Effect of cerebrospinal fluid area mask correction on 123I-FP-CIT SPECT images in idiopathic normal pressure hydrocephalus.

BACKGROUND: Cerebrospinal fluid (CSF) area mask correction reduces the influence of low [123I]-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) accumulation in the volume of interest (VOI) by CSF area dilatation on the specific binding ratio (SBR) calculated using the Southampton method. We assessed the effect of CSF area mask correction on the SBR for idiopathic normal pressure hydrocephalus (iNPH) characterized by CSF area dilatation. METHODS: We enrolled 25 patients with iNPH who were assessed using 123I-FP-CIT single-photon emission computed tomography (SPECT) before shunt surgery or the tap test. The SBRs with and without CSF area mask correction were calculated, and changes in quantitative values were verified. Additionally, the number of voxels in the striatal and background (BG) VOI before and after CSF area mask correction were extracted. The number of voxels after correction was subtracted from that before correction, and the volume removed by the CSF area mask correction was calculated. The volumes removed from each VOI were compared to verify their effect on SBR. RESULTS: The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF area mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively than those in the striatal region. CONCLUSIONS: The SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results suggest that CSF area mask correction is effective in patients with iNPH. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826. 11/07/2021.

Clinicopathological diversity of semantic dementia: Comparisons of patients with early-onset versus late-onset, left-sided versus right-sided temporal atrophy, and TDP-type A versus type C pathology.

Semantic dementia (SD) is a unique clinicopathological entity associated with TDP-type C pathology. We present four cases of SD that illustrate the clinicopathological diversity of TDP-43 pathology, including early-onset cases of TDP-type C with corticospinal tract (CST) and motor neuron pathology and late-onset cases of TDP-type A with combined pathology. Case 1 was a 62-year-old man with semantic variant of primary progressive aphasia (svPPA) with left-predominant temporal atrophy and TDP-type C pathology with low Alzheimer's disease neuropathologic changes (ADNC). Case 2 was a 63-year-old woman with right-predominant temporal atrophy and TDP-type C pathology who had prosopagnosia and personality changes. Phosphorylated(p)-TDP-43-positive long dystrophic neurites (DNs) were observed throughout the cerebral cortex; they were more abundant in the relatively spared cortices and less so in the severely degenerated cortices. We observed CST degeneration with TDP-43 pathology in the upper and lower motor neurons, without apparent motor symptoms, in SD with TDP-type C pathology. Case 3 was a 76-year-old man who had svPPA and personality changes, with left-predominant temporal atrophy and TDP-type A pathology with high ADNC and argyrophilic grain (AG) stage 3. Case 4 was an 82-year-old man who had prosopagnosia and later developed symptoms of dementia with Lewy bodies (DLB) with right-predominant temporal atrophy and TDP-type A pathology with high ADNC, DLB of diffuse neocortical type, and AG stage 3. The distribution of p-TDP-43-positive NCIs and short DNs was localized in the anterior and inferior temporal cortices. An inverse relationship between the extent of TDP pathology and neuronal loss was also observed in SD with TDP-type A pathology. In contrast, the extent of AD, DLB, and AG pathology was greater in severely degenerated regions. CST degeneration was either absent or very mild in SD with TDP-type A. Understanding the clinicopathological diversity of SD will help improve its diagnosis and treatment.

Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report.

BACKGROUND: Variants in the valosin-containing protein (VCP) gene were identified as one of the causes for inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (FTD). Previously identified pathogenic variants in VCP are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathologically, but p.Asp395Gly VCP was recently reported to cause familial FTD with tauopathy characterized by neurofibrillary tau tangles (NFT) and not FTLD-TDP. We describe the clinical and genetic findings of a patient with p.Asp395Gly valosin-containing protein (VCP), who was diagnosed with FTD without a family history and in the absence of muscle or bone disease comorbidity. CASE PRESENTATION: The patient was a 62-year-old man, who developed atypical depression at the age of 37 years. Subsequently, he presented with self-centered behavior at the age of 45 years. The self-centered behavior intensified from around the age of 50 years, which was accompanied by the development of executive dysfunction; therefore, he visited our hospital at 52 years of age. Magnetic resonance imaging revealed bilateral frontal lobe atrophy. Brain perfusion single-photon emission computed tomography revealed bilateral frontal lobe hypoperfusion. The patient fulfilled the diagnostic criteria for behavioral variant of FTD. Ten years after the diagnosis, computed tomography of the trunk and limbs, muscle biopsy, and bone scintigraphy revealed the absence of concomitant muscle and bone disease. The concentrations of cerebrospinal fluid (CSF) total tau and phosphorylated tau proteins were 389 pg/mL and 53.2 pg/mL (cut-off: 50 pg/mL), respectively. Genetic analyses were performed using the whole-exome and Sanger sequencing methods. We identified p.Asp395Gly VCP in this patient with pure FTD. CONCLUSIONS: p.Asp395Gly VCP was identified in a patient with likely sporadic FTD without concomitant muscle and bone disease. The CSF analysis suggested that our patient may have FTD due to NFT accumulation similar to the familial FTD patients with p.Asp395Gly VCP recently reported. Our findings suggest that a genetic search for the pathogenic variants of VCP should be considered not only for familial FTD, but also for patients with sporadic FTD, even in the absence of comorbid muscle or bone disease.

Uncoupling root hair formation and defence activation from growth inhibition in response to damage-associated Pep peptides in Arabidopsis thaliana.

In Arabidopsis thaliana, PROPEPs and their derived elicitor-active Pep epitopes provide damage-associated molecular patterns (DAMPs), which trigger defence responses through cell-surface receptors PEPR1 and PEPR2. In addition, Pep peptides induce root growth inhibition and root hair formation, however their relationships and coordinating mechanisms are poorly understood. Here, we reveal that Pep1-mediated root hair formation requires PEPR-associated kinases BAK1/BKK1 and BIK1/PBL1, ethylene, auxin and root hair differentiation regulators, in addition to PEPR2. Our analysis on 69 accessions unravels intraspecies variations in Pep1-induced root hair formation and growth inhibition. The absence of a positive correlation between the two traits suggests their separate regulation and diversification in natural populations of A. thaliana. Restricted PEPR2 expression to certain root tissues is sufficient to induce root hair formation and growth inhibition in response to Pep1, indicating the capacity of non-cell-autonomous receptor signalling in different root tissues. Of particular note, root hair cell-specific PEPR2 expression uncouples defence activation from root growth inhibition and root hair formation, suggesting a unique property of root hairs in root defence activation following Pep1 recognition.

Clinicopathological heterogeneity of Alzheimer's disease with pure Alzheimer's disease pathology: Cases associated with dementia with Lewy bodies, very early-onset dementia, and primary progressive aphasia.

We report four cases depicting the heterogeneity of Alzheimer's disease (AD) associated with pure AD pathology. Case 1 was a 77-year-old man with a false positive diagnosis of dementia with Lewy bodies with reduced dopamine transporter uptake activity of the striatum but no Lewy body pathology. There were tau deposits in the large neurons in the putamen, which may be related to the development of parkinsonism. Case 2 was an AD patient in his early 30s who presented with a psychotic episode and a cognitive decline, and later developed myoclonus and seizures. He demonstrated considerable amyloid-beta deposits in the cerebral cortex, including cotton wool plaques, basal ganglia, and cerebellum. Tau deposits were also abundant in the cerebral neocortex, hippocampus, basal ganglia, and brain stem. Case 3 was a 60-year-old woman who exhibited typical symptoms characteristic of the logopenic variant of primary progressive aphasia (lvPPA). Case 4 was a 68-year-old man who exhibited the semantic variant of primary progressive aphasia (svPPA) plus repetition impairment, a rare case associated with AD pathology. In addition to tau pathology, astrocytic pathology was prominent in the white matter and cortical layers of the left temporoparietal cortices. While the main AD lesion in case 4 was evaluated by tau accumulation and astrogliosis in the left temporal lobe, that in case 3 in was evaluated by the same points in the left parietal lobe. Within the spectrum of lvPPA, case 4 may be regarded as a temporal variant of lvPPA presenting svPPA. The pathology of PPA associated with AD may have broader clinical manifestations than that in previously described cases. Case 4 also showed pathological features characteristic of cerebral amyloid angiopathy throughout the cerebral cortex. The distribution of tau and astrocytic pathologies in the cerebral cortex, basal ganglia, brain stem, and cerebellum may explain the various symptoms of atypical pure AD patients.

Comparison of the decreases in regional cerebral blood flow in the posterior cingulate cortex, precuneus, and parietal lobe between suspected non-Alzheimer's disease pathophysiology and Alzheimer's disease.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) shows Alzheimer's disease (AD)-like neurodegeneration; however, amyloid ß, which is a biological marker in AD, remains within normal levels. Since the effectiveness of anti-dementia drugs for AD on SNAP is unknown, it is important to distinguish between patients with SNAP and AD. We aimed to compare decreases in regional cerebral blood flow (rCBF) of the posterior cingulate cortex (PCC), precuneus, and parietal lobe critical to AD between SNAP and AD groups using the easy Z-score imaging system in single-photon emission computed tomography (eZIS-SPECT). METHODS: We retrospectively analysed eZIS-SPECT data of 13 SNAP and 24 AD patients. The three indicators (severity, extent, and ratio) that distinguished AD patients from healthy controls in previous studies were automatically calculated and were compared between the SNAP and AD groups. Receiver operating characteristic curve analysis and the area under the curve (AUC) were used to evaluate the diagnostic performance of the three indicators of eZIS in discriminating between the two groups. RESULTS: The mean values of severity, extent, and ratio were significantly lower in the SNAP group than in the AD group (P = 0.024, P = 0.044, and P = 0.045, respectively). The AUC values for severity, extent, and ratio were 0.668, 0.683, and 0.692, respectively. CONCLUSIONS: The present study suggests that SNAP shows milder reduction of rCBF in the PCC, precuneus, and parietal lobe as compared to AD. However, it may be difficult to distinguish between SNAP and AD with the degrees of decrease in rCBF in these regions.

Implication of core beliefs about negative-self in neuroticism.

Objective: Core beliefs about negative-self are beliefs about self-deficiencies in basic aspects of human adaptation. Meanwhile, neuroticism is a personality trait characterised by negative emotionality, i.e., a tendency to react to stress with negative emotions. The present study tested the hypothesis that core beliefs about negative-self are implicated in neuroticism.Methods: The subjects were 309 Japanese healthy volunteers. Core beliefs about negative-self were evaluated by the Brief Core Schema Scales, and neuroticism was evaluated by the NEO Personality Inventory-Revised.Results: In both multiple regression analysis and structural equation modelling, higher neuroticism was strongly predicted by higher levels of core beliefs about negative-self.Limitations: The present study cannot determine the causal relationship between core beliefs about negative-self and neuroticism, because of its cross sectional design.Conclusions: The present study suggests that core beliefs about negative-self are deeply implicated in neuroticism.Key PointsImplication of core beliefs about negative-self in neuroticism was examined.Neuroticism was predicted by higher levels of these core beliefs.These core beliefs may be involved in negative emotionality of neuroticism.

Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases.

Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

Suicide as a result of stereotypic behaviour in a case with semantic dementia.

Semantic dementia (SD) is characterized by semantic aphasia and prosopagnosia, but it may also include behavioural disturbances such as stereotypic behaviour. We report the case of a 50-year-old man with SD accompanied by stereotypic behaviour who committed suicide despite not being in a depressive state. He initially had major depressive disorder accompanied by suicide attempts, but he gradually showed remarkable impairment in single-word semantic comprehension, naming memory, and facial recognition memory. After the diagnosis of SD, his suicidal behaviour by hanging with a cord became stereotypic and lacked seriousness. He repeatedly attempted to hang himself and finally completed suicide. The present report suggests that the risk for suicide in SD is increased not only by the presence of a depressive state, but also by stereotypic behaviour related to suicide attempts before the onset of the disorder.

[18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review.

BACKGROUND: Semantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal lobe. [18F]THK-5351 was originally developed to trace tau protein. However, it has recently been suggested that [18F]THK-5351 binds to monoamine oxidase B in astrocytes, which reflects gliosis. Herein, the authors present two cases involving patients with early-stage svPPA who underwent [18F]THK-5351 positron emission tomography (PET) imaging, and examined whether [18F]THK-5351 PET imaging is more sensitive to neurodegenerative lesions than conventional imaging modalities such as magnetic resonance imaging (MRI) and cerebral blood flow (CBF)-single photon emission computed tomography (SPECT). CASE PRESENTATION: Two patients, 64- and 79-year-old men, without notable medical or family history, exhibited disturbances in word comprehension and mild anomia with fluent speech and spared repetition. In both cases, surface dyslexia was observed but prosopagnosia was absent. Although mild depression was detected in 1 of the 2 patients, no behavioral disorders were present in either case. In both cases, MRI revealed atrophy in the anterior and inferior portions of the left temporal lobe. Technetium-99-ethyl cysteinate dimer ([99mTc]ECD) SPECT revealed hypoperfusion in the left temporal lobe. Alzheimer's disease was ruled out by [11C]Pittsburgh Compound-B (PiB) PET scan. Both patients fulfilled the diagnostic criteria for svPPA. Because of mild language deficits and lack of right temporal atrophy, they were considered to be at an early stage of the disease. In both cases, [18F]THK-5351 retention was observed in bilateral temporal lobes, predominantly on the left side. Comparison of different imaging modalities suggested that [18F]THK-5351 was more sensitive in detecting neurodegenerative change in the right temporal lobe than MRI and [99mTc]ECD SPECT. CONCLUSIONS: [18F]THK-5351 retention was clearly demonstrated at an early stage of svPPA. Results of the present study suggest that [18F]THK-5351 PET imaging may facilitate very early diagnosis of the disease.

Relationship between interpersonal sensitivity and leukocyte telomere length.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere length represents a biological marker for cellular aging. Interpersonal sensitivity, excessive sensitivity to the behavior and feelings of others, is one of the vulnerable factors to depression. In the present study, we examined the effect of interpersonal sensitivity on telomere length in healthy subjects. METHODS: The subjects were 159 unrelated healthy Japanese volunteers. Mean age ± SD (range) of the subjects was 42.3 ± 7.8 (30-61) years. Interpersonal sensitivity was assessed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Leukocyte telomere length was determined by a quantitative real-time PCR method. RESULTS: Higher scores of the total IPSM were significantly (ß = -0.163, p = 0.038) related to shorter telomere length. In the sub-scale analysis, higher scores of timidity were significantly (ß = -0.220, p = 0.044) associated with shorter telomere length. CONCLUSIONS: The present study suggests that subjects with higher interpersonal sensitivity have shorter leukocyte telomere length, implying that interpersonal sensitivity has an impact on cellular aging.

Link of dysfunctional attitudes with the negative self-model.

BACKGROUND: Beck's cognitive theory postulates that dysfunctional attitudes predisposing to depression are formed by early negative experiences. Meanwhile, Bowlby's attachment theory contends that distorted working models built through insecure attachment relationships lead to various psychopathologies such as depression. The present study examined the correlations of dysfunctional attitudes about achievement, dependency, and self-control with working models of the self and other, and tried to promote understanding of those dysfunctional attitudes from an attachment perspective. METHODS: The subjects were 591 Japanese healthy volunteers. Dysfunctional attitudes about achievement, dependency, and self-control were evaluated by the corresponding subscales of the 24-item Dysfunctional Attitude Scale, and working models of the self and other were assessed by the relationship scales questionnaire. RESULTS: The scores of the achievement (ß = -0.26, P < 0.001), dependency (ß = -0.41, P < 0.001), and self-control (ß = -0.14, P < 0.01) subscales had negative correlations with the self-model score, suggesting the connections of all clusters of dysfunctional attitudes with the negative self-model. The score of the dependency subscale (ß = 0.21, P < 0.001) had a positive correlation with the other-model score, suggesting the connection of this cluster of dysfunctional attitudes with the positive other-model. Meanwhile, the scores of the achievement (ß = -0.17, P < 0.001) and self-control (ß = -0.13, P < 0.01) subscales had negative correlations with the other-model score, suggesting the connections of these clusters of dysfunctional attitudes with the negative other-model. CONCLUSION: The present study suggests that dysfunctional attitudes as a whole are linked with the negative self-model built through negative attachment experiences, while the content specificity of each cluster is related to the differential correlations with the other-model.

Expression and localization of the diacylglycerol kinase family and of phosphoinositide signaling molecules in adrenal gland.

Adrenal glands play a central role in the secretion of steroid hormones and catecholamines. Previous studies have revealed that molecules engaged in phosphoinositide (PI) turnover are expressed in the adrenal gland, suggesting the importance of PI signaling in adrenal signal transduction. Diacylglycerol kinase (DGK) catalyzes the phosphorylation of diacylglycerol (DG), a major second messenger in the PI signaling cascade. The DGK family is expressed in distinct patterns in endocrine organs at the mRNA and protein levels. Nevertheless, little is known about the characteristics and morphological aspects of DGKs in the adrenal gland. We have performed immunohistochemical analyses to investigate the expression and localization of DGK isozymes, together with PI signaling molecules, in the adrenal gland at the protein level. Our results show that the DGK family and a set of PI signaling molecules are expressed intensely in zona glomerulosa cells and medullary chromaffin cells in the adrenal gland. In adrenal cells, DGKγ localizes to the Golgi complex, DGKε to the plasma membrane, and DGKζ to the nucleus. These findings show the distinct expression and subcellular localization of DGK isozymes and PI signaling molecules in the adrenal gland, suggesting that each DGK isozyme has a role in signal transduction in adrenal cells, especially in the zona glomerulosa and medulla.

Associations of working models of the self and other with Cloninger's personality dimensions.

The present study examined the associations of working models of the self and other, one of the key concepts of Bowlby's attachment theory, with the seven dimensions of Cloninger's personality model. The subjects were 542 healthy Japanese volunteers. Working models of the self and other were assessed by the Relationship Scales Questionnaire, and the seven dimensions of personality were evaluated by the Temperament and Character Inventory. In the correlation analysis, the self-model was correlated most strongly with self-directedness (SD) (r=0.50, P<0.001) and second strongly with harm avoidance (HA) (r=-0.43, P<0.001), while the other-model was correlated most strongly with cooperativeness (C) (r=0.43, P<0.001) and second strongly with reward dependence (RD) (r=0.41, P<0.001). In the principal component analysis, the self-model formed a group with SD and HA, while the other-model formed a group with C and RD. The present study suggests that the self-model is reflected in SD and HA, while the other-model is reflected in C and RD.