ABSTRACT
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.
Subject(s)
Disease Models, Animal , Lewy Body Disease , Parkinson Disease , Positron-Emission Tomography , alpha-Synuclein , Animals , alpha-Synuclein/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Parkinson Disease/diagnostic imaging , Humans , Mice , Positron-Emission Tomography/methods , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Lewy Body Disease/diagnostic imaging , Callithrix , Male , Brain/metabolism , Brain/diagnostic imaging , Brain/pathology , Female , Aged , Mice, Inbred C57BLABSTRACT
Aim: Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder characterized by Parkinsonism, supranuclear ophthalmoplegia, postural instability, and cognitive impairment. Patients: This case series describes three patients initially diagnosed with late-life mood disorders (depression and bipolar disorder) who were later diagnosed with PSP because of the development of typical neurological symptoms. Result: The diagnostic challenge of PSP is highlighted in this case report, particularly in the early stages, when characteristic symptoms may not be present. The importance of considering PSP in the differential diagnosis of late-life mood disorders, especially in the absence of response to standard antidepressant therapy, is also emphasized. The heterogeneity of PSP is described, with various subtypes and atypical variants presenting with different clinical features. The psychiatric symptoms of PSP include apathy, disinhibition, depression, and anxiety, whereas hallucinations and delusions are less frequent. Tau positron emission tomography imaging is discussed as a potential biomarker for atypical PSP. Conclusion: Early diagnosis and intervention are crucial for improved outcomes in PSP, necessitating further research to enhance the diagnostic and treatment strategies for PSP and other neurodegenerative diseases.
ABSTRACT
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.
Subject(s)
Astrocytes , Glial Fibrillary Acidic Protein , Gyrus Cinguli , Inositol , Lactic Acid , Supranuclear Palsy, Progressive , Humans , Supranuclear Palsy, Progressive/metabolism , Supranuclear Palsy, Progressive/diagnostic imaging , Supranuclear Palsy, Progressive/pathology , Astrocytes/metabolism , Astrocytes/pathology , Male , Female , Aged , Middle Aged , Glial Fibrillary Acidic Protein/metabolism , Glial Fibrillary Acidic Protein/blood , Lactic Acid/blood , Lactic Acid/metabolism , Inositol/metabolism , Gyrus Cinguli/metabolism , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/pathology , Biomarkers/blood , tau Proteins/metabolism , Positron-Emission TomographyABSTRACT
Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer's disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aß) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aß-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aß-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Brain/pathology , Amyloid beta-Peptides , Magnetic Resonance Imaging/methods , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Machine Learning , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , ApolipoproteinsABSTRACT
Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV-adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK-SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann-Whitney U test, p < 0.05) underwent partial correlation analysis, adjusting for age and sex, to assess its connection with neuropsychological test results. Compared with the control group, the rmTBI group showed significantly lower the MBs volume/TBV ratio (0.13 ± 0.05 vs. 0.19 ± 0.03 × 10-3, p < 0.001). The MBs volume/TBV ratio correlated with visual memory, as assessed, respectively, by the Rey-Osterrieth Complex Figure test delayed recall (ρ = 0.62, p < 0.001). In conclusion, retired athletes with rmTBI have MB atrophy, potentially contributing to memory impairment linked to the Papez circuit disconnection.
Subject(s)
Brain Concussion , Brain Injuries, Traumatic , Humans , Mammillary Bodies , Brain , Memory Disorders/etiology , Athletes/psychology , Brain Injuries, Traumatic/complicationsABSTRACT
Frontotemporal dementia refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of frontotemporal dementia at an individual level have hitherto not been successful. In this study, we aim to classify patients with frontotemporal dementia based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607 and 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer's disease as well as in non-Alzheimer's disease tauopathies. Twenty-six patients with frontotemporal dementia, 15 with behavioural variant frontotemporal dementia and 11 with other frontotemporal dementia phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the patients with behavioural variant frontotemporal dementia were classified into the following subgroups: (i) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3), (ii) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = 4); (iii) amyloid and tau accumulations consistent with Alzheimer's disease (n = 4); and (iv) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioural variant frontotemporal dementia subgroups. The patients with other frontotemporal dementia phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with frontotemporal dementia on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.
ABSTRACT
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.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/pathology , tau Proteins/metabolism , Creatine/metabolism , Case-Control Studies , Magnetic Resonance Imaging , Amyloid beta-Peptides/metabolism , Positron-Emission Tomography , Brain/pathology , Glutamic Acid/metabolism , Magnetic Resonance Spectroscopy , Biomarkers/metabolism , Receptors, Antigen, T-Cell/metabolismABSTRACT
BACKGROUND: Plasma biomarkers have emerged as promising screening tools for Alzheimer's disease (AD) because of their potential to detect amyloid ß (Aß) accumulation in the brain. One such candidate is the plasma Aß42/40 ratio (Aß42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aß42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection. METHODS: We recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson's disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aß42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aß pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Using the best cut-off derived from the Youden Index, plasma Aß42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aß42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aß42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman's rank correlation coefficient between plasma Aß42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aß42/40 categorized 61.5% (8/13) as Aß-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive. CONCLUSION: Plasma Aß42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aß accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Humans , Amyloidogenic Proteins , Immunoassay , Positron-Emission Tomography , Alzheimer Disease/diagnostic imagingABSTRACT
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.
ABSTRACT
PURPOSE: The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution. METHODS: We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman's rank correlation. RESULTS: We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140). CONCLUSION: We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.
Subject(s)
Brain , Dopamine , Humans , Dopamine/metabolism , Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography/methods , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/genetics , Receptors, Dopamine D3/metabolism , Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Gene ExpressionABSTRACT
Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = - 0.55, p = 0.022; r = - 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.
Subject(s)
Autistic Disorder , Glutamine , Male , Adult , Humans , Glutamine/metabolism , Glutamic Acid/metabolism , Autistic Disorder/metabolism , Astrocytes/metabolism , Dopamine/metabolism , Brain/diagnostic imaging , Brain/metabolism , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/metabolismABSTRACT
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury (rmTBI). Clinically, CTE experienced by athletes with rmTBI can lead to long-term neurological impairment, including memory disturbances, Parkinsonism, behavioral changes, speech irregularities, and gait abnormalities, formerly described as punch-drunk syndrome and dementia pugilistica. CTE has gained significant public interest owing to dramatic cases involving retired professional athletes wherein severe behavioral problems and tragic incidents were reported. However, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can only be made via postmortem neuropathological examination. CTE is characterized by abnormal accumulation of hyperphosphorylated tau proteins. Neuropathological studies have revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes and accumulation of other misfolded proteins such as TDP-43. Furthermore, gross pathological findings were revealed, especially in severe CTE. Thus, we hypothesized that objective neuroimaging patterns linking the history of rmTBI or CTE might be established using tau positron emission tomography (PET) and magnetic resonance imaging (MRI). In this review, we present the clinical and neuropathological features of CTE and our efforts to develop a prenatal diagnostic method using MRI and tau PET. The unique findings of tau PET images and various signal and morphological abnormalities on conventional MRI in retired athletes with rmTBI may be useful in diagnosing CTE.
Subject(s)
Brain , Chronic Traumatic Encephalopathy , Humans , Athletes , Brain/diagnostic imaging , Brain/metabolism , Brain/pathology , Chronic Traumatic Encephalopathy/diagnostic imaging , Chronic Traumatic Encephalopathy/metabolism , Chronic Traumatic Encephalopathy/pathology , Magnetic Resonance Imaging , Positron-Emission Tomography , tau Proteins/metabolismABSTRACT
BACKGROUND: Central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts, but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression. METHODS: Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BPND). RESULTS: Patients treated with antidepressants showed significantly lower 18F-MPPF BPND in neocortical regions and raphe nuclei, but not in limbic regions, than controls. No significant group differences in 11C-WAY-100635 BPND were found in any of the regions. Significant correlations of BPND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BPND in limbic regions was significantly correlated with the severity of depressive symptoms. CONCLUSIONS: These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment.
Subject(s)
Brain , Serotonin , Humans , Carbon Radioisotopes , Brain/diagnostic imaging , Brain/metabolism , Serotonin/metabolism , Radiopharmaceuticals/metabolism , Positron-Emission Tomography/methods , Antidepressive Agents/therapeutic use , Antidepressive Agents/metabolism , Synaptic Transmission , Receptor, Serotonin, 5-HT1A/metabolismABSTRACT
OBJECTIVE: Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. Florzolotau (18F) (florzolotau, APN-1607, PM-PBB3) has been shown to be a probe for tau fibrils in an animal model and patients with Alzheimer's disease and those with non-Alzheimer's disease tauopathies. The objective of this study is to evaluate the safety, pharmacokinetics, and radiation dose following a single intravenous administration of florzolotau in healthy Japanese subjects. METHODS: Three healthy male Japanese subjects aged between 20 and 64 were enrolled in this study. Subjects were determined to be eligible based on the screening assessments at the study site. Subjects received a single intravenous dose of 195.0 ± 0.5 MBq of florzolotau and underwent the whole-body PET scan 10 times in total to calculate absorbed doses to major organs/tissues and effective dose. Radioactivities in whole blood and urine were also measured for pharmacokinetic evaluation. Absorbed doses to major organs/tissues and effective dose were estimated using the medical internal radiation dose (MIRD) method. Vital signs, electrocardiography (ECG), and blood tests were done for safety evaluation. RESULTS: The intravenous injection of florzolotau was well tolerated. There were no adverse events or clinically detectable pharmacologic effects related to the tracer in any subjects. No significant changes in vital signs and ECG were observed. The highest mean initial uptake at 15 min after injection was in the liver (29.0 ± 4.0%ID), intestine (4.69 ± 1.65%ID), and brain (2.13 ± 0.18%ID). The highest absorbed dose was 508 µGy/MBq of the gallbladder wall, followed by the liver of 79.4 µGy/MBq, the pancreas of 42.5 µGy/MBq, and the upper large intestine of 34.2 µGy/MBq. The effective dose was calculated as 19.7 µSv/MBq according to the tissue weighting factor reported by ICRP-103. CONCLUSION: Florzolotau intravenous injection was well tolerated in healthy male Japanese subjects. The effective dose was determined as 3.61 mSv when 185 MBq florzolotau was given.
Subject(s)
East Asian People , Positron-Emission Tomography , Humans , Male , Positron-Emission Tomography/methods , Radiometry , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Young Adult , Adult , Middle AgedABSTRACT
BACKGROUND AND HYPOTHESIS: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. STUDY DESIGN: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. STUDY RESULTS: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. CONCLUSIONS: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.
Subject(s)
Schizophrenia , Humans , Schizophrenia/diagnostic imaging , Phosphoric Diester Hydrolases/metabolism , Positron-Emission Tomography/methods , Basal Ganglia , GlutamatesABSTRACT
Patients with progressive supranuclear palsy (PSP) frequently exhibit apathy but the neuropathological processes leading to this phenotype remain elusive. We aimed to examine the involvement of tau protein depositions, oxidative stress (OS), and neuronal loss in the apathetic manifestation of PSP. Twenty patients with PSP and twenty-three healthy controls were enrolled. Tau depositions and brain volumes were evaluated via positron-emission tomography (PET) using a specific probe, 18F-PM-PBB3, and magnetic resonance imaging, respectively. Glutathione (GSH) levels in the anterior and posterior cingulate cortices were quantified by magnetic resonance spectroscopy. Tau pathologies were observed in the subcortical and cortical structures of the patient brains. The angular gyrus exhibited a positive correlation between tau accumulations and apathy scale (AS). Although PSP cases did not show GSH level alterations compared with healthy controls, GSH levels in posterior cingulate cortex were correlated with AS and tau depositions in the angular gyrus. Marked atrophy was observed in subcortical areas, and gray matter volumes in the inferior frontal gyrus and anterior cingulate cortex were positively correlated with AS but showed no correlation with tau depositions and GSH levels. Path analysis highlighted synergistic contributions of tau pathologies and GSH reductions in the posterior cortex to AS, in parallel with associations of gray matter atrophy in the anterior cortex with AS. Apathetic phenotypes may arise from PET-visible tau aggregation and OS compromising the neural circuit resilience in the posterior cortex, along with neuronal loss, with neither PET-detectable tau pathologies nor OS in the anterior cortex.
Subject(s)
Apathy , Supranuclear Palsy, Progressive , Humans , tau Proteins/metabolism , Supranuclear Palsy, Progressive/diagnostic imaging , Supranuclear Palsy, Progressive/complications , Brain/pathology , Positron-Emission Tomography/methods , Oxidative StressABSTRACT
BACKGROUND AND OBJECTIVES: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort. METHODS: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. RESULTS: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. DISCUSSION: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.
Subject(s)
Cognitive Dysfunction , Dementia , Humans , tau Proteins , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/complications , Amyloid , Amyloidogenic Proteins , Positron-Emission Tomography/methods , Dementia/diagnostic imaging , Dementia/therapy , Amyloid beta-Peptides , BiomarkersABSTRACT
BACKGROUND: Neurodegenerative pathologies, including tau depositions, have been implicated in late-onset depression (LOD), while there is a lack of in-vivo evidence for the neuropathological basis of late-onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F-florzolotau, a radioligand for Alzheimer's disease (AD) and non-AD tau fibrils. METHODS: We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty-one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age-matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F-florzolotau and 11C-PiB, respectively. Amyloid positivity was determined by a visual read of 11C-PiB-PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z-score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z-score ≥ 2.0. RESULTS: 18F-florzolotau-PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C-PiB-PET-positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C-PiB-PET-positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C-PiB-negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations. CONCLUSION: Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non-AD tauopathies indicative of distinct early-stage frontotemporal lobar degeneration subcategories.
Subject(s)
Positron-Emission Tomography , tau Proteins , Humans , Female , Male , Aged , tau Proteins/metabolism , Middle Aged , Bipolar Disorder/diagnostic imaging , Bipolar Disorder/pathology , Bipolar Disorder/metabolism , Brain/diagnostic imaging , Brain/pathology , Brain/metabolism , Carbolines , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Age of OnsetABSTRACT
We report a patient with logopenic variant primary progressive aphasia (lv-PPA) who was diagnosed as having non-Alzheimer's disease (AD) tauopathy after multiple biophysical/biological examinations, including amyloid and 18F-florzolotau tau positron emission tomography (PET), had been performed. A woman in her late 60s who had previously been diagnosed as having AD was referred to us for a further, detailed examination. She had been unaware of any symptoms at the time of AD diagnosis, but she subsequently became gradually aware of a speech impairment. She talked nearly completely and fluently, although she occasionally exhibited word-finding difficulty and made phonological errors during naming, word fluency testing, and sentence repetition; these findings met the criteria for the diagnosis of lv-PPA, which is known to be observed more commonly in AD than in other proteinopathies. Magnetic resonance imaging, single photon emission computed tomography, and plasma phosphorylated tau and plasma neurofilament light chain measurements showed an AD-like pattern. However, both 11C-Pittsburgh compound-B and 18F-florbetaben amyloid PET showed negative results, whereas 18F-florzolotau tau PET yielded positive results, with radio signals predominantly in the left superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and frontal operculum. Whole-genome sequencing revealed no known dominantly inherited mutations in AD or frontotemporal lobar degeneration genes, including the genes encoding amyloid precursor protein, microtubule-associated protein tau, presenilin 1 and 2. To the best of our knowledge, this patient was a rare case of lv-PPA who was diagnosed as having non-AD tauopathy based on the results of multiple examinations, including whole-genome sequencing, plasma measurement, and amyloid and 18F-florzolotau tau PET. This case underscores the clinicopathologically heterogeneous nature of this syndrome.