Behavioral changes and mechanisms – an experimental study on aging in rodents

In paper I, we studied alterations in behavior with advancing age in female C57BL/6 mice (of Jackson origin). In parallel, growth and survival data were collected. In a protected environment the median survival age was 32 months. Our behavioral data show that aging modulates certain aspects of basic behavior in a continuous manner. However, behavioral aging differentially affects genetically closely related individuals housed under strictly standardized conditions. Thus, subtle environmental factors and epigenetic modifications may be important modulators of aging. In paper II, we analyzed behavioral changes during aging in male C57BL/6J mice. A group of aged males maintained on dietary restriction (DR) was included. The most conspicuous alteration was the decline in exploration activity with advancing age. Comparison with results from paper I revealed that alterations in aged males and females are similar. Moreover, behavioral indices in 22-month-old males could predict remaining life span; exploratory activity and motor skills accounted for up to 65% of the variance in survival. Consistent with a high level of exploratory activity and preserved motor capacity indicated a long post-test survival, aged mice maintained on DR were more successful in such tests than ad libitum fed age-matched males. In paper III, we studied changes in DNA methylation during aging in the central nervous system in a Sprague-Dawley rat model. Using the LUminometric Methylation Assay (LUMA), which assays methylation status in CCGG sequences across the entire genome, and 5-methyl cytosine labelling in neurons, we report a decline in global DNA methylation in several but not all regions examined. In females there was a gradual drop in DNA methylation in the spinal cord, while both cerebellum and striatum were unaffected. The unexpected observation of a decrease in DNA methylation confined to the middle-ages when reproduction ceases suggested that gonadal steroids influence DNA methylation. To test this, ovariectomy was performed in fertile females, resulting in lowered DNA methylation in frontal cortex to levels observed in middle-aged and aged females. In males, DNA methylation was unchanged in the frontal cortex and the decline in DNA methylation in hippocampus occurred at more advanced age than in females. Another conspicuous difference between sexes was the demethylation of DNA in the aged male striatum. In paper IV, we compared age-related loss of muscle mass (sarcopenia) in C57BL/6J mice (wild type; WT) and a transgenic model with accelerated aging: the mtDNA mutator mice; in an effort to asses if an increased load of mtDNA mutations is sufficient to phenocopy sarcopenia as it occurs in normal aging. We found that both WTs and mutator mice lose muscle mass during aging but that this process is more advanced in normal aging. A distinct difference between WTs and mutator mice, was the dramatic re-expression of γ-subunit of the nicotinic acetylcholine receptor (nAChR-γ) caused by failure of muscle innervations in normal aging. In mtDNA mutator mice increased levels of nAChR-γ were infrequent and importantly seen in both young adults and aged; with only a small increase across adult life-span

Multiple meningiomas : Epidemiology, management, and outcomes

Meningiomas are the most common nonmalignant brain tumor in adults, with an increasing incidence of asymptomatic meningiomas diagnosed on more ubiquitous neuroimaging. A subset of meningioma patients bear 2 or more spatially separated synchronous or metachronous tumors termed "multiple meningiomas" (MM), reported to occur in only 1%-10% of patients, though recent data indicate higher incidence. MM constitute a distinct clinical entity, with unique etiologies including sporadic, familial and radiation-induced, and pose special management challenges. While the pathophysiology of MM is not established, theories include independent origin in disparate locations through unique genetic events, and the "monoclonal hypothesis" of a transformed neoplastic clone with subarachnoid seeding precipitating numerous distinct meningiomas. Patients with solitary meningiomas carry the risk of long-term neurological morbidity and mortality, as well as impaired health-related quality of life, despite being a generally benign and surgically curable tumor. For patients with MM, the situation is even less favorable. MM should be regarded as a chronic disease, and in many cases, the management goal is disease control, as cure is seldom possible. Multiple interventions and lifelong surveillance are sometimes necessary. We aim to review the MM literature and create a comprehensive overview, including an evidence-based management paradigm

Favorable clinical outcome following surgical evacuation of deep-seated and lobar supratentorial intracerebral hemorrhage : a retrospective single-center analysis of 123 cases

Background: In spontaneous supratentorial intracerebral hemorrhage (ICH), the role of surgical treatment remains controversial, particularly in deep-seated ICHs. We hypothesized that early mortality and long-term functional outcome differ between patients with surgically treated lobar and deep-seated ICH. Method: Patients who underwent craniotomy for ICH evacuation from 2009 to 2015 were retrospectively evaluated and categorized into two subgroups: lobar and deep-seated ICH. The modified Rankin Scale (mRS) was used to evaluate long-term functional outcome. Result: Of the 123 patients operated for ICH, 49.6% (n = 61) had lobar and 50.4% (n = 62) deep-seated ICH. At long-term follow-up (mean 4.2 years), 25 patients (20.3%) were dead, while 51.0% of survivors had a favorable outcome (mRS score ≤ 3). Overall mortality was 13.0% at 30 days and 17.9% at 6 months post-ictus, not influenced by ICH location. Mortality was higher in patients ≥ 65 years old (p = 0.020). The deep-seated group had higher incidence and extent of intraventricular extension, younger age (52.6 ± 9.0 years vs. 58.5 ± 9.8 years; p < 0.05), more frequently pupillary abnormalities, and longer neurocritical care stay (p < 0.05). The proportion of patients with good outcome was 48.0% in deep-seated vs. 54.1% in lobar ICH (p = 0.552). In lobar ICH, independent predictors of long-term outcome were age, hemorrhage volume, preoperative level of consciousness, and pupillary reaction. In deep-seated ICHs, only high age correlated significantly with poor outcome. Conclusions: At long-term follow-up, most ICH survivors had a favorable clinical outcome. Neither mortality nor long-term functional outcome differed between patients operated for lobar or deep-seated ICH. A combination of surgery and neurocritical care can result in favorable clinical outcome, regardless of ICH location

Long-Term Functional Outcome and Quality of Life After Surgical Evacuation of Spontaneous Supratentorial Intracerebral Hemorrhage : Results from a Swedish Nationwide Cohort

Objective: To investigate long-term survival, neurologic outcome, and quality of life in patients with spontaneous supratentorial intracerebral hemorrhage (ICH) treated with craniotomy and hematoma evacuation. Methods: A nationwide multicenter retrospective analysis of 341 patients who underwent craniotomy and evacuation of supratentorial ICH between January 1, 2011, and December 31, 2015, was performed. Baseline characteristics associated with 6-month mortality and long-term mortality were investigated. Survivors received a questionnaire about their state of health from which EuroQol 5D (EQ-5D) and modified Rankin scale (mRS) were obtained. Predictors of mortality, unfavorable outcome, and life quality were analyzed. Results: The mean follow-up time was 55.2 months. Predictors of 6-month mortality in multiple regression analysis were age ≥75 years, previous myocardial infarction, lower level of consciousness, and mechanical ventilation. Predictors of long-term mortality were higher age and mechanical ventilation. At follow-up, 49.5% of survivors had a favorable neurologic outcome (mRS ≤3). Predictors of an unfavorable functional outcome were higher age and ICH volume ≥50 mL. The mean EQ-5D health index was 0.719, and the mean EQ-5D visual analog scale score was 53.9. In multiple regression, only a higher mRS score was significantly associated with worse life quality. Conclusions: Knowledge about survival, functional outcome, and life quality as well as their predictors in this specific patient group is previously primarily described in short-term follow-up. This multicenter study provides novel information in the long-term perspective, which is important for improved surgical decision-making and prognostication

Differences in neurosurgical treatment of intracerebral haemorrhage : a nation-wide observational study of 578 consecutive patients

Background: Supratentorial intracerebral haemorrhage (ICH) carries an excessive mortality and morbidity. Although surgical ICH treatment can be life-saving, the indications for surgery in larger cohorts of ICH patients are controversial and not well defined. We hypothesised that surgical indications vary substantially among neurosurgical centres in Sweden. Objective: In this nation-wide retrospective observational study, differences in treatment strategies among all neurosurgical departments in Sweden were evaluated. Methods: Patient records, neuroimaging and clinical outcome focused on 30-day mortality were collected on each operated ICH patient treated at any of the six neurosurgical centres in Sweden from 1 January 2011 to 31 December 2015. Results: In total, 578 consecutive surgically treated ICH patients were evaluated. There was a similar incidence of surgical treatment among different neurosurgical catchment areas. Patient selection for surgery was similar among the centres in terms of patient age, pre-operative level of consciousness and co-morbidities, but differed in ICH volume, proportion of deep-seated vs. lobar ICH and pre-operative signs of herniation (p &lt; .05). Post-operative patient management strategies, including the use of ICP-monitoring, CSF-drainage and mechanical ventilation, varied among centres (p &lt; .05). The 30-day mortality ranged between 10 and 28%. Conclusions: Although indications for surgical treatment of ICH in the six Swedish neurosurgical centres were homogenous with regard to age and pre-operative level of consciousness, important differences in ICH volume, proportion of deep-seated haemorrhages and pre-operative signs of herniation were observed, and there was a substantial variability in post-operative management. The present results reflect the need for refined evidence-based guidelines for surgical management of ICH

A grading scale for surgically treated patients with spontaneous supratentorial intracerebral hemorrhage : The Surgical Swedish ICH Score

OBJECTIVE The authors aimed to develop the first clinical grading scale for patients with surgically treated spontaneous supratentorial intracerebral hemorrhage (ICH). METHODS A nationwide multicenter study including 401 ICH patients surgically treated by craniotomy and evacuation of a spontaneous supratentorial ICH was conducted between January 1, 2011, and December 31, 2015. All neurosurgical centers in Sweden were included. All medical records and neuroimaging studies were retrospectively reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the Surgical Swedish ICH [SwICH] Score) was developed using weighting of independent predictors based on strength of association. RESULTS Factors independently associated with 30-day mortality were Glasgow Coma Scale (GCS) score (p = 0.00015), ICH volume ≥ 50 mL (p = 0.031), patient age ≥ 75 years (p = 0.0056), prior myocardial infarction (MI) (p = 0.00081), and type 2 diabetes (p = 0.0093). The Surgical SwICH Score was the sum of individual points assigned as follows: GCS score 15–13 (0 points), 12–5 (1 point), 4–3 (2 points); age ≥ 75 years (1 point); ICH volume ≥ 50 mL (1 point); type 2 diabetes (1 point); prior MI (1 point). Each increase in the Surgical SwICH Score was associated with a progressively increased 30-day mortality (p = 0.0002). No patient with a Surgical SwICH Score of 0 died, whereas the 30-day mortality rates for patients with Surgical SwICH Scores of 1, 2, 3, and 4 were 5%, 12%, 31%, and 58%, respectively. CONCLUSIONS The Surgical SwICH Score is a predictor of 30-day mortality in patients treated surgically for spontaneous supratentorial ICH. External validation is needed to assess the predictive value as well as the generalizability of the Surgical SwICH Score