The SPEAK study rationale and design: A linguistic corpus-based approach to understanding thought disorder.

AIM: Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of "linguistic corpus-based analyses of language output". Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. METHODS: This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome. CONCLUSIONS: This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.

Elevated fatty acid amide hydrolase in the prefrontal cortex of borderline personality disorder: a [11C]CURB positron emission tomography study.

Amygdala-prefrontal cortex (PFC) functional impairments have been linked to emotion dysregulation and aggression in borderline personality disorder (BPD). Fatty acid amide hydrolase (FAAH), the major catabolic enzyme for the endocannabinoid anandamide, has been proposed as a key regulator of the amygdala-PFC circuit that subserves emotion regulation. We tested the hypothesis that FAAH levels measured with [11C]CURB positron emission tomography in amygdala and PFC would be elevated in BPD and would relate to hostility and aggression. Twenty BPD patients and 20 healthy controls underwent FAAH genotyping (rs324420) and scanning with [11C]CURB. BPD patients were medication-free and were not experiencing a current major depressive episode. Regional differences in [11C]CURB binding were assessed using multivariate analysis of covariance with PFC and amygdala [11C]CURB binding as dependent variables, diagnosis as a fixed factor, and sex and genotype as covariates. [11C]CURB binding was marginally elevated across the PFC and amygdala in BPD (p = 0.08). In a priori selected PFC, but not amygdala, [11C]CURB binding was significantly higher in BPD (11.0%, p = 0.035 versus 10.6%, p = 0.29). PFC and amygdala [11C]CURB binding was positively correlated with measures of hostility in BPD (r > 0.4; p < 0.04). This study is the first to provide preliminary evidence of elevated PFC FAAH binding in any psychiatric condition. Findings are consistent with the model that lower endocannabinoid tone could perturb PFC circuitry that regulates emotion and aggression. Replication of these findings could encourage testing of FAAH inhibitors as innovative treatments for BPD.

Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review.

Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.

In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA.

Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer's disease (AD) by using positron emission tomography (PET) with translocator protein 18 kDa (TSPO)-specific radioligand [(18)F]-FEPPA. [(18)F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47- 81 years) and 21 control subjects (49-82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [(18)F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [(18)F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen's d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [(18)F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= -0.7, P= 0.005), and posterior limb of the internal capsule (r= -0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [(18)F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= -0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [(18)F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits.

Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA.

One of the cellular markers of neuroinflammation is increased microglia activation, characterized by overexpression of mitochondrial 18kDa Translocator Protein (TSPO). TSPO expression can be quantified in-vivo using the positron emission tomography (PET) radioligand [(18)F]-FEPPA. This study examined microglial activation as measured with [(18)F]-FEPPA PET across the adult lifespan in a group of healthy volunteers. We performed genotyping for the rs6971 TS.PO gene polymorphism to control for the known variability in binding affinity. Thirty-three healthy volunteers (age range: 19-82years; 22 high affinity binders (HAB), 11 mixed affinity binders (MAB)) underwent [(18)F]-FEPPA PET scans, acquired on the High Resolution Research Tomograph (HRRT) and analyzed using a 2-tissue compartment model. Regression analyses were performed to examine the effect of age adjusting for genetic status on [(18)F]-FEPPA total distribution volumes (VT) in the hippocampus, temporal, and prefrontal cortex. We found no significant effect of age on [(18)F]-FEPPA VT (F (1,30)=0.918; p=0.346), and a significant effect of genetic polymorphism (F (1,30)=8.767; p=0.006). This is the first in-vivo study to evaluate age-related changes in TSPO binding, using the new generation TSPO radioligands. Increased neuroinflammation, as measured with [(18)F]-FEPPA PET was not associated with normal aging, suggesting that healthy elderly individuals may serve as useful benchmark against patients with neurodegenerative disorders where neuroinflammation may be present.

Insight and danger in Alzheimer's disease.

To determine the frequency, and demographic and clinical correlates of dangerous behaviours in Alzheimer's disease (AD). We assessed a consecutive series of 278 patients with AD and 45 age-comparable healthy controls with a comprehensive psychiatric and neuropsychological evaluation. Caregivers rated the frequency of patients' exposure to dangerous situations or commission of dangerous behaviours. The frequency of dangerous behaviours was 16% in the AD group and 2% in the healthy control group. The presence of anosognosia was associated with a threefold increase in the risk of dangerous behaviours, but there was no significant association between dangerous behaviours and patients' age, years of education, diagnosis of major or minor depression and presence of suicide ideation. Sixteen per cent of a consecutive series of patients with AD had dangerous behaviours during the month preceding the clinical evaluation. Anosognosia was the main clinical correlate of dangerous behaviours in this population.

A diagnostic formulation for anosognosia in Alzheimer's disease.

OBJECTIVE: To determine the earliest symptoms of anosognosia in people with Alzheimer's disease and to validate a criteria-guided strategy to diagnose anosognosia in dementia. METHODS: A consecutive series of 750 patients with very mild or probable Alzheimer's disease attending a memory clinic, as well as their respective care givers, was assessed using a comprehensive psychiatric evaluation. RESULTS: The factors of anosognosia for (1) basic activities of daily living (bADL), (2) instrumental activities of daily living (iADL), (3) depression and (4) disinhibition were produced by a principal component analysis on the differential scores (ie, caregiver score minus patient score) on the anosognosia questionnaire for dementia. A discrepancy of two or more points in the anosognosia-iADL factor was found to have a high sensitivity and specificity to identify clinically diagnosed anosognosia in people with Alzheimer's disease. By logistic regression analysis, the severity of dementia and apathy were both shown to be noticeably associated with anosognosia in people with Alzheimer's disease. CONCLUSION: Anosognosia in those with Alzheimer's disease is manifested as poor awareness of deficits in iADL and bADL, depressive changes and behavioural disinhibition. The frequency of anosognosia is found to increase considerably with the severity of dementia. The validity of a specific set of criteria to diagnose anosognosia in people with Alzheimer's disease was shown, which may contribute to the early identification of this condition.

A prospective longitudinal study of apathy in Alzheimer's disease.

BACKGROUND: Apathy and depression are the most frequent behavioural and psychiatric disorders in Alzheimer's disease, and may both have a negative impact on the progression of the illness. OBJECTIVES: To examine the clinical correlates of apathy in Alzheimer's disease (AD), and to determine whether apathy is a significant predictor of more rapid cognitive, functional and emotional decline. METHODS: Using a structured psychiatric evaluation, we examined a consecutive series of 354 subjects meeting clinical criteria for AD. Apathy was assessed by the Apathy Scale, and diagnosed using standardised criteria. Additional measurements included scales for depression, functional impairment, and global cognitive functions. A follow up evaluation was carried out in 247 patients (70% of the total sample) between 1 and 4 years after the baseline evaluation. RESULTS: Apathy was significantly associated with older age (p = 0.009), and a higher frequency of minor and major depression (p < 0.0001). Apathy at baseline was a significant predictor of depression at follow up (p = 0.01), and was associated with a faster cognitive (p = 0.0007) and functional decline (p = 0.006). CONCLUSIONS: Apathy in AD is a behavioural marker of a more aggressive dementia, characterised by a faster progression of cognitive, functional, and emotional impairment.

On the overlap between apathy and depression in dementia.

BACKGROUND: Whereas apathy is increasingly recognised as a frequent abnormal behaviour in dementia, its overlap with depression remains poorly understood. AIMS: To assess the psychometric characteristics of a structured interview for apathy, and to examine the overlap between apathy and depression in dementia. METHODS: A total of 150 patients with Alzheimer's disease (AD) underwent a comprehensive psychiatric and cognitive assessment. RESULTS: Twelve per cent of the sample met criteria for both apathy and depression, 7% met criteria for apathy only, and 31% met criteria for depression only. Apathy (but not depression) was significantly associated with more severe cognitive deficits. Apathy and anxiety scores accounted for 65% of the variance of depression scores in dementia, and the diagnosis of apathy had a minor impact on the rating of severity of depression. CONCLUSIONS: The Structured Interview for Apathy demonstrated adequate psychometric characteristics. Using a novel structured interview for apathy in AD we demonstrated that whereas the construct of depression primarily consists of symptom clusters of apathy and anxiety, apathy is a behavioural dimension independent of depression.

White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease.

BACKGROUND AND OBJECTIVE: Methodological variability in the assessment of white matter hyperintensities (WMH) in dementia may explain inconsistent reports of its prevalence and impact on cognition. We used a method of brain MRI segmentation for quantifying both tissue and WMH volumes in Alzheimer's disease (AD) and examined the association between WMH and structural and cognitive variables. METHODS: A consecutive series of 81 patients meeting NINCDS-ADRDA criteria for probable AD was studied. Nineteen healthy volunteers of comparable age served as the control group. Patients had a complete neurological and neuropsychological evaluation, and a three dimensional MRI was obtained. Images were segmented into grey matter, white matter, and cerebrospinal fluid. WMH were edited on segmented images, and lobar assignments were based on Talairach coordinates. RESULTS: Mild and moderate to severe AD patients had significantly more WMH than controls (p<0.05). WMH preferentially involved the frontal lobes (70%), were inversely correlated with grey matter cortical volume (R(2) = 0.23, p<0.001), and were significantly associated with vascular risk factors and with a worse performance on memory tasks. CONCLUSION: Objective measurements of tissue volumes in AD demonstrated that WMH are significantly related to cortical atrophy and neuropsychological impairment.

Reconstruction of a neocondyle using transport distraction osteogenesis.

The process of slow bone expansion by distraction osteogenesis in conjunction with functional remodeling can also be used for the reconstruction of a neomandible and neocondyle. This is the technique of transport distraction osteogenesis. A transport disc is surgically created adjacent to the area of a discontinuity defect, and the transport disc is advanced by the process of distraction osteogenesis, using the Ilizarov principles. The mandible therefore acts as the bony template for reconstruction such that the neomandible created from the distraction process has the same size and shape as the native mandible covered by gingiva. This allows for enhanced prosthetic reconstruction. A reverse-L osteotomy of the ramus can also be performed to create a transport disc to reconstruct a neocondyle. Because the leading edge of the transport disc becomes enveloped by a fibrocartilagenous cap, the ramal transport disc can be moved superiorly to create a new articulation. Patients are encouraged to open and close their mouths during the distraction process, such that the transport disc remodels to form a neocondyle. This technique was successfully used to treat patients with degenerative joint disease, condylar resorption, and bony ankylosis.

Interrelationships between heat acclimation and salivary cooling mechanism in conscious rats.

1. Adaptation of salivary cooling mechanism during acclimation to heat (34 degrees C) and its role in thermoregulation of the rats was studied on conscious rats with either one submaxillary gland chronically cannulated or both submaxillaries ligated. 2. During heat stress (40 degrees C) acclimated rats showed a decrease both in rectal temperature threshold for salivation (Tre-TS), in salivary flow rate and in Tre (hyperthermic plateau). Animals survived for extended periods and rats with ligated glands survived 40% less than non-ligated rats. 3. For both cannulated and ligated rats short term acclimation (5 days) was the most effective. 4. It is suggested that earlier activation of salivation mechanism is associated with the decreased hyperthermic plateau and that the decreased salivary flow rate allows better control of water balance of the animals. Consequently, survival period during heat stress is extended.

[Four-year follow-up of thyrotoxic patients treated with antithyroid drugs bases on thyroid suppressibility-Prognostic value of the 20-min 131-I thyroid uptake (author's transl)]. / Traitement de l'hyperthyroïde par les antithyroïdiens de synthèse: valeur pronostique de la captation thyrïdienne précoce (recul de 4 an).

Out of 77 thyrotoxic patients treated with Carbimazole (30-15 mg/day) in combination with 1-triiodothyronine (75 micron/day) for 5-48 months applying 20-min 131I-thyroid uptake test at the end of treatment as a parameter for thyroid suppressibility, 39 cases (51%) have maintained euthyroid state for more than 4 years, while 20 (26%) relapsed within 3 months and the remaining 18 (23%) recurred within 6 years after antithyroid-drug (ATD) therapy. The predictable value of 20-min 131I-thyroid uptake was useful for distinguishing relapses from others, but there was no statiscally significant difference between recurrent cases and remittent ones. Since the negative correlation between the 20-min 131I-thyroid uptake and the recurrent phase was noted, the continuation of ATD therapy until the uptake reaches below 8% postpones this phase of recurrence.