Minna Oinas

Neuropathologic Findings of Dementia with Lewy Bodies (DLB) in a Population-based Vantaa 85+ Study

The consortium on dementia with Lewy bodies has established consensus guidelines for the neuropathologic diagnosis of dementia with Lewy bodies (DLB) including the likelihood that the neuropathologic findings associate with the clinical syndrome. Nevertheless, clinico-pathological correlations remain controversial. We applied the consensus guidelines for determining Lewy-related pathology (LRP) and evaluated the clinical presentation in the prospective, population-based Vantaa 85+ study consisting of individuals at least 85 years of age. LRP was seen in 36% of 304 subjects and categorized as follows: 3% brainstem-predominant, 14% limbic, 15% diffuse neocortical type (4% could not be categorized). The likelihood that the neuropathology predicts the DLB clinical syndrome was low in 6%, intermediate in 13%, and high in 13% of all 304 subjects. In the latter two groups, 77% were demented, 35% had at least one extrapyramidal symptom, and 15% had visual hallucinations. Surprisingly, DLB clinical features associated better with high neurofibrillary stage than with diffuse neocortical LRP. Moreover, the neurofibrillary stage, substantia nigra neuron loss, and grade of Lewy neurites in hippocampal CA2-3 region, each showed a significant association with the extent of LRP. In conclusion, the neuropathologic DLB in this very elderly population was common, but the clinical symptoms tended to associate better with severe neurofibrillary pathology than with extensive LRP.

α-Synuclein pathology in the spinal cord autonomic nuclei associates with α-synuclein pathology in the brain: a population-based Vantaa 85+ study

In most subjects with Parkinson’s disease and dementia with Lewy bodies, α-synuclein (αS) immunoreactive pathology is found not only in the brain but also in the autonomic nuclei of the spinal cord. However, neither has the temporal course of αS pathology in the spinal cord in relation to the brain progression been established, nor has the extent of αS pathology in the spinal cord been analyzed in population-based studies. Using immunohistochemistry, the frequency and distribution of αS pathology were assessed semiquantitatively in the brains and spinal cord nuclei of 304 subjects who were aged at least 85 in the population-based Vantaa 85+ study. αS pathology was common in the spinal cord; 102 (34%) subjects had classic αS pathology in the thoracic and/or sacral autonomic nuclei. Moreover, 134 (44%) subjects showed grain- or dot-like immunoreactivity in neuropil (mini-aggregates) without classic Lewy neurites or Lewy bodies (LBs). The latter type of αS accumulation is associated with age, but also the classic αS pathology was found more often in the oldest compared to the youngest age group. The severity of αS pathology in the spinal cord autonomic nuclei is significantly associated with the extent and severity of αS pathology in the brain. Of the subjects, 60% with moderate to severe thoracic αS pathology and up to 89% with moderate to severe sacral αS pathology had diffuse neocortical type of LB pathology in the brain. αS pathology exclusively in the spinal cord was rare. Our study indicates that in general αS pathology in the spinal cord autonomic nuclei is associated with similar pathology in the brain.

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

BACKGROUND Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinsons disease, and Alzheimers disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. METHODS In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. FINDINGS This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14-2·70; p=1·05 × 10-48), SNCA (rs7681440; OR 0·73, 0·66-0·81; p=6·39 × 10-10), an GBA (rs35749011; OR 2·55, 1·88-3·46; p=1·78 × 10-9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27-1·79; p=2·32 × 10-6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. INTERPRETATION Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. FUNDING The Alzheimers Society and the Lewy Body Society.

Population‐based analysis of pathological correlates of dementia in the oldest old

The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population.

Genome-wide association study of neocortical Lewy-related pathology.

Dementia with Lewy bodies is an α‐synucleinopathy characterized by neocortical Lewy‐related pathology (LRP). We carried out a genome‐wide association study (GWAS) on neocortical LRP in a population‐based sample of subjects aged 85 or over.

Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Familial idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimers disease and APOE ε4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH.

Intracranial Suppurative Complications of Sinusitis

Background: Intracranial complications of paranasal sinusitis have become rare due to widespread and early use of antibiotics. Potentially life-threatening intracranial complications of sinusitis include subdural empyema, epidural and intracerebral abscess, meningitis, and sinus thrombosis. Patients with intracranial complication of sinusitis can present without neurological signs, which may delay diagnosis and correct treatment. Aims: Our aim was to evaluate the diagnostics, treatment, and outcome of sinusitis-related intracranial infections at our tertiary referral hospital with a catchment area of 1.9 million people. Materials and Methods: We retrospectively collected data on all patients diagnosed and treated with an intracranial infection at the Helsinki University Hospital, Helsinki, Finland, during a 10-year period between 2003 and 2013. Results: Six patients were diagnosed to have a sinusitis-related intracranial infection. Four patients had an epidural abscess, one both an epidural abscess and a subdural empyema and one a subdural empyema. The most common presenting complaint was headache (100%) followed by fever (83%), vomiting (50%), nasal congestion (50%), forehead lump (34%), and neck stiffness (17%). All patients were managed surgically. Most (83%) patients recovered to premorbid state without neurological sequelae. One patient died intraoperatively. Conclusion: Patients with a sinusitis-related intracranial suppuration typically present with signs of raised intracranial pressure rather than signs of sinusitis. Most are likely to need neurosurgical intervention and evacuation of the abscess without delay.

Amygdala α-Synuclein Pathology in the Population-Based Vantaa 85+ Study

We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N = 304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. The amygdala-predominant category was a rare (4%) and heterogeneous group.

Superficial Temporal Artery: Distal Posterior Cerebral Artery Bypass through the Subtemporal Approach: Technical Note and Pilot Surgical Cases

BACKGROUND Posterior cerebral artery (PCA) aneurysms are rare and the majority are fusiform in shape. Proximal occlusion of PCA represents a treatment option for these lesions. However, this procedure carries a high risk of ischemic complications. OBJECTIVE To describe the technique of trapping a fusiform PCA aneurysm and revascularization of the distal PCA using a superficial temporal artery (STA) graft through the same microsurgical approach. METHODS From September 2012 to October 2014, we retrospectively identified 3 patients harboring a fusiform PCA aneurysm (P2 segment aneurysm) who underwent trapping of the aneurysm and reconstruction of the distal PCA through the same subtemporal approach. We analyzed immediate morbidity, surgical complications, and the patency of the bypass to determine the feasibility of this procedure. RESULTS All 3 patients underwent successful trapping of the fusiform PCA aneurysm and revascularization of the distal PCA. The origin of P3 segment or posterior temporal artery (PTA) served as recipient arteries. In all 3 cases, adequate blood flow was evident after performing the STA-P3/PTA bypass. None of the patients experienced a new permanent neurological deficit. At 1-year follow-up, the STA-PTA/PCA bypasses remained patent. CONCLUSION The STA-P3/PTA bypass through the subtemporal approach is a feasible option to maintain blood flow in cases of PCA fusiform aneurysms requiring trapping of the P2 segment.