A 64-year progression of an intradiploic epidermoid of the frontal skull: illustrative case.

BACKGROUND: Epidermoid cyst tumors can arise as intradiploic tumors in the frontal skull bones around the fontanel in childhood but are mostly found at the frontal or frontotemporal base of the brain or in the cerebellopontine angle. Therefore, finding a symptomatic intradiploic lesion in the convexity in late adulthood is uncommon. Intradiploic epidermoids can cause complications as they grow, by eroding and perforating their surroundings, and in cases of destruction of the wall of a pneumatized sinus, they can cause pneumocephalus. OBSERVATIONS: In the present case, a female patient presented with a skull lesion that had grown progressively over 64 years, resulting in spontaneous pneumocephalus. Surgery with subsequent cranioplasty was performed. The histological examination confirmed the presence of an intradiploic epidermoid. LESSONS: This case highlights that complete resection of the lesion with subsequent cranioplasty is recommended before symptoms and reconstructive challenges due to the enormous size of the defect. This case serves as a reminder that intradiploic epidermoids, although uncommon, will expand throughout life and can cause significant complications such as pneumocephalus after decades. Timely surgical interventions after diagnosis are recommended to prevent further complications and to achieve a successful outcome in terms of complete resection and reconstruction.

Role of interhemispheric connectivity in recovery from postoperative supplementary motor area syndrome in glioma patients.

OBJECTIVE: Surgical resection of gliomas involving the supplementary motor area (SMA) frequently results in SMA syndrome, a symptom complex characterized by transient akinesia and mutism. Because the factors influencing patient functional outcomes after surgery remain elusive, the authors investigated network-based predictors in a multicentric cohort of glioma patients. METHODS: The participants were 50 patients treated for glioma located in the SMA at one of the three centers participating in the study. Postoperative functional outcomes (motor deficits, mutism) and duration of symptoms were assessed during hospitalization. Long-term outcome was assessed 3 months after surgery. MRI-based lesion-symptom mapping was performed to estimate the severity of gray matter damage and white matter disconnection. RESULTS: The median duration of acute symptoms was 3 days (range 1-42 days). Long-term deficits involving fine motor movements and speech were found at follow-up in 27 patients (54%). Disconnection of the central callosal fibers was associated with prolonged acute symptoms (p < 0.05). Postoperative mutism was significantly related to disconnection severity of the left frontopontine tract, frontal aslant tract, cingulum, and corticostriatal tract (p < 0.05). Disconnection of midposterior callosal fibers and lesion loads within the left medial Brodmann area 4 were associated with long-term motor deficits (p < 0.05). CONCLUSIONS: This study provides evidence for the pathophysiology and predictive factors of postoperative SMA syndrome by demonstrating the relation of the disconnection of callosal fibers with prolonged symptom duration (central segment) and long-term motor deficits (midposterior segment). These data may be useful for presurgical risk assessment and adequate consultation for patients prior to undergoing resection of glioma located within the SMA region.

Altered inhibition and excitation in neocortical circuits in congenital microcephaly.

Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, Cdk5rap2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for Cdk5rap2 in the regulation of dendritic development and synaptogenesis of neocortical layer 2/3 pyramidal neurons. Cdk5rap2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo. Moreover, the excitatory drive is enhanced in ex vivo brain slice preparations of Cdk5rap2 mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation - inhibition balance towards excitation in Cdk5rap2 mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.

No Effect of Anodal Transcranial Direct Current Stimulation on Gamma-Aminobutyric Acid Levels in Patients with Recurrent Mild Traumatic Brain Injury.

In patients in the chronic phase after recurrent mild traumatic brain injury (mTBI), alterations in gamma-aminobutyric acid (GABA) concentration and receptor activity have been reported, possibly mediating subtle but persistent cognitive deficits and increased rate of dementia in older age. We evaluated whether anodal transcranial direct current stimulation (atDCS) over the primary motor cortex reduces GABA concentration and GABAB receptor activity in patients with recurrent mTBI. Seventeen patients (mean age 25, two women) in the chronic phase after recurrent mTBI and 22 healthy control subjects (mean age 26, two women) were included. All participants received comprehensive cognitive testing and detailed questionnaires on post-concussive symptoms at baseline. Subsequently, they participated in four experimental sessions, consisting of either magnetic resonance spectroscopy (MRS)/atDCS/MRS, transcranial magnetic stimulation (TMS)/atDCS/TMS, MRS/sham/MRS, or TMS/sham/TMS to determine GABA concentration (from MRS) and GABAB receptor activity (from TMS) after atDCS and after sham stimulation. Patients with mTBI scored significantly lower on verbal fluency tasks compared with healthy control subjects. GABA concentration at baseline was associated with the number of mTBI, although no group differences in GABA concentration and GABAB receptor activity were found. Moreover, no effects of atDCS on GABA concentration and receptor activity were seen in patients with mTBI or healthy control subjects. GABA concentration may increase with the number of mTBI, but atDCS did not modulate GABA concentration and receptor activity, as has been reported previously. Specifics of experimental design and analysis, but also characteristics of the respective samples, may account for these differential findings, and should be addressed in future larger studies.

Behavioral phenotyping of minipigs transgenic for the Huntington gene.

BACKGROUND: While several novel therapeutic approaches for HD are in development, resources to conduct clinical trials are limited. Large animal models have been proposed to improve assessment of safety, tolerability and especially to increase translational reliability of efficacy signals obtained in preclinical studies. They may thus help to select candidates for translation to human studies. We here introduce a battery of novel tests designed to assess the motor, cognitive and behavioral phenotype of a transgenic (tg) HD minipig model. NEW METHODS: A group of tgHD and wildtype (wt) Libechov minipigs (n=36) was available for assessment with (1) a gait test using the GAITRite(®) automated acquisition system, (2) a hurdle-test, (3) a tongue coordination test, (4) a color discrimination test, (5) a startbox back and forth test and (6) a dominance test. Performance of all tests and definition of measures obtained is presented. RESULTS: Minipigs were able to learn performance of all tests. All tests were safe, well tolerated and feasible. Exploratory between group comparisons showed no differences between groups of tgHD and wt minipigs assessed, but low variability within and between groups. COMPARISON WITH EXISTING METHOD(S): So far there are no established or validated assessments to test minipigs in the domains described. CONCLUSIONS: The data shows that the tests presented are safe, well tolerated and all measures defined can be assessed. Prospective longitudinal application of these tests is warranted to determine their test-retest reliability, sensitivity and validity in assessing motor, cognitive and behavioral features of tg and wt minipigs.

Neuroimaging of a minipig model of Huntington's disease: Feasibility of volumetric, diffusion-weighted and spectroscopic assessments.

BACKGROUND: As novel treatment approaches for Huntington's disease (HD) evolve, the use of transgenic (tg) large animal models has been considered for preclinical safety and efficacy assessments. It is hoped that large animal models may provide higher reliability in translating preclinical findings to humans, e.g., by using similar endpoints and biomarkers. NEW METHOD: We here investigated the feasibility to conduct MRI assessments in a recently developed tgHD model in the Libechov minipig. The model is characterized by high genetic homology to humans and a similar body mass and compartments. The minipig brain provides anatomical features that are attractive for imaging studies and could be used as endpoints for disease modifying preclinical studies similar to human HD. RESULTS: We demonstrate that complex MRI protocols can be successfully acquired with tgHD and wild type (wt) Libechov minipigs. We show that acquisition of anatomical images applicable for volumetric assessments is feasible and outline the development of a segmented MRI brain atlas. Similarly diffusion-weighted imaging (DWI) including fiber tractography is presented. We also demonstrate the feasibility to conduct in vivo metabolic assessments using MR spectroscopy. COMPARISON WITH EXISTING METHODS: In human HD, these MRI methods are already validated and used as reliable biomarker of disease progression even before the onset of a clinical motor phenotype. CONCLUSIONS: The results show that the minipig brain is well suited for MRI assessments in preclinical studies. We conclude that further characterization of phenotypical differences between tg and wt animals in sufficiently powered cross-sectional and longitudinal studies is warranted.

Cognitive function and brain structure after recurrent mild traumatic brain injuries in young-to-middle-aged adults.

Recurrent mild traumatic brain injuries (mTBIs) are regarded as an independent risk factor for developing dementia in later life. We here aimed to evaluate associations between recurrent mTBIs, cognition, and gray matter volume and microstructure as revealed by structural magnetic resonance imaging (MRI) in the chronic phase after mTBIs in young adulthood. We enrolled 20 young-to-middle-aged subjects, who reported two or more sports-related mTBIs, with the last mTBI > 6 months prior to study enrolment (mTBI group), and 21 age-, sex- and education matched controls with no history of mTBI (control group). All participants received comprehensive neuropsychological testing, and high resolution T1-weighted and diffusion tensor MRI in order to assess cortical thickness (CT) and microstructure, hippocampal volume, and ventricle size. Compared to the control group, subjects of the mTBI group presented with lower CT within the right temporal lobe and left insula using an a priori region of interest approach. Higher number of mTBIs was associated with lower CT in bilateral insula, right middle temporal gyrus and right entorhinal area. Our results suggest persistent detrimental effects of recurrent mTBIs on CT already in young-to-middle-aged adults. If additional structural deterioration occurs during aging, subtle neuropsychological decline may progress to clinically overt dementia earlier than in age-matched controls, a hypothesis to be assessed in future prospective trials.

[Assessment of a Bull Terrier bloodline regarding possible hypertrophic aggressive behaviour in situations of dog-dog-contact of the temperament test of Lower Saxony]. / Untersuchung einer Bullterrier-Zuchtlinie hinsichtlich einer möglichen Hypertrophie des Aggressionsverhaltens im Hund- Hund-Kontakt des Niedersächsischen Wesenstests.

The expertise on the interpretation of and 11 b TierSchG assumes that a hypertrophy of aggressive behaviour exists in some blood lines of Bull Terriers, American Staffordshire Terriers and Pitbull type dogs. This study was carried out to detect whether a hypertrophy of aggressive behaviour occurred in a certain Bull Terrier breed line. A total of 38 dogs representing this line were tested according to the guidelines of the Dangerous Animals Act of Lower Saxony, Germany (GefTVO) enacted on July 5th, 2000. Furthermore, the results of their behaviour towards other dogs during the test were compared to those of 347 dogs tested by Böttjer (2003) in order to investigate possible significant differences in the occurrence of inadequate or disturbed aggressive behaviour. The comparison was aimed at exposing a possible significant accumulation of intraspecific aggressive behaviour. In the situations of dog-dog-contact of the test, 25 threatening behaviour"was displayed by 9 dogs (23.68%). Four dogs (10.53%) responded with "non-stationary threatening behaviour". All Bull Terriers reacted appropriately in every situation. A significant difference when comparing the results of the Bull Terriers to those of the dogs examined by Böttjer (2003) was not found. In conclusion, there were no indications for inadequate or disturbed aggressive behaviour in this Bull Terrier breed line. Furthermore, the broad majority of dogs proved to possess excellent social skills as well as the ability to communicate competently and to solve conflicts appropriately.

[Assessment of a Bullterrier bloodline in the temperament test of Lower Saxony--comparison with six dog breeds affected by breed specific legislation and a control group of Golden Retrievers]. / Untersuchung einer Bullterrier-Zuchtlinie hinsichtlich ihres Verhaltens im Nds. Wesenstest--Vergleich mit sechs von der Gesetzgebung betroffenen Hunderassen und einer Kontrollgruppe von Golden Retrievern.

The expertise on the interpretation of section 11b TierSchG implies a hypertrophy of aggressive behaviour in some bloodlines of Bullterriers, American Staffordshire Terriers, and Pitbull type dogs. This study aimed at finding out whether a hypertrophy of aggressive behaviour occurred in a certain Bullterrier bloodline. Dogs of this line were tested according to the guidelines of the Dangerous Animals Act of Lower Saxony, Germany (GefTVO) enacted on July 5th 2000. The Bullterriers' test results towards humans and environment were compared to those of 415 dogs affected by the legislation (Mittmann, 2002) and those of 70 Golden Retrievers (Johann, 2004) in order to detect possible differences in the occurrence of inadequate or disturbed aggressive behaviour. Of 38 Bullterriers, ten showed no aggressive behaviour towards humans and the environment. 27 dogs displayed visual or acoustic threats at most. Only one dog reacted by "biting or attacking with preceding threatening behaviour". Thus, according to the test guidelines, 37 dogs (97.37%) reacted appropriately in all test situations. Only one dog (2.63%) displayed inadequate agressive behaviour. No indication for inadequate or disturbed aggressive behaviour in this Bullterrier bloodline was found. Furthermore, no significant differences were found when comparing Bullterriers and dogs of the two others studies concerning inadequate or disturbed aggressive towards humans and the environment. On the contrary, throughout the entire study the broad majority of dogs proved to possess excellent social skills as well as the ability to communicate competently and to solve conflicts appropriately.

Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter.

Endogenous isoquinoline (IQ) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>tetrahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-Me-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.