Constantinos Kallis

Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important?

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinsons disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinsons disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinsons disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinsons disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.

The Microbleed Anatomical Rating Scale (MARS): Reliability of a tool to map brain microbleeds

Objective: Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI may be a useful biomarker for bleeding-prone small vessel diseases, with potential relevance for diagnosis, prognosis (especially for antithrombotic-related bleeding risk), and understanding mechanisms of symptoms, including cognitive impairment. To address these questions, it is necessary to reliably measure their presence and distribution in the brain. We designed and systematically validated the Microbleed Anatomical Rating Scale (MARS). We measured intrarater and interrater agreement for presence, number, and anatomical distribution of microbleeds using MARS across different MRI sequences and levels of observer experience. Methods: We studied a population of 301 unselected consecutive patients admitted to our stroke unit using 2 GRE T2*-weighted MRI sequences (echo time [TE] 40 and 26 ms). Two independent raters with different MRI rating expertise identified, counted, and anatomically categorized microbleeds. Results: At TE = 40 ms, agreement for microbleed presence in any brain location was good to very good (intrarater κ = 0.85 [95% confidence interval (CI) 0.77–0.93]; interrater κ = 0.68 [95% CI 0.58–0.78]). Good to very good agreement was reached for the presence of microbleeds in each anatomical region and in individual cerebral lobes. Intrarater and interrater reliability for the number of microbleeds was excellent (intraclass correlation coefficient [ICC] = 0.98 [95% CI 0.97–0.99] and ICC = 0.93 [0.91–0.94]). Very good interrater reliability was obtained at TE = 26 ms (κ = 0.87 [95% CI 0.61–1]) for definite microbleeds in any location. Conclusion: The Microbleed Anatomical Rating Scale has good intrarater and interrater reliability for the presence of definite microbleeds in all brain locations when applied to different MRI sequences and levels of observer experience.

The Relationship Between Childbearing and Transitions From Marriage and Cohabitation in Britain

In this article, we describe a general framework for the analysis of correlated event histories, with an application to a study of partnership transitions and fertility among a cohort of British women. Using a multilevel, multistate competing-risks model, we examine the relationship between prior fertility outcomes (the presence and characteristics of children and current pregnancy) and the dissolution of marital and cohabiting unions and movements from cohabitation to marriage. Using a simultaneous-equations model, we model these partnership transitions jointly with fertility, allowing for correlation between the unobserved woman-level characteristics that affect each process. The analysis is based on the partnership and birth histories that were collected for the 1958 birth cohort (National Child Development Study) aged 16–42. The findings indicate that preschool children have a stabilizing effect on their parents’ partnership, whether married or cohabiting, but the effect is weaker for older children. There is also evidence that although pregnancy precipitates marriage among cohabitors, the odds of marriage decline to prepregnancy levels following a birth.

Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: A case-control study

Purpose:  To determine whether abnormal cardiac repolarization and other electrocardiography (ECG) predictors for cardiac mortality occur in epilepsy patients and whether they are associated with an increased risk for sudden unexpected death in epilepsy (SUDEP).

A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials.

Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.

Brain stem pathology in Parkinson's disease: An evaluation of the Braak staging model

The lower brain stem of 25 pathologically‐confirmed Parkinsons disease (PD) cases was examined by alpha synuclein immunohistochemistry to characterize pathological accumulation of alpha synuclein (Lewy‐type α‐synucleinopathy, LTS) in the medulla oblongata, to examine differences between affected regions and test a proposed model of staging of pathology in PD. All cases had LTS in the medulla, including the dorsal motor nucleus of the vagus (dmX), when present. The distribution followed a consistent pattern and appeared to be concentrated in a tyrosine hydroxylase (TH) immunoreactive region, probably representing the dorsal IX/X nuclear complex and the intermediate reticular zone. LTS density was greatest in the dmX. A similar distribution pattern to PD was seen in 14 incidental Lewy body disease (ILBD) cases, five derived from the Queen Square Brain Bank tissue collection and nine identified in separate series of 60 neurologically‐normal individuals, and in three cases with the G2019S mutation of LRRK2. Semiquantitative assessment showed that severity of pathology in the dmX was not correlated with the severity of cortical pathology. Semiquantitative assay of TH and ChAT peptide expression in the medulla showed that TH expression in PD and ILBD did not differ from controls. These findings broadly support the Braak hypothesis of caudo‐rostral development but indicate that the extent of the disease in the cortex and the severity of pathology in the medulla were independent of one another.

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinsons disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohens kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The “hummingbird” and “morning glory” signs were highly specific for PSP, and “the middle cerebellar peduncle sign” and “hot cross bun” for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.

Brain microbleeds as a potential risk factor for antiplatelet-related intracerebral haemorrhage: hospital-based, case–control study

Background Intracerebral haemorrhage (ICH) is an uncommon but devastating complication of regular antiplatelet use: identifying high-risk patients before treatment could potentially reduce this hazard. Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI are considered a biomarker for bleeding-prone small-vessel diseases. The authors hypothesised that microbleeds are a risk factor for antiplatelet-related ICH, and investigated this in a hospital-based matched case–control study. Methods Cases of spontaneous ICH were ascertained, using overlapping methods, from a prospective database of 1017 consecutive unselected patients referred to our stroke unit and associated clinics. For each case of antiplatelet-related ICH, two controls matched for age, sex and hypertension without history of ICH on antiplatelet therapy were selected. Microbleeds were identified by a trained observer blinded to clinical details. Results Microbleeds were more frequent in antiplatelet users with ICH than in matched antiplatelet users without ICH (13/16 (81%) vs 6/32 (19%), p=0.004) and patients with non-antiplatelet-related ICH (13/16 (81%) vs 15/33 (45%), p=0.03). The frequency of lobar microbleeds was 11/16 (69%) in antiplatelet-related ICH versus 11/33 (33%) in non antiplatelet-related ICH (p=0.032). Microbleeds were more numerous in antiplatelet users with ICH compared with controls (p=0.016). The number of microbleeds was associated with the risk of antiplatelet-related ICH (adjusted OR 1.33 per additional microbleed, 95% CI 1.06 to 1.66, p=0.013). Conclusions Brain microbleeds are associated with antiplatelet-related ICH. In patients with a large number of lobar microbleeds, the risk of ICH could outweigh the benefits of antiplatelet therapy. Larger prospective studies to investigate the prognostic significance of microbleeds in regular antiplatelet users are warranted.

Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study.

Osteosarcoma is the most common malignant bone tumor in children and young people. Efficacy of multiagent MAP (methotrexate, doxorubicin [Adriamycin], cisplatin) chemotherapy may be influenced by multiple cellular pathways. This pilot study aimed to investigate the association of 36 candidate genetic polymorphisms in MAP pathway genes with histological response, survival, and grade 3‐4 chemotherapy toxicity in osteosarcoma.

The midbrain to pons ratio A simple and specific MRI sign of progressive supranuclear palsy

Objectives: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP. Methods: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21). Results: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm. Conclusions: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.