Serge Weis

Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder

Increased concentrations of kynurenine pathway metabolites have been reported by several groups for disorders involving psychosis, including schizophrenia and bipolar disorder. To identify components of the pathway that may be relevant as biomarkers or may underlie the etiology of psychosis, it is essential to characterize the extent of kynurenine pathway activation and to investigate known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), previously shown in this laboratory to be increased commensurate with kynurenine in postmortem anterior cingulate brain tissue from individuals with schizophrenia. Using this same anterior cingulate sample set from individuals with schizophrenia, bipolar disorder, depression and controls (N=12-14 per group), we measured the precursor of kynurenine and two downstream products. The precursor, tryptophan, was significantly increased only in the schizophrenia group (1.54-fold the mean control value, p=0.02), and through substrate-induced activation, may be one cause of the increased kynurenine and kynurenine metabolites. This finding for tryptophan differs from some, but not all, previous reports and methodological reasons for the discrepancies are discussed. A product of kynurenine metabolism, 3-OH-anthranilic acid was also significantly increased only in the schizophrenia group (1.68-fold the mean control value, p=0.03). 3-OH-anthranilic acid is a reactive species with cytotoxic properties, although the threshold for such effects is not known for neurons. Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons. Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03).

Is there a place for FET PET in the initial evaluation of brain lesions with unknown significance

PurposeThe aim of this study was to evaluate the clinical value of the use of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) positron emission tomography (PET)/computed tomography (CT) in patients of a neurological clinic for evaluation of brain lesions newly diagnosed by magnetic resonance imaging (MRI).MethodsWe evaluated 88 patients (44 women and 44 men) with a mean age of 50u2009±u200919xa0years who were sent consecutively for evaluation of an intracerebral mass or lesion observed by MRI from 2006 to 2008. Hospitalization was necessary due to neurological clinical symptoms. Images were obtained by PET/CT 30xa0min after i.v. injection of 185xa0MBq FET. Coregistration with MRI was done by HERMES workstation.ResultsFET uptake above the cortical level was observed in 60 patients. Neurosurgery was performed in 60 patients (51 with FET-positive imaging); 36 high-grade and 19 low-grade tumours were verified histologically. The sensitivity of FET PET for high-grade tumours (WHO III–IV) was 94% in this setting. Among the low-grade brain tumours (WHO I–II) 13 of 19 were FET positive, which indicates a sensitivity of 68%. Five of ten (50%) astrocytomas I and II could not be visualized by FET. Histological data were not provided for 28 of 88 patients, so the diagnostic approach is based upon longitudinal observation. Radiological and/or clinical control was done at a median of 7xa0months later. Three patients (all FET positive) died a few months after the examination because of rapid progression of the malignant brain tumour. A malignant entity could be excluded in the other 25 patients. Considering the whole cohort of 88 patients, 43 patients with malignant tumour could be identified, including high-grade glioma, intracerebral lymphoma (nu2009=u20091) and metastasis (nu2009=u20093). The sensitivity of FET PET for detecting a malignant tumour entity was 93%. We observed two false-positive cases with postischaemic lesions. Remarkably, the two patients with cerebral gliomatosis were false-negative on FET PET imaging. The negative predictive value for a malignant entity was calculated to be 89%.ConclusionOur results indicate a high sensitivity of FET PET for detecting high-grade glioma in patients with neurological symptoms and recently observed brain lesions by MRI. In the setting of evaluating new brain lesions of unknown significance via FET PET a negative image can encourage a wait and see strategy—of course in accordance with the clinical picture and morphological imaging.

Damage to histaminergic tuberomammillary neurons and other hypothalamic neurons with traumatic brain injury

The need for increased sleep after traumatic brain injury is a common and disabling complaint, yet its etiology is unknown. Previous studies have demonstrated diffuse damage to various hypothalamic systems, but the integrity of the histaminergic tuberomammillary nucleus, a major arousal‐promoting system located in the posterior hypothalamus, has never been examined in head trauma patients. Here, we demonstrate that severe head trauma is associated with a marked loss (41%) of histaminergic neurons. Reduced histamine signaling may contribute to increased sleep need, and therapies that enhance histaminergic tone may improve arousal after head trauma or other conditions. ANN NEUROL 2015;77:177–182

Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up

BACKGROUNDnSurgical clipping of intracranial aneurysms is the gold standard for the prevention of rupture. However, the biological processes that occur following clipping are poorly understood. To better understand these effects, retrieved and clipped human intracranial aneurysms were examined histologically.nnnMETHODSnAt autopsy, 17 aneurysms from 10 patients were retrieved 3-21 days after clipping. The tissues were embedded in paraffin, and microtome sections were stained using hematoxylin-eosin and Movat pentachrome. Using light microscopy, clip placement relative to the internal elastic lamina of the parent artery, endothelialization of the aneurysm neck, thrombus organization inside the aneurysm sac, inflammation in the sac, wall, and parent artery, and atherosclerotic changes were determined.nnnRESULTSnDespite complete reconstruction of the artery with the clip, diseased vessel wall was frequently observed outside the clip. By 10 days postsurgery, the beginnings of endothelialization and neointima formation were observed at the neck. However, the neck coverage was variable and incomplete at these early time points. Thrombus organization inside the aneurysm sac was rarely observed, and inflammatory cells were not present inside the aneurysm sac. Inflammatory cells were commonly observed in the aneurysm wall, and atherosclerotic change was present in each sample.nnnCONCLUSIONSnComplete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.nnnSUMMARYnComplete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.

A case of variably protease-sensitive prionopathy treated with doxycyclin.

Variably protease-sensitive prionopathy (VPSPr) is a recently described neurodegenerative disorder characterised by the presence of spongiform encephalopathy and an unusual immunostaining and immunoblotting pattern for the disease-associated prion protein (PrPSc).1 This links VPSPr to human prion diseases, which are uniformly fatal disorders. The clinical symptoms and the longer duration of illness make VPSPr distinct from sporadic or idiopathic Creutzfeldt-Jakob disease (sCJD).1 Doxycycline treatment has been evaluated in patients with prion disease, however, there is little evidence that it can reverse the clinical symptoms or reduce the underlying disease progression once established.2 We present a patient with VPSPr who received doxycycline and survived for an extended period of time in an akinetic and mute state.nnNeuropathological examination was performed using published methods and various anti-PrP antibodies.3 Frozen tissues from selected brain regions were available for biochemical analysis. Tissues were analysed for the presence of protease-resistant PrP (PrPres) as previously described (see online supplementary material).4 nnIn May 2007, a registered psychiatrist suspected an organic affective disorder in a 54-year-old Austrian woman. Two months earlier, medical work-up for presumed weight loss of 16u2005kg within the past 18u2005months had been unremarkable. In June 2007, the patient was admitted to a clinic that specialised in disorders of the nervous system. Her family history was negative for neurodegenerative diseases and there was no evidence of exposure to toxins. She reported depressed mood and short-term memory problems, and difficulties with balance, walking, driving and cooking. On neuropsychological examination she was oriented to time, place, person and situation, Mini-Mental State Examination score was 22/30, clock drawing test score was 3/9. She had word-finding difficulties, ideational apraxia, acalculia and visuoconstructive deficits. She displayed affective incontinence with crying fits. She had gait ataxia, and extensor plantar responses were observed with increased tone …

Screening for α-synuclein immunoreactive neuronal inclusions in the hippocampus allows identification of atypical MSA (FTLD-synuclein).

brainstem, and cerebellum. According to Aoki et al. [2], we used a four-tiered scoring system (none—0, mild—1, moderate—2, severe—3) for the evaluation of α-synuclein NCIs regardless of their morphology (ring, NFT, or Pick body like). The selection was blinded to the clinical diagnosis, age, gender, and macroscopic observations. We observed α-synuclein immunoreactive NCIs in the granule cells of the dentate gyrus in seven cases (38 %). Five out of seven cases (online supplemental file 1) showed only relatively few NCIs in the dentate gyrus and CA1/Subiculum (score 1) (Fig. 1a, b). There was a lack of α-synuclein immunoreactive thin neurites and eosinophilic Pick body-like spherical inclusions in the hematoxylin and eosin (H&E) staining. Three of these five cases did not show clinical symptoms of dementia. Gait disturbance, parkinsonism, cerebellar symptoms, and dementia (not compatible with FTD) were reported in the two additional cases (57and 71-year-old women) during the final 24 months of illness (total duration of illness was 120 and 75 months, respectively). Both brains showed Aβ plaques (both Thal phase 3) [9] and neurofibrillary degeneration (both Braak stage II) [1, 3]. In the Atypical multiple system atrophy (aMSA) is a term recently introduced by Aoki et al. to describe cases that show hallmark neuropathological changes of glial cytoplasmic inclusions (Papp–Lantos bodies) characteristic of MSA, while clinically presenting with frontotemporal dementia (FTD) syndromes associated with frontotemporal lobar degeneration (FTLD) and severe limbic and cortical α-synuclein neuronal pathology [2]. The authors evaluated FTD syndrome cases and showed that the evaluation of α-synuclein immunoreactive neuronal cytoplasmic inclusions (NCIs) in the hippocampus (dentate gyrus and CA1/Subiculum) seems to be of great importance [2]. We aimed to determine if these morphological features in the hippocampus are reliable to identify similar cases in our archives. We evaluated α-synuclein immunostaining in the hippocampus from a cohort of 18 neuropathologically confirmed MSA cases [10]: all cases contained characteristic Papp–Lantos bodies and NCIs in the basal ganglia,

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

BackgroundHuman prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms.ResultsIn the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2–12xa0months; age at death: 55–81xa0years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups.ConclusionsOur observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases.

Damage to arousal-promoting brainstem neurons with traumatic brain injury

STUDY OBJECTIVESnComa and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI.nnnMETHODSnPostmortem examination of 8 TBI patients and 10 controls.nnnRESULTSnCompared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls.nnnCONCLUSIONSnTBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries.

Sarcoidois and Radiation-Induced Astrogliosis Causes Pitfalls in Neuro-Oncologic Positron Emission Tomography Imaging by O-(2-[18F]Fluoroethyl)-l-Tyrosine

Positron emission tomography (PET) imaging has become popular in staging and restaging of cancer because of the possibility that the radiopharmaceutical [F]fluorodeoxyglucose (FDG) could show increased glucose metabolism. Because of the high background activity in normal cortical brain tissue and low FDG avidity in some gliomas, Cand F-labeled amino acids usually replace FDG in brain tumor imaging. There is less information about false-positive pitfalls in amino acid PET imaging compared with FDG. L-[C]methionine (C-MET) can be accumulated by inflammatory processes whereas O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) should not accumulate. We observed false-positive FET-PET imaging in lesions with reactive astrogliosis, which was revealed later on by histology. In the first case report, a 38-year-old man was referred to our neurologic hospital because of seizures in August 2009. A lesion 1 cm in diameter located at the mesial right temporal lobe suggestive of tumor was observed by magnetic resonance imaging. FET-PET revealed faint but clearly visible tracer accumulation in the lesion, indicating low-grade brain glioma (Figs 1A and 1B). Small, soft, whitishpink tissue fragments were histopathologically examined. Many sharply delineated granulomas were found in the gray matter. In the center of each granuloma, epithelioid cells and multinucleated giant cells were visible. In the adjacent gray matter, distinct reactive astrogliosis was clearly detectable on hematoxylin and eosin staining (Fig 2) and immunhistochemically with an antibody against glial fibrillary acidic protein (Fig 3). A brain tumor was not evident. The lesion was diagnosed as cerebral sarcoidosis. Restaging by FDG-PET computed tomography revealed active thoracic lymph nodes, so corticoids were added to anticonvulsive treatment. At last follow-up in April 2010, no residual disease was observed. In the second case report, a 79-year-old man underwent magnetic resonance brain imaging for evaluation of slow progressive cognitive deficit. A lesion of unknown significance was observed in the left polar temporal lobe in July 2009. FET-PET proved the lesion to be markedly FET avid (Figs 4A and 4B) and was suggestive of a brain tumor; the lesion was extirpated by neurosurgery. In histologic sections, massive reactive astrogliosis and hypercellularity were noted in the white matter (Fig 5). Blood vessels with

Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG)

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 wasu2009>60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.