally, the UX-TMT scores showed significant correlation with the Mini-Mental State Examination (Japanese version) scores (r = .77, p = .001), and Cronbach's alpha (.71-.83) indicated acceptable internal consistency. CONCLUSION: The UX-TMT demonstrated high reliability and validity to detect cognitive decline in Japanese adults, highlighting its utility as a screening tool for epidemiological and clinical research.

Vitrectomy using 0.025% povidone-iodine in balanced salt solution plus for the treatment of postoperative endophthalmitis.

PURPOSE: To investigate the bactericidal effect of 0.025% povidone-iodine in Balanced Salt Solution PLUS (0.025% PI-BSS PLUS) and its use in vitrectomy for postoperative endophthalmitis. METHODS: First, an experimental laboratory model using Staphylococcus aureus was used to evaluate the bactericidal effect of PI-BSS PLUS. Next, in a case series of 4 eyes with postoperative endophthalmitis, vitrectomy using 0.025% PI-BSS PLUS as irrigation solution was conducted, followed by postoperative intravitreal and intravenous antibiotics. RESULTS: In in vitro study, PI at concentrations of 0.01% and above in BSS PLUS exhibited marked bactericidal effect after 15 seconds of exposure. Bactericidal effect of 0.025% PI-BSS PLUS was maintained at room temperature storage for 15 minutes but was attenuated after 30 minutes. Among 4 eyes that underwent vitrectomy using 0.025% PI-BSS PLUS, coagulase-negative Staphylococcus sp. was isolated in 1 eye at the beginning but not at completion of surgery. In all four eyes, endophthalmitis was resolved with no adverse events. Ocular toxicity was not observed. CONCLUSION: The 0.025% PI-BSS PLUS is bactericidal and nontoxic when used as irrigation solution in vitrectomy. In 4 cases of postoperative endophthalmitis, vitrectomy using 0.025% PI-BSS PLUS followed by postoperative antibiotics resolved endophthalmitis.

Neurobehavioral and hemodynamic evaluation of Stroop and reverse Stroop interference in children with attention-deficit/hyperactivity disorder.

Failure of executive function (EF) is a core symptom of attention-deficit/hyperactivity disorder (ADHD). However, various results have been reported and sufficient evidence is lacking. In the present study, we evaluated the characteristics of children with ADHD using the Stroop task (ST) and reverse Stroop task (RST) that reflects the inhibition function of EF. We compared children with ADHD, typically developing children (TDC), and children with autism spectrum disorder (ASD), which is more difficult to discriminate from ADHD. A total of 10 children diagnosed with ADHD, 15 TDC, and 11 children diagnosed with ASD, all matched by age, sex, language ability, and intelligence quotient, participated in this study. While each subject performed computer-based ST and RST with a touch panel, changes in oxygenated hemoglobin (oxy-Hb) were measured in the prefrontal cortex (PFC) by near-infrared spectroscopy (NIRS) to correlate test performance with neural activity. Behavioral performance significantly differed among 3 groups during RST but not during ST. The ADHD group showed greater color interference than the TDC group. In addition, there was a negative correlation between right lateral PFC (LPFC) activity and the severity of attention deficit. Children with ADHD exhibit several problems associated with inhibition of color, and this symptom is affected by low activities of the right LPFC. In addition, it is suggested that low hemodynamic activities in this area are correlated with ADHD.

Facial identity recognition in children with autism spectrum disorders revealed by P300 analysis: a preliminary study.

BACKGROUND: To reveal the neural substrate of communication difficulties in children with autism spectrum disorders (ASDs), we investigated the P300 component of event-related potentials (ERPs) as represented by the average of electroencephalography findings time-locked to events and behavior. Because the P300 amplitude influences attentional resource allocation during discrimination, the component elicited during perception of known and unknown faces should indicate familiarity processing. METHODS AND RESULTS: Nine typically developing children (TD) and nine children with ASDs participated in this study (Experiment 1). The P300 amplitude in TD children was significantly larger during familiar face perception than during unfamiliar face perception (p<0.01). However, there was no evidence of familiarity effect in children with ASDs. In three children with ASDs, we also assessed the P300 amplitude during perception of a therapist's face one month before (baseline), a few days before and after social skills training (SST) sessions (Experiment 2). To evaluate the effect of familiarity on facial identity processing, we analyzed the therapist/unknown ratio of P300 amplitudes related to the face discrimination task as an index. The ratio was larger after SST sessions than before, but there was no difference in the ratio between baseline and before SST assessments. CONCLUSION: The P300 might be influenced by attentional resource allocation depending on the stage of learning face identification in children with ASDs. We speculate that this approach to evaluating brain responses during facial identity recognition could be used as a tool to clarify children's communication difficulties.

Developmental change of visuo-spatial working memory in children: quantitative evaluation through an Advanced Trail Making Test.

AIM: The present study aimed to investigate the developmental change in Visuo-Spatial Working Memory (VSWM) in typically developed children using a specially designed Advanced Trail Making Test for children (ATMT-C). METHODS: We developed a new method for evaluating VSWM efficiency in children using a modified version ATMT to suit their shorter sustained attention. The ATMT-C consists of two parts; a number-based ATMT and a hiragana (Japanese phonogram)-based ATMT, both employing symbols familiar to young children. A total of 94 healthy participants (6-28 years of age) were enrolled in this study. RESULTS: A non-linear developmental change of VSWM efficiency was observed in the results from the ATMT-C. In the number-based ATMT, children under 8 years of age showed a relatively rapid increase in VSWM efficiency while older children (9-12 years) had a more gradual increase in VSWM efficiency. Results from the hiragana-based ATMT-C showed a slightly delayed increase pattern in VSWM efficiency compared to the pattern from the number-based ATMT. There were no significant differences in VSWM efficiency for gender, handedness and test order. INTERPRETATION: VSWM in children gradually matures in a non steady-state manner and there is an important stage for VSWM maturation before reaching 12 years of age. VSWM efficiency may also vary depending on developmental condition of its cognitive subsystems.

Variations of the ulnar nerve in Guyon's canal: in vivo demonstration using ultrasound and 3 T MRI.

BACKGROUND: The clinical importance of Guyon's canal is emphasized due to the various branching patterns of the ulnar nerve. So far, the arborization pattern of the ulnar nerve in Guyon's canal has been investigated mostly by cadaveric studies. PURPOSE: To demonstrate anatomic variations of the ulnar nerve in Guyon's canal in vivo by using high definition ultrasound (US) and 3 T magnetic resonance imaging (MRI). MATERIAL AND METHODS: US imaging and 3 T MRI with an 8-channel coil was applied to 30 hands of 15 volunteers. The main trunk and the branched superficial and deep ulnar nerves, including neural bifurcation or trifurcation, were recognized on US and confirmed by 3 T MR images. The ulnar artery and vein and its branches were traced on color Doppler US and also visualized by MRI. The branching pattern of the ulnar nerve was determined from the inlet to the outlet of Guyon's canal. RESULTS: Of 30 hands, 21 (70%) revealed bifurcation and 9 (30%) had trifurcation branching pattern of the ulnar nerve. In 16 hands (54%), imaging demonstrated that a single nerve entered the canal and divided into two trunks, one superficial and one deep, then exited the canal. The bifurcation occurred predominantly just after entering the canal inlet. The typical trifurcation pattern indicated that a single trunk entered the canal and divided into two, then one of the two bifurcated, producing a trifurcated pattern with two superficial and one deep bundle. Of 15 participants, symmetrical branching of bilateral hands was identified in 4 cases (27%), whereas 11 (73%) had asymmetrical branching. CONCLUSION: US and 3 T MRI readily delineated the branching pattern of the ulnar nerve in Guyon's canal in vivo. Morphological understanding about this neural branching can be informative in presurgical planning and also in diagnosis.

[Cerebral inhibitory functioning in patients with attention deficit/hyperactivity disorder. I. Analysis of non-target-P300 component in a visual oddball paradigm].

The present study was organized to evaluate the cerebral inhibitory function in children with developmental disorders such as attention deficit/hyperactivity disorder (AD/HD) and pervasive developmental disorder (PDD). Target and non-target-P300 event related potential (ERP) in response to stimuli of a visual oddball paradigm was analyzed. Ten children with AD/HD, 10 children with PDD and 10 healthy children were included in the study participants. Target-P300 component was observed in all subjects, which showed predominant amplitudes in Pz electrode. No significant differences were observed in amplitude and latency of target-P300 among three groups. In healthy children, Non-target-P300 component was observed mainly in Cz and Pz electrodes, while children with AD/HD had significantly reduced amplitudes of the component at Cz and children with PDD showed shorter latency at Oz. These results suggest that Non-target-P300 component in visual oddball paradigm possibly reflects the brain function associated with inhibitory processing and there is a relationship between the non-target-P300 potential abnormality and the AD/HD behavior.

Symptom profile of multiple chemical sensitivity in actual life.

OBJECTIVE: This study was conducted to confirm the definition of multiple chemical sensitivity (MCS) in actual life: that multiple symptoms are provoked in multiple organs by exposure to, and ameliorated by avoidance of, multiple chemicals at low levels. We used the Ecological Momentary Assessment to monitor everyday symptoms and the active sampling and passive sampling methods to measure environmental chemical exposure. METHODS: Eighteen patients with MCS, diagnosed according to the 1999 consensus criteria, and 12 healthy controls participated in this study. Fourteen patients and 12 controls underwent 1-week measurement of physical and psychologic symptoms and of the levels of exposure to various chemicals. Linear mixed models were used to test the hypotheses regarding the symptom profile of MCS patients. RESULTS: Some causative chemicals were detected in 11 of 14 MCS patients. Two other patients did not report any hypersensitivity episodes, whereas passive sampling showed far less exposure to chemicals than control subjects. Another subject reported episodic symptoms but was excluded from the following analyses because no possible chemical was detected. Eleven of the 17 physical symptoms and all four mood subscales examined were significantly aggravated in the interview based on "patient-initiated symptom prompts." On the other hand, there were no differences in physical symptoms or mood subscales between MCS patients and control subjects in the interview based on "random prompts." CONCLUSIONS: MCS patients do not have either somatic or psychologic symptoms under chemical-free conditions, and symptoms may be provoked only when exposed to chemicals.

Catalase, a specific antigen in the feces of human subjects infected with Helicobacter pylori.

Recently, we reported the production of three new monoclonal antibodies with high specificity for a Helicobacter pylori antigen suitable for diagnosis of H. pylori infection. The aim of the present study was to identify the antigen recognized by these monoclonal antibodies concerning both H. pylori and the feces of human subjects infected with H. pylori. The cellular antigen was purified from an H. pylori cell extract by immunoaffinity column chromatography with the monoclonal antibody as a ligand. The amino-terminal amino acid sequences (eight residues) of the purified antigen and H. pylori catalase were the same. The molecular weights of native and subunit, specific catalase activity, and UV and visible spectra of the purified antigen were in good agreement with those of H. pylori catalase. The human fecal antigens were purified from two fecal samples of two H. pylori-positive subjects by ammonium sulfate precipitation, CM-Sephadex C(50) chromatography, and the same immunoaffinity chromatography used for the H. pylori cellular antigen. The fecal antigens had catalase activity. The amino-terminal amino acid sequences (five residues) of the human fecal antigen and H. pylori catalase were the same. The monoclonal antibodies reacted with the native cellular antigen, but did not react with the denatured antigen, human catalase, and bovine catalase. The results show that the target antigen of the monoclonal antibodies is native H. pylori catalase and that the monoclonal antibodies are able to specifically detect the antigen, which exists in an intact form, retaining the catalase activity in human feces.