Toshimitsu Momose’s research while affiliated with The University of Tokyo and other places

Introduction Nociplastic pain (NP), a third category of chronic pain, offers a framework for elucidating its pathophysiology and treatment strategies. One of the characteristics of NP is comorbidity of symptoms other than pain, such as psychological and cognitive problems; therefore, these can be clues to understanding NP. Recently, we reported several cases with comorbid symptoms of attention-deficit/hyperactivity disorder (ADHD). Notably, ADHD medications, including methylphenidate (MP) and atomoxetine, improved chronic pain as well as the symptoms of ADHD. However, in clinical settings, identifying comorbid ADHD in patients with chronic pain is challenging, and underlying mechanisms have not been elucidated. To explore the common characteristics of brain function in patients with ADHD-comorbid NP, we identified brain regions where cerebral blood flow (CBF) distributions changed between pre- and post-treatment using single-photon emission computed tomography (SPECT). Additionally, we examined brain regions where CBF values correlated with clinical scores. Methods We retrospectively studied 65 patients (mean age 53 ± 14 years; 30 males and 35 females) with ADHD-comorbid NP who underwent CBF-SPECT before and after ADHD medication initiation. Clinical scores included the clinical global impression severity (CGI-S), pain numerical rating scale, hospital anxiety and depression scale, pain catastrophizing scale, and Conners’ adult ADHD rating scale-self report scores. Voxel-based statistical methods were used to compare pre- and post-treatment CBF-SPECT images to identify significant differences and investigate brain regions correlated with clinical scores. Results The CBF was higher in the precuneus, insular gyrus, and thalamus before treatment than after treatment (paired t-test, cluster-definition p < 0.001, cluster-extent threshold p < 0.05, with family-wise error [FWE] correction). The hyperperfusion in the precuneus was positively correlated with the CGI-S score and significantly reduced after treatment with MP (paired t-test, cluster-definition p < 0.005, cluster-extent threshold p < 0.05, with FWE correction). Conclusion The finding of precuneal hyperperfusion may provide insight into the mechanisms of NP and help identify patients who would benefit most from ADHD medications.

Introduction Nociplastic pain (NP), classified as a third type of pain alongside nociceptive and neuropathic pain, is chronic pain arising from the amplification of nociceptive stimuli through central sensitization, despite the absence of tissue damage, sensory nerve damage, or disease. An important clinical feature of NP is that it is not only associated with pain but also with sensory hypersensitivity to sound and light and cognitive dysfunction, including mood and attention disorders. Recent studies have suggested that depression and developmental disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), coexist with NP at high frequency. Additionally, cognitive impairment in individuals with NP may be associated with these psychiatric comorbidities. However, to our knowledge, there are no reports on (1) multidimensional evaluation and diagnostic details of abdominal NP in adults with ADHD/ASD; (2) how ADHD drugs and antidepressants are administered when ADHD and depression coexist with NP; and (3) how central sensitization, brain function, and family relationship problems underlying NP are altered by treatments of ADHD and depression. Case presentation Herein, we present the case of a 51-year-old woman with abdominal NP. She developed severe right lower abdominal pain and underwent a thorough medical examination; however, the physical, medical cause remained unknown, making treatment challenging. Additionally, she took time off work as she began to complain of insomnia and anxiety. She was referred to our pain center, where a diagnosis of depression, ADHD, and ASD was confirmed, and treatment with ADHD medication was initiated. While ADHD medications alone did not yield sufficient improvement, a combination of methylphenidate and the antidepressant venlafaxine eventually led to improvements in abdominal NP, depression, ADHD symptoms, central sensitization, and family relationship issues. During treatment, cerebral blood flow in the anterior cingulate, prefrontal, and parietal cortices also improved. Conclusion The treatment of comorbid depression is important while treating NP, and venlafaxine may be effective, especially in cases of comorbid ADHD/ASD. Screening for developmental disorders and depression is required in patients with abdominal NP.

Background Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans. Methods In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort ( n = 565) and the North American ADNI (NA-ADNI) cohort ( n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD. Results The PRS using 131 SNPs had an effect independent of APOE . The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels ( β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results. Conclusions We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by the bilateral development of multiple cysts in the kidneys. Pain management is a clinically important issue, especially because approximately 60% of patients with ADPKD experience chronic pain related to hemorrhage from renal cysts, which significantly reduces their daily life. The cystic fibrosis transmembrane conductance regulator, the molecule responsible for cyst formation in ADPKD, is also the cause of cystic fibrosis. Since attention deficit hyperactivity disorder (ADHD) is known to occur frequently in conjunction with cystic fibrosis, ADPKD may be associated with ADHD. However, to our knowledge, no study has investigated 1) ADHD or autism spectrum disorder (ASD) as comorbidities with ADPKD, 2) the effects of ADHD medications on chronic pain in ADPKD, or 3) cerebral blood flow corresponding to guanfacine (GF) or methylphenidate (MP) treatment for chronic pain. We report the case of a 15-year-old girl with ADPKD, who had chronic back pain associated with ADPKD and had to withdraw from high school because the pain interfered with her daily life. Although she took antihypertensive medications to prevent bleeding, they did not provide adequate blood pressure control. The patient was referred to a child psychiatrist and diagnosed with ASD; however, the pain did not improve. Subsequently, she was referred to our pain center. The diagnosis of ADHD was confirmed and treatment with ADHD medications was initiated. Monotherapy with MP, atomoxetine, and GF resulted in hypertension and hypotension as side effects; however, a combination of MP 18 mg and GF 4 mg provided pain relief and moderate blood pressure control, and the patient was able to go on to college. During the course of treatment, there was an improvement in the distribution of cerebral blood flow in the prefrontal and insular cortices. Confirmation of an ADHD diagnosis comorbid with ASD enabled the use of ADHD medications. The combination of MP and GF improved chronic back pain and high blood pressure due to ADPKD and cerebral blood flow. Screening for ADHD is important in the treatment of ADPKD.

Background It is known that patients reporting chronic pain often experience trauma or post-traumatic stress disorder (PTSD) and tend to be more difficult to treat. Attention deficit hyperactivity disorder (ADHD), a neurodevelopmental disorder, is frequently associated with chronic pain. Furthermore, patients diagnosed with ADHD are more likely to encounter trauma and develop PTSD because of their inattentive and impulsive tendencies. There are reports stating that atomoxetine (ATX), a selective noradrenaline reuptake inhibitor for ADHD, is effective in patients diagnosed with PTSD and ADHD. However, there have been no reports on cases of comorbid PTSD and ADHD with chronic pain, and ATX’s potential in improving chronic pain coexisting PTSD. Furthermore, no reports have evaluated patient cerebral blood flow in conjunction with the course of treatment with ATX for chronic pain. Case report In this study, we reported a case where ATX improved chronic pain with PTSD and improved cerebral blood flow. The patient was a 56-year-old woman exhibiting chronic pain with PTSD, resulting from 6 years of severe domestic violence from her common-law husband. She had no history of ADHD diagnosis, but through aggressive screening, comorbid ADHD was diagnosed. When treated with ATX, there were significant improvements in her pain, quality of life, anxiety, depression, catastrophic thoughts, and cerebral blood flow. As a result, she could resume work after 11 years. Conclusion The study showed that chronic pain with PTSD may be comorbid with ADHD. Moreover, we found that ATX can improve chronic pain with PTSD and cerebral blood flow. Aggressive screening of ADHD is important because once the diagnosis of comorbidity is confirmed, an ideal ADHD treatment can be selected. Therefore, based on the results of this study, ATX may be a candidate for treatment for cases of chronic pain with PTSD and ADHD.

Introduction: Oral dysesthesia is a disease characterized by pain and/or abnormal sensations in the oral region, without any organic abnormality. Its symptoms include pain, and it is considered to be a disorder associated with idiopathic oral-facial pain. It is also known that idiopathic oral-facial pain tends to coexist with chronic musculoskeletal pain, including low back pain, even before its onset. Such coexisting idiopathic pain conditions are also called chronic overlapping pain conditions (COPCs). In general, COPCs are often refractory to treatment. Recently, it has been reported that attention deficit hyperactivity disorder (ADHD) is associated with many COPCs, such as pain in the facial and lower back regions and so on. However, there are no reports of (1) ADHD as a comorbidity with oral dysesthesia (OD) or (2) of the therapeutic effects of ADHD medications or dopamine agonists on low back pain and OD or an (3) evaluation of cerebral blood flow over time after treatment with these medications for OD and low back pain. Case presentation: In this study, we report the case of an 80-year-old man with OD and chronic low back pain that persisted for more than 25 years. His OD and chronic back pain were refractory to standard treatment, prevented him from continuing work, and tended to be exacerbated by conflicts in his relationship with his son. In recent years, ADHD has often been found to be comorbid with chronic pain, and ADHD medications have been reported to improve chronic pain as well. The patient was confirmed to have undiagnosed ADHD and was treated with the ADHD medication atomoxetine and dopamine agonist pramipexole, which dramatically improved his OD, chronic back pain, and cognitive function. Furthermore, along the course of treatment, there was improvement in cerebral blood flow in his prefrontal cortex, which was thought to reflect improved function in the region. Consequently, he was able to resume work and improve his family relationships. Conclusion: Therefore, in the cases of ODs and COPCs, screening for ADHD and, if ADHD is diagnosed, ADHD medications or dopamine agonists may be considered.

Encephalitic episodes are a clinical manifestation of neuronal intranuclear inclusion disease (NIID) and often show transient disturbance of consciousness. We herein report a genetically confirmed patient with NIID who initially presented progressive dementia and showed prolonged disturbance of consciousness preceded by an acute-onset headache. During that time, we performed N-isopropyl-p-[123I]iodoamphetamine single-photon-emission computed tomography twice and found that the blood flow increased in different regions. Prolonged disturbance of consciousness following an encephalitic episode may be associated with repeated hyperperfusion in various regions resulting from mitochondrial dysfunction. NIID patients presenting with encephalitic episodes can recover gradually and spontaneously even after prolonged disturbances of consciousness.

Objective The clinical significance of decreased physiological lung uptake of ¹²³ I-metaiodobenzylguanidine (MIBG) has not been well investigated. This study aimed to elucidate the association between a decrease in lung MIBG uptake with antidepressant intake and the myocardial MIBG uptake in patients who were clinically diagnosed with Lewy body disease (LBD) and patients who were diagnosed as not having LBD. Methods We retrospectively reviewed the heart and lung uptakes on 167 consecutive MIBG scans, antidepressant status, and clinical diagnosis of LBD. The images were visually classified into two groups: decreased lung uptake and preserved lung uptake. A semi-quantitative analysis was performed using the heart-to-mediastinum ratio (H/M), lung-to-mediastinum ratio (L/M), and myocardial washout rate (WR). Results All 17 patients with decreased lung uptake were on treated with antidepressants, while none of the 150 patients with preserved lung uptake were treated with any antidepressants. Of the 17 patients with decreased lung uptake, 6 patients were clinically diagnosed as LBD and other 11 were clinically diagnosed as non-LBD. There was not significant difference in early H/M, delayed H/M, and myocardial WR between the 11 non-LBD patients with decreased lung uptake and 83 non-LBD patients with preserved lung uptake (2.87 ± 0.69 vs. 2.89 ± 0.44, 3.09 ± 0.48 vs. 2.98 ± 0.59, and 21.8 ± 11.3% vs. 21.1 ± 12.5%, respectively). Moreover, in LBD patients, there were no significant differences in those values between six patients with decreased lung uptake and 67 patients with preserved lung uptake (1.68 ± 0.32 vs. 1.73 ± 0.42, 1.34 ± 0.21 vs. 1.54 ± 0.57, 46.2 ± 22.8% vs. 42.8 ± 21.3%, respectively). Conclusions Antidepressants probably blocked MIBG uptake in the lungs, and a decreased lung uptake was not significantly associated with heart uptake. A remarkable decrease in lung uptake can be a signal to check a patient’s medication status.

Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer’s disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1. Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.