Jaakko Rinne

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the worlds third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Assessment of β-Amyloid in a Frontal Cortical Brain Biopsy Specimen and by Positron Emission Tomography With Carbon 11–Labeled Pittsburgh Compound B

OBJECTIVE To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens. DESIGN Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens. SETTING Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus. INTERVENTIONS [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests. MAIN OUTCOME MEASURES Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET. RESULTS In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits. CONCLUSIONS Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings

Objective: To assess the relationship between Alzheimer disease (AD)–related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. Methods: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Aβ plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Aβ42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. Results: The patients with Aβ plaques in the cortical biopsy had lower (p = 0.009) CSF Aβ42 levels than those with no Aβ plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Aβ42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Aβ42 and highest tau and p-tau 181 levels in CSF. The Aβ42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Aβ was independently predicted by the APOE ϵ4 carrier status and age but not by CSF Aβ42 or tau levels. Conclusions: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aβ42 and high CSF tau and p-tau levels, respectively.

Wide-necked intracranial aneurysms: treatment with stent-assisted coil embolization during acute (<72 hours) subarachnoid hemorrhage--experience in 61 consecutive patients.

PURPOSE To evaluate the safety and efficacy of stent-assisted embolization of ruptured wide-necked intracranial aneurysms during acute subarachnoid hemorrhage (SAH). MATERIALS AND METHODS Institutional review board approval for this retrospective study was obtained; the need to obtain informed consent was waived. Results in 61 consecutive patients (20 men, 41 women; mean age, 55.1 years; range, 26-83 years) with acutely ruptured wide-necked intracranial aneurysms who were treated with stent-assisted coil embolization were evaluated. The mean length of angiographic follow-up was 12.1 months (range, 0-52 months). Statistical analysis was performed to determine whether the features of the patient and the ruptured aneurysm affected the primary angiographic result or the patients clinical outcome. Categoric and dichotomous variables were examined with the chi(2) test or the Fisher exact test; the Mann-Whitney U test and Kruskal-Wallis one-way analysis were used to compare continuous-scale data for non-normally distributed variables. RESULTS The technical success rate was 72% (44 of 61). The technique-related complication rate was 21% (13 of 61), and the 30-day mortality rate was 20% (12 of 61). There was only one case of rebleeding, and clinical outcome was good for the majority of the patients (69% [42 of 61] had Glasgow Outcome Scale scores of 4 or 5 at the end of the study period). CONCLUSION Stent-assisted coil embolization is a feasible method for the endovascular treatment of wide-necked intracranial aneurysms that are difficult to treat surgically or with balloon-assisted embolization during acute SAH. The risk of subsequent rerupture of the aneurysm seems to be reduced for aneurysms treated early compared with that for nonsecured aneurysms.

Multiple intracranial aneurysms in a defined population: prospective angiographic and clinical study.

Multiple intracranial aneurysms (MIA) have been detected in up to one-third of patients with cerebral aneurysms. Three main external factors influence these figures as follows: the quality of angiographies, the quantity of vessels studied, and referral policy. In a 1-year prospective study, we determined the incidence of MIA in a defined catchment area in East Finland by investigating all of the patients with intracranial aneurysms with panangiography. In 114 unselected patients, a total of 170 intracranial aneurysms were detected, and, of these, 39 (34%) harbored MIA. In contrast to most other reports, there was a male predominance in patients with MIA, and half of these men had hypertension. Intracavernous carotid and pericallosal aneurysms were more frequent in patients with MIA. The number of asymptomatic vertebrobasilar aneurysms was extremely low, and most of the nonruptured aneurysms were found in bilateral carotid angiograms. In spite of the active search, the proportion of vertebrobasilar aneurysms remained at 6%. Although our surgical policy was most active, one-third of the asymptomatic aneurysms remained untreated, mainly because of the poor condition of the patient.

Microneurosurgical management of anterior communicating artery aneurysms

BACKGROUND Anterior communicating artery complex is the most frequent site of intracranial aneurysms in most reported series. Anterior communicating artery aneurysms are the most complex aneurysms of the anterior circulation due to the angioarchitecture and flow dynamics of the ACoA region, frequent anatomical variations, deep interhemispheric location, and danger of severing the perforators with ensuing neurologic deficits. The authors review the practical microsurgical anatomy, importance of preoperative imaging in surgical planning, and microneurosurgical steps in dissection and clipping of ACoAAs. METHODS This review, and the whole series on intracranial aneurysms, are mainly based on the personal microneurosurgical experience of the senior author (JH) in 2 Finnish centers (Helsinki and Kuopio), which serve, without patient selection, the catchment area in Southern and Eastern Finland. RESULTS These 2 centers have treated more than 10000 patients with aneurysm since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 aneurysms, 1145 patients (38%) had altogether 1179 ACA aneurysms; of them, 898 patients harbored 921 (78%) ACoAAs. In this series, 715 patients (80%) presented with ruptured ACoAAs with the median diameter of 7 mm. Giant ACoAAs were present in 15 (2%), whereas only 3 (0.3%) were classified as fusiform. CONCLUSIONS Anterior communicating artery aneurysms present frequently with SAH at small size. Furthermore, unruptured ACoAAs may have increased risk of rupture regardless of size, also as an associated aneurysm, and require treatment. The aim in microneurosurgical management of an ACoAA is total occlusion of the aneurysm sac with preservation of flow in all branching and perforating arteries. This demanding task necessitates perfect surgical strategy based on review of the 3D angioarchitecture and abnormalities of the patients ACoA complex with its ACoAA and to orientate accordingly during the microsurgical dissection. The surgical trajectory should provide optimal visualization of the ACoA complex without massive brain retraction. Precise dissection in the 3D anatomy of the ACoA complex and perforators requires not only experience and skill but patience to work the dome and base under repeated protection of temporary clips and pilot clips. This is particularly important with the complex, large, and giant aneurysms.

Management outcome for multiple intracranial aneurysms.

The management outcome of 302 patients with multiple intracranial aneurysms (MIA) from a series of 1314 patients with cerebral aneurysms was assessed using the Glasgow Outcome Scale 1 year after diagnosis and/or treatment. The outcome was significantly poorer for patients with MIA than for those with single intracranial aneurysms (SIA). The difference in the frequencies of poor outcome (Glasgow Outcome Scale Grades 3-5) was most evident in patients with Hunt and Hess Grades 2 or 3 (MIA, 29%; SIA, 19%). The management mortality in all grades attributable to all causes was 24% in patients with MIA and 20% in those with SIA and 16 and 11%, respectively, after surgery. At the 1-year follow-up point, 66% of the patients with MIA were independent (SIA, 72%); after surgery, 74% (SIA, 81%); after subarachnoid hemorrhage, 65% (SIA, 71%); and after subarachnoid hemorrhage and surgery, 73% (SIA, 80%). Patients with aneurysms at the vertebrobasilar arteries fared badly; otherwise, the sites of the aneurysms and their different combinations had no effect on outcome, nor did the timing of surgery. In this study, again, only two-thirds of the detected aneurysms could be secured. The aneurysms left without treatment were mostly in patients with very poor grade (n, 55) and/or old (n, 23) patients or were intracavernous (n, 26). The results seemed to be more unsatisfactory as the number of aneurysms increased. In multivariate analysis, delayed neurological deficit had the most significant independent contribution to outcome in patients with MIA, far more than in patients with SIA. This can be explained by the increased manipulation of cerebral arteries during multiple aneurysm surgery.

Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease

Amyloid‐β(Aβ) aggregates are presumed to be found in the brain at an early stage of Alzheimers disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients.

De novo aneurysms: special multiple intracranial aneurysms.

Very few patients develop completely new intracranial aneurysms during long-term follow-up after successfully treated subarachnoid hemorrhages. Aneurysms appearing after therapeutic ligation of proximal major vessels or failed surgery and the growth of previously noticed infundibular widenings or small aneurysms must be excluded to find true de novo aneurysms. Twenty-nine true cases of de novo aneurysms were reported in the literature, and 13 additional cases of our own are described. The incidence of de novo aneurysm formation and rupture is 63 per 100,000 per year in patients known to have a subarachnoid hemorrhage. Young patients could benefit from long-term neuroradiological follow-up.

Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus

BACKGROUND Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities.