Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

CMOS-compatible, piezo-optomechanically tunable photonics for visible wavelengths and cryogenic temperatures.

We demonstrate a platform for phase and amplitude modulation in silicon nitride photonic integrated circuits via piezo-optomechanical coupling using tightly mechanically coupled aluminum nitride actuators. The platform, fabricated in a CMOS foundry, enables scalable active photonic integrated circuits for visible wavelengths, and the piezoelectric actuation functions without performance degradation down to cryogenic temperatures. As an example of the potential of the platform, we demonstrate a compact (∼40 µm diameter) silicon nitride ring resonator modulator operating at 780 nm with intrinsic quality factors in excess of 1.5 million, >10 dB change in extinction ratio with 2 V applied, a switching time less than 4 ns, and a switching energy of 0.5 pJ/bit. We characterize the exemplary device at room temperature and 7 K. At 7 K, the device obtains a resistance of approximately 20 teraohms, allowing it to operate with sub-picowatt electrical power dissipation. We further demonstrate a Mach-Zehnder modulator constructed in the same platform with piezoelectrically tunable phase shifting arms, with 750 ns switching time constant and 20 nW steady-state power dissipation at room temperature.

Microglia - mediated immunity partly contributes to the genetic association between Alzheimer's disease and hippocampal volume.

Genome-wide association studies (GWAS) suggest that Alzheimer's disease (AD) is partly explained by a burden of risk alleles (single nucleotide polymorphisms; SNPs) with relatively small effects. However, the mechanisms by which these loci cumulatively confer susceptibility remain largely unknown. Accumulating evidence suggests an association between increased AD risk allele burden (measured via a polygenic risk profile score; AD-RPS) with reduced hippocampal volume (HV) across a number of independent cohorts. These lines of research suggest that the reduced HV may be a causal mechanism of risk in the development of late-onset Alzheimer's disease (AD). However, as RPS assesses broad, cumulative genetic risk, little is known about the biological processes which may explain this observation. Here, we leverage GWAS data from i) 17,008 late onset AD cases & 37,154 controls and ii) hippocampal volume (N = 12,147; N = 9707) to explore putative pathways that may explain this association. We first demonstrate an association between whole genome AD-RPS and HV (PT < 0.5, Z = -2.07, P = 0.038), confirming previous associations. Second, we restrict our analysis to SNPs within AD genes within a microglia mediated immunity network (NGENES = 56). A microglia AD-RPS was further associated with HV (PT < 0.01; Z = -2.152, P = 0.031). Last, using a competitive, permutation based approach, we show that the common variation within this candidate gene-set is associated with HV, controlling for SNP set-size (P = 0.024). Together, the observations suggest that the relationship between AD and HV is partially explained by genes within an AD-linked microglia mediated immunity network.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

High-power spectral beam combining of linearly polarized Tm:fiber lasers.

To date, high-power scaling of Tm:fiber lasers has been accomplished by maximizing the power from a single fiber aperture. In this work, we investigate power scaling by spectral beam combination of three linearly polarized Tm:fiber MOPA lasers using dielectric mirrors with a steep transition from highly reflective to highly transmissive that enable a minimum wavelength separation of 6 nm between individual laser channels within the wavelength range from 2030 to 2050 nm. Maximum output power is 253 W with M(2)<2, ultimately limited by thermal lensing in the beam combining elements.

Association of fasting glucose with subclinical cerebrovascular disease in older adults without Type 2 diabetes.

AIMS: To examine how fasting glucose and glucose tolerance are related to magnetic resonance imaging-assessed indicators of subclinical cerebrovascular disease and brain atrophy and their variation according to age, sex and education. METHODS: Participants in the present study were 172 healthy, community-dwelling older adults. An oral glucose tolerance test was administered and magnetic resonance imaging performed. Fasting, 2-h, and 2-h area-under-the-curve glucose levels, their associations with subclinical cerebrovascular disease and brain atrophy, and their respective interactions with age, sex and education were examined. RESULTS: A positive association between fasting glucose and subclinical cerebrovascular disease (but not brain atrophy) emerged; this association was more pronounced for participants with < 12 years of education; however, glucose tolerance was not related to subclinical cerebrovascular disease or brain atrophy. CONCLUSIONS: Findings revealed a potential link between fasting glucose levels and the presence of subclinical cerebrovascular disease indicators - white matter hyperintensities and silent brain infarction - in older adults without diabetes and with an education level below high school. Additional research is needed to confirm these associations and to determine the need for interventions aimed at closely monitoring and preventing elevated glucose levels in this population to reduce the prevalence of subclinical cerebrovascular disease.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

1 µJ, sub-500 fs chirped pulse amplification in a Tm-doped fiber system.

We demonstrate a Tm-doped fiber laser system producing ~300 fs pulses with 1 µJ energy, corresponding to peak powers greater than 3 MW. Pulses of 150 fs with 30 nm spectral bandwidth and 3 nJ pulse energy are generated in a Raman-soliton self-frequency shift amplifier, then stretched to ~160 ps using a chirped Bragg grating. The 60 MHz oscillator repetition rate is reduced to 100 kHz using an electro-optic modulator. After a single-mode fiber preamplifier and a large-mode-area fiber power amplifier, pulses were compressed using a folded Treacy grating setup to below 500 fs with up to 1 µJ pulse energy. To the best of our knowledge, this is the highest energy yet demonstrated as well as the first demonstration of peak powers exceeding 1 MW from a Tm:fiber laser system.

Genome-wide association study of Alzheimer's disease with psychotic symptoms.

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

Comparison of higher-order mode suppression and Q-switched laser performance in thulium-doped large mode area and photonic crystal fibers.

We report the influence of higher order modes (HOMs) in large mode fibers operation in Q-switched oscillator configurations at ~2 µm wavelength. S(2) measurements confirm guiding of LP(11) and LP(02) fiber modes in a large mode area (LMA) step-index fiber, whereas a prototype photonic crystal fiber (PCF) provides nearly single-mode performance with a small portion of light in the LP(11) mode. The difference in HOM content leads to a significant difference in Q-switched oscillator performance. In the step-index fiber, the percentage of cladding light increases by 20% to >40% with increasing pulse energy to ~250 µJ. We accredit this degradation to saturation of the gain in the fundamental mode leading to more light generated in the HOMs, which is eventually converted into cladding light. No such degradation is seen in PCF laser system for >400 µJ energies.

Integrated Tm:fiber MOPA with polarized output and narrow linewidth with 100 W average power.

We report on a Tm:fiber master oscillator power amplifier (MOPA) system producing 109 W CW output power, with >15 dB polarization extinction ratio, sub-nm spectral linewidth, and M2 <1.25. The system consists of polarization maintaining (PM) fiber and PM-fiber components including tapered fiber bundle pump combiners, a single-mode to large mode area mode field adapter, and a fiber-coupled isolator. The laser components ultimately determine the system architecture and the limits of laser performance, particularly considering the immature and rapidly developing state of fiber components in the 2 µm wavelength regime.

Q-switched thulium-doped photonic crystal fiber laser.

We report a novel, Tm-doped photonic crystal fiber (PCF) actively Q-switched oscillator that provides ~8.9 kW peak power with 435 µJ, 49 ns pulses at 10 kHz repetition rate at 2 µm wavelength. This fiber has a mode-field area >1000 µm2, the largest of any flexible PCF providing diffraction-limited beam quality to the best of our knowledge. As an application, the oscillator is used as pump to generate >350 nm broadening in ~50 m of SMF-28 fiber.

Differential localization of GABA(A) receptor subunits in relation to rat striatopallidal and pallidopallidal synapses.

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. The GP is composed of a network of inhibitory GABA-containing projection neurons which receive GABAergic input from axons of the striatum (Str) and local collaterals of GP neurons. Here, using electrophysiological techniques and immunofluorescent labeling we have investigated the differential cellular distribution of α1, α2 and α3 GABA(A) receptor subunits in relation to striatopallidal (Str-GP) and pallidopallidal (GP-GP) synapses. Electrophysiological investigations showed that zolpidem (100 nm; selective for the α1 subunit) increased the amplitude and the decay time of both Str-GP and GP-GP IPSCs, indicating the presence of the α1 subunits at both synapses. However, the application of drugs selective for the α2, α3 and α5 subunits (zolpidem at 400 nm, L-838,417 and TP003) revealed differential effects on amplitude and decay time of IPSCs, suggesting the nonuniform distribution of non-α1 subunits. Immunofluorescence revealed widespread distribution of the α1 subunit at both soma and dendrites, while double- and triple-immunofluorescent labeling for parvalbumin, enkephalin, gephyrin and the γ2 subunit indicated strong immunoreactivity for GABA(A) α3 subunits in perisomatic synapses, a region mainly targeted by local axon collaterals. In contrast, immunoreactivity for synaptic GABA(A) α2 subunits was observed in dendritic compartments where striatal synapses are preferentially located. Due to the kinetic properties which each GABA(A) α subunit confers, this distribution is likely to contribute differentially to both physiological and pathological patterns of activity.

Lasing in thulium-doped polarizing photonic crystal fiber.

We describe lasing of a thulium-doped polarizing photonic crystal fiber. A 4 m long fiber with 50 µm diameter core, 250 µm diameter cladding, and d/Λ ratio of 0.18 was pumped with a 793 nm diode and produced a polarized output with a polarization extinction ratio (PER) of 15 dB and an M(2) of <1.15. An intracavity polarizer and half-wave plate minimally increased the PER to 16 dB. The output power had 35% slope efficiency relative to the absorbed pump power. The maximum cw output power was limited to 4 W due to the quantum defect heating of the fiber.

Spectral narrowing and stabilization of thulium fiber lasers using guided-mode resonance filters.

We used guided-mode resonance filters (GMRFs), fabricated using thin-film deposition and chemical etching, as intracavity feedback elements to stabilize and narrow the output spectrum in thulium-doped fiber oscillators operating in the 2 µm wavelength regime, producing linewidths of <700 pm up to 10 W power levels. A Tm fiber-based amplified spontaneous emission source was used to characterize the reflective properties of the GMRFs. Linewidths of 500 pm and a 7.3 dB reduction in transmission were measured on resonances.

DISC1 exon 11 rare variants found more commonly in schizoaffective spectrum cases than controls.

We previously performed a linkage study using families identified through probands meeting criteria for DSM-IV schizoaffective disorder, bipolar type (SABP) and observed a genome-wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM-IV SABP samples from the linkage study identified 2 non-synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P-value = 0.008, Fisher's exact trend test).

Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort.

BACKGROUND: Large randomized controlled trials have shown significant decreases in morbidity and mortality in leukaemia patients with posaconazole prophylaxis. However, the value of prophylaxis has been questioned in centres with a low incidence of invasive fungal diseases (IFDs) and pre-emptive treatment strategies. METHODS: We prospectively evaluated the epidemiology of IFDs in acute myelogenous leukaemia (AML) patients undergoing first remission-induction chemotherapy before and after posaconazole prophylaxis had been introduced as a standard of care. Patients admitted from January 2003 to December 2005 received topical polyenes as antifungal prophylaxis (first group), while those admitted between January 2006 and December 2008 received 200 mg of oral posaconazole three times daily (second group). Other diagnostic and therapeutic standard operating procedures remained unchanged. RESULTS: A total of 82 patients in the polyene prophylaxis group and 77 in the posaconazole prophylaxis group were included in the final analysis. Baseline characteristics were well matched between groups. Patients receiving topical polyene prophylaxis were more likely to experience breakthrough IFDs (19.5% and 3.9%; P = 0.003) or breakthrough aspergillosis (13.4% and 2.6%; P = 0.018) than patients receiving systemic posaconazole prophylaxis. They also had more febrile days (mean 10.7 +/- 9.66 and 7.3 +/- 5.73; P = 0.007), longer need for inpatient treatment (mean 53.0 +/- 24.16 and 46.0 +/- 14.39; P = 0.026) and a shorter fungal-free survival (78.7 and 90.4 days; P = 0.024). No significant differences were observed for persistent fever, pneumonia, lung infiltrates indicative of invasive pulmonary aspergillosis, or attributable and overall mortality. CONCLUSIONS: After introduction of posaconazole prophylaxis for patients with AML, the number of febrile days, the incidence rate of IFDs and aspergillosis and the duration of hospitalization decreased significantly.

The effect of core stability training on balance and mobility in ambulant individuals with multiple sclerosis: a multi-centre series of single case studies.

BACKGROUND: Core stability training is popular in the management of people with multiple sclerosis (MS); however, scientific evidence to support its effectiveness is scarce. OBJECTIVE: To explore the effectiveness of core stability training on balance and mobility. METHOD: A multi-centre series of eight single case studies was undertaken. Eight ambulant individuals with stable MS participated in 16 face-to-face core stability training sessions, delivered by a neurophysiotherapist, plus a daily home exercise programme. A range of outcomes were measured: 10-m timed walk, 12-item MS walking scale, timed get up and go, functional reach tests, timed single leg stance, visual analogue scales of two activities, and the Activities-specific Balance Confidence Scale. RESULTS: Visual analysis of trend, level and slope demonstrated improvement in five subjects (62%) in seven measures. This was confirmed by the two standard deviation band method of analysis for six measures. Analysis of group data (repeated measures within subjects analysis of variance) indicated significant improvement between baseline and intervention phases for timed walk (p = 0.019), MSWS-12 Scale (p = 0.041), forward (p = 0.015) and lateral reach (p = 0.012). In general, no further improvements were made following withdrawal of the intervention. CONCLUSIONS: This study provides preliminary evidence of the effectiveness of an 8-week core stability training programme in improving balance and mobility in ambulant people with MS. Variations in response to intervention are evident. Assessor-blinded randomized controlled studies are required to confirm these findings and determine patient characteristics which identify those who benefit most from this intervention.

High-power widely tunable thulium fiber lasers.

Applications requiring long-range atmospheric propagation are driving the development of high-power thulium fiber lasers. We report on the performance of two different laser configurations for high-power tunable thulium fiber lasers: one is a single oscillator utilizing a volume Bragg grating for wavelength stabilization; the other is a master oscillator power amplifier system with the oscillator stabilized and made tunable by a diffraction grating. Each configuration provides >150 W of average power, >50% slope efficiency, narrow output linewidth, and >100 nm tunability in the wavelength range around 2 µm.