Quantification of MPTP-induced dopaminergic neurodegeneration in the mouse substantia nigra by laser capture microdissection

The neurotoxin MPTP is widely used to cause damage to the dopaminergic system in rodents and non-human primates to model various aspects of Parkinson's disease. In mice, depletion of striatal dopamine is the commonly used endpoint to assess neuronal damage. However, it has proved technically challenging to quantify dopaminergic cell bodies as an index of neuronal integrity. To meet this challenge, we applied laser pressure catapult microdissection (LCM) of the substantia nigra in combination with quantitative Western blot to provide an index of dopamine neurodegeneration in mice treated with MPTP. Seven days following initiation of MPTP treatment, striatal dopamine depletion was maximal and there was histological evidence of neuronal degeneration in the substantia nigra. To index the integrity of dopamine cell bodies, tyrosine hydroxylase (TH) and beta-actin were quantified by Western blot in LCM extracts. In untreated mice, TH was detected in LCM extracts of substantia nigra but was undetectable in equivalently sized extracts of cortex from the same animals. In MPTP-treated mice, there was a significant 70% reduction in TH relative to beta-actin in LCM extracts as compared to vehicle-injected controls. This reduction corresponded to decreases in striatal dopamine and loss of immunocytochemically detected TH but not beta-actin in the substantia nigra (SN). Thus, this method provides a quantitative means to measure dopamine neuron toxicity in the substantia nigra and, as such has potential application in evaluating regimens that may be neuroprotective or neurorestorative for dopaminergic neurons.     

Prefrontal but not temporal grey matter changes in males with first-episode schizophrenia

INTRODUCTION: Changes of brain morphology are now considered as a part of the pathology of schizophrenia. Voxel-based morphometry may be used to study regional changes of the grey matter in the whole brain. It is advantageous to study first-episode patients to prevent the influence of many possible biasing factors when trying to identify primary pathological processes underlying the manifestation of the illness. OBJECTIVE: To investigate regional grey matter changes in the first-episode schizophrenia patients. METHODS: Optimized voxel-based morphometry was used to detect changes in grey matter volume in 22 patients with first-episode schizophrenia compared with 18 healthy volunteers of comparable age, gender and handedness. RESULTS: The first-episode schizophrenia group had significantly reduced grey matter volume in the prefrontal cortex (inferior and middle prefrontal gyrus, cingulate gyrus). We identified no differences in the temporal cortex. CONCLUSION: Our data support the theoretical assumption that prefrontal dysfunction underlines the primary pathology and clinical manifestation of schizophrenia. We are inclined to explain the differences in the pattern of morphological changes reported in other first-episode studies--especially the lack of changes in the temporal cortex--by heterogeneity of schizophrenia, potential progression and antipsychotic medication effect.     

Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies

The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10–15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.     

Histaminergic Activity in a Rodent Model of Parkinson’s Disease

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson’s disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson’s disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 μg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites l-3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H₁; cimetidine, H₂; thioperamide, H₃ agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H₃ antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson’s disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.     

Striatal volumes in affected and unaffected relatives of bipolar patients - high-risk study

Background

Striatal volume changes reported in bipolar disorders could represent artifacts of medication or comorbid conditions, or illness related changes, either biological predispositions or consequences of illness burden. We conducted volumetric high-risk study to investigate whether striatal volume changes represent primary biological risk factor for bipolar disorders.

Methods

High-risk (HR) participants (age range 15-30 years) were recruited from families multiply affected with bipolar disorders. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Striatal volumes were measured on 1.5T 3D anatomical MRI images using standard methods.

Results

There was a significant difference between groups (affected, unaffected HR and control subjects) in caudate volumes (F = 3.50, DF = 2; 74 and p = 0.04) in absence of putamen volume changes. The caudate volumes were largest in unaffected HR subjects without differences between affected and control or affected and unaffected HR subjects. The maximum changes were found in the head of the caudate. Controlling for non-independence of observations in multiple subjects per family yielded non-significant differences.

Conclusions

Despite the biological plausibility, partial agreement with previous studies and nominal statistical significance, controlling for non-independence of observations within families changed the increased caudate volumes among unaffected subjects to non-significant. We thus present these findings as negative, pending further replication. Striatal volume abnormalities did not meet criteria for endophenotype in this study.     

Behavioral and functional neuroanatomical correlates of anterograde autobiographical memory in isolated retrograde amnesic patient M.L.

Patient M.L. [Levine, B., Black, S. E., Cabeza, R., Sinden, M., Mcintosh, A. R., Toth, J. P., et al. (1998). Episodic memory and the self in a case of isolated retrograde amnesia. Brain, 121, 1951-1973], lost memory for events occurring before his severe traumatic brain injury, yet his anterograde (post-injury) learning and memory appeared intact, a syndrome known as isolated or focal retrograde amnesia. Studies with M.L. demonstrated a dissociation between episodic and semantic memory. His retrograde amnesia was specific to episodic autobiographical memory. Convergent behavioral and functional imaging data suggested that his anterograde memory, while appearing normal, was accomplished with reduced autonoetic awareness (awareness of the self as a continuous entity across time that is a crucial element of episodic memory). While previous research on M.L. focused on anterograde memory of laboratory stimuli, in this study, M.L.’s autobiographical memory for post-injury events or anterograde autobiographical memory was examined using prospective collection of autobiographical events via audio diary with detailed behavioral and functional neuroanatomical analysis. Consistent with his reports of subjective disconnection from post-injury autobiographical events, M.L. assigned fewer “remember” ratings to his autobiographical events than comparison subjects. His generation of event-specific details using the Autobiographical Interview [Levine, B., Svoboda, E., Hay, J., Winocur, G., & Moscovitch, M. (2002). Aging and autobiographical memory: dissociating episodic from semantic retrieval. Psychology and Aging, 17, 677-689] was low, but not significantly so, suggesting that it is possible to generate episodic-like details even when re-experiencing of those details is compromised. While listening to the autobiographical audio diary segments, M.L. showed reduced activation relative to comparison subjects in midline frontal and posterior nodes previously identified as part of the autobiographical memory network. Reductions were also evident in M.L. in association with personal semantic stimuli (e.g., recordings describing personal habits and routines). These data suggest an association between M.L.’s impoverished recollection of autobiographical material and reduced activation in midline sectors of the autobiographical memory network that support the autonoetic, first-person element of episodic memory.     

The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice

Parkin suppression induces accumulation of β-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP_swe mutant mice. We produced double mutant mice with human mutated APP_swe + partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP_swe overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK^+/− and PK^−/−, respectively), and double mutants (APP/PK^+/− and APP/PK^−/−).APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK^+/− and APP/PK^−/− mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK^+/− and APP/PK^−/− mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK^+/− and APP/PK^−/− mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK^+/− heterozygotic and homozygotic APP/PK^−/− mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK^+/− and APP/PK^−/−. Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK^−/− mice.We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP_swe mice.     

Multimodal fusion of structural and functional brain imaging in depression using linked independent component analysis

Previous structural and functional neuroimaging studies have implicated distributed brain regions and networks in depression. However, there are no robust imaging biomarkers that are specific to depression, which may be due to clinical heterogeneity and neurobiological complexity. A dimensional approach and fusion of imaging modalities may yield a more coherent view of the neuronal correlates of depression. We used linked independent component analysis to fuse cortical macrostructure (thickness, area, gray matter density), white matter diffusion properties and resting‐state functional magnetic resonance imaging default mode network amplitude in patients with a history of depression (n = 170) and controls (n = 71). We used univariate and machine learning approaches to assess the relationship between age, sex, case–control status, and symptom loads for depression and anxiety with the resulting brain components. Univariate analyses revealed strong associations between age and sex with mainly global but also regional specific brain components, with varying degrees of multimodal involvement. In contrast, there were no significant associations with case–control status, nor symptom loads for depression and anxiety with the brain components, nor any interaction effects with age and sex. Machine learning revealed low model performance for classifying patients from controls and predicting symptom loads for depression and anxiety, but high age prediction accuracy. Multimodal fusion of brain imaging data alone may not be sufficient for dissecting the clinical and neurobiological heterogeneity of depression. Precise clinical stratification and methods for brain phenotyping at the individual level based on large training samples may be needed to parse the neuroanatomy of depression.     

Relationship between stroke etiology and collateral status in anterior circulation large vessel occlusion

Journal of Neurology - Clinical outcome after mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is influenced by the intracerebral collateral status. We tested the hypothesis...     

Large artery ischemic stroke in severe COVID-19

Journal of Neurology -