A Deep Reinforcement Learning Approach to Droplet Routing for Erroneous Digital Microfluidic Biochips.

Digital microfluidic biochips (DMFBs), which are used in various fields like DNA analysis, clinical diagnosis, and PCR testing, have made biochemical experiments more compact, efficient, and user-friendly than the previous methods. However, their reliability is often compromised by their inability to adapt to all kinds of errors. Errors in biochips can be categorized into two types: known errors, and unknown errors. Known errors are detectable before the start of the routing process using sensors or cameras. Unknown errors, in contrast, only become apparent during the routing process and remain undetected by sensors or cameras, which can unexpectedly stop the routing process and diminish the reliability of biochips. This paper introduces a deep reinforcement learning-based routing algorithm, designed to manage not only known errors but also unknown errors. Our experiments demonstrated that our algorithm outperformed the previous ones in terms of the success rate of the routing, in the scenarios including both known errors and unknown errors. Additionally, our algorithm contributed to detecting unknown errors during the routing process, identifying the most efficient routing path with a high probability.

Optimizing the Deep Neural Networks by Layer-Wise Refined Pruning and the Acceleration on FPGA.

To accelerate the practical applications of artificial intelligence, this paper proposes a high efficient layer-wise refined pruning method for deep neural networks at the software level and accelerates the inference process at the hardware level on a field-programmable gate array (FPGA). The refined pruning operation is based on the channel-wise importance indexes of each layer and the layer-wise input sparsity of convolutional layers. The method utilizes the characteristics of the native networks without introducing any extra workloads to the training phase. In addition, the operation is easy to be extended to various state-of-the-art deep neural networks. The effectiveness of the method is verified on ResNet architecture and VGG networks in terms of dataset CIFAR10, CIFAR100, and ImageNet100. Experimental results show that in terms of ResNet50 on CIFAR10 and ResNet101 on CIFAR100, more than 85% of parameters and Floating-Point Operations are pruned with only 0.35% and 0.40% accuracy loss, respectively. As for the VGG network, 87.05% of parameters and 75.78% of Floating-Point Operations are pruned with only 0.74% accuracy loss for VGG13BN on CIFAR10. Furthermore, we accelerate the networks at the hardware level on the FPGA platform by utilizing the tool Vitis AI. For two threads mode in FPGA, the throughput/fps of the pruned VGG13BN and ResNet101 achieves 151.99 fps and 124.31 fps, respectively, and the pruned networks achieve about 4.3× and 1.8× speed up for VGG13BN and ResNet101, respectively, compared with the original networks on FPGA.

Minimization of MEDA Biochip-Size in Droplet Routing.

With the increasing demand for fast, accurate, and reliable biological sensor systems, miniaturized systems have been aimed at droplet-based sensor systems and have been promising. A micro-electrode dot array (MEDA) biochip, which is one kind of the miniaturized systems for biochemical protocols such as dispensing, dilutions, mixing, and so on, has become widespread due to enabling dynamical control of the droplets in microfluidic manipulations. In MEDA biochips, the electrowetting-on-dielectric (EWOD) technique stands out since it can actuate droplets with nano/picoliter volumes. Microelectrode cells on MEDA actuate multiple droplets simultaneously to route locations for the purpose of the biochemical operations. Taking advantage of the feature, droplets are often routed in parallel to achieve high-throughput outcomes. Regarding parallel manipulation of multiple droplets, however, the droplets are known to be initially placed at a distant position to avoid undesirable mixing. The droplets thus result in traveling a long way for a manipulation, and the required biochip size for routing is also enlarged. This paper proposes a routing method for droplets to reduce the biochip size on a MEDA biochip with the allowance of splitting during routing operations. We mathematically derive the routing problem, and the experiments demonstrate that our proposal can significantly reduce the biochip size by 70.8% on average, compared to the state-of-the-art method.

Pix2Pix-Based Monocular Depth Estimation for Drones with Optical Flow on AirSim.

In this work, we propose a method for estimating depth for an image of a monocular camera in order to avoid a collision for the autonomous flight of a drone. The highest flight speed of a drone is generally approximate 22.2 m/s, and long-distant depth information is crucial for autonomous flights since if the long-distance information is not available, the drone flying at high speeds is prone to collisions. However, long-range, measurable depth cameras are too heavy to be equipped on a drone. This work applies Pix2Pix, which is a kind of Conditional Generative Adversarial Nets (CGAN). Pix2Pix generates depth images from a monocular camera. Additionally, this work applies optical flow to enhance the accuracy of depth estimation. In this work, we propose a highly accurate depth estimation method that effectively embeds an optical flow map into a monocular image. The models are trained with taking advantage of AirSim, which is one of the flight simulators. AirSim can take both monocular and depth images over a hundred meter in the virtual environment, and our model generates a depth image that provides the long-distance information than images captured by a common depth camera. We evaluate accuracy and error of our proposed method using test images in AirSim. In addition, the proposed method is utilized for flight simulation to evaluate the effectiveness to collision avoidance. As a result, our proposed method is higher accuracy and lower error than a state of work. Moreover, our proposed method is lower collision than a state of work.

Paclobutrazol elevates auxin and abscisic acid, reduces gibberellins and zeatin and modulates their transporter genes in Marubakaido apple (Malus prunifolia Borkh. var. ringo Asami) rootstocks.

To examine the dwarfing mechanism in apples, one-year-old Marubakaido (Malus prunifolia Borkh.) (invigorating) apple rootstock stools were foliar-sprayed with 860 mg L-1 of paclobutrazol (PBZ) as a single application or without. M.9 apple rootstock (dwarf) was used as a positive control. The phytohormones were estimated in the shoot bark and sub-apical shoot and gene expression in the apices of terminal shoots. Evident responses to PBZ were observed a fortnight after treatment, as the shoot and internode lengths were suppressed significantly. Endogenous indole-3-acetic acid increased in the PBZ treatment, and the polar auxin transporter genes MdPIN1 and MdLAX1 and the biosynthesis gene MdYUCCA10a were upregulated along with the MdARF2 gene. Additionally, PBZ increased the abscisic acid (ABA) concentration and the biosynthesis-related gene MdNCED1 but repressed the degradation gene MdCYP707A1. The ABA transporter gene MdAITb-like was upregulated by PBZ. The concentrations of the gibberellins (GAs) GA1 and GA4 decreased in the PBZ-treated rootstocks. The GA transporter gene MdNFP3.1-like and the signaling gene MdGID1b-like were strongly downregulated by PBZ, whereas the catabolic gene MdGA2OX2 was upregulated. PBZ treatment significantly reduced trans-zeatin (tZ) levels and downregulated the cytokinin biosynthesis gene MdIPT6 but upregulated the MdCKX7 degradation gene. Additionally, PBZ upregulated the cytokinin-related transporter genes MdPUP7-like and MdPUP9-like. Collectively, our results show that the physiological and molecular effect of PBZ was observed within two weeks, and this was indicated by the modulation of phytohormonal levels as well as transporter and other gene expression in Marubakaido apple rootstocks.

[Impact of C9orf72 on Japanese Patients with Amytrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD)].

In 2011, C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) in intron 1 was reported as the most common cause of sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population. In the Japanese population, the C9orf72 repeat expansion was found to account for 0.2% cases of sporadic ALS and 2.6% of familial ALS. Notably, among individuals in the Kii peninsula which has recorded high incidence of ALS or ALS/PDC (parkinsonism-dementia complex), the frequency of C9orf72 repeat expansion was 20% (3/15) indicating high prevalence. It is important to obtain detailed family history of ALS and FTD to understand the cause of the diseases including the C9orf72 mutation.

Robust Self-Adaptation Fall-Detection System Based on Camera Height.

Vision-based fall-detection methods have been previously studied but many have limitations in terms of practicality. Due to differences in rooms, users do not set the camera or sensors at the same height. However, few studies have taken this into consideration. Moreover, some fall-detection methods are lacking in terms of practicality because only standing, sitting and falling are taken into account. Hence, this study constructs a data set consisting of various daily activities and fall events and studies the effect of camera/sensor height on fall-detection accuracy. Each activity in the data set is carried out by eight participants in eight directions and taken with the depth camera at five different heights. Many related studies heavily depended on human segmentation by using Kinect SDK but this is not reliable enough. To address this issue, this study proposes Enhanced Tracking and Denoising Alex-Net (ETDA-Net) to improve tracking and denoising performance and classify fall and non-fall events. Experimental results indicate that fall-detection accuracy is affected by camera height, against which ETDA-Net is robust, outperforming traditional deep learning based fall-detection methods.

Establishing diagnostic criteria for Perry syndrome.

OBJECTIVE: To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. METHODS: Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome. RESULTS: Eighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%). CONCLUSIONS: Based on our findings, we propose the following definitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed 'Perry disease.'

Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism.

A recessive mutation in PLA2G6, which is known to cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration associated with brain iron accumulation (NBIA), has recently been shown to be responsible for PARK14-linked dystonia-parkinsonism. To study the frequency of PLA2G6 mutations, including those caused by gene rearrangement in patients with parkinsonism, we performed direct sequencing and investigated copy number variations (CNVs) of this gene in 109 Japanese patients with parkinsonism. Direct sequencing revealed a homozygous mutation (c.1495G>A; p.A499T), which is likely to be pathogenic and is already registered as rs141045127, and two compound-heterozygous mutations we have previously reported. No CNVs in PLA2G6 were detected in our subjects. Our results suggest that CNV in PLA2G6 is rare in parkinsonism, at least in the Japanese population, in contrast to the reports of its frequency in INAD. Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism.

Evaluation of the survival of bone marrow-derived mononuclear cells and the growth factors produced upon intramedullary transplantation in rat models of acute spinal cord injury.

Intramedullary bone marrow-derived mononuclear cell (BM-MNC) transplantation has demonstrated neuroprotective effects in the chronic stage of spinal cord injury (SCI). However, no previous study has evaluated its effects in the acute stage, even though cell death occurs mainly within 1week after injury in all neuronal cells. Moreover, the mechanism underlying these effects remains unclear. We aimed to investigate the survival of intramedullary transplanted allogeneic BM-MNCs and the production of growth factors after transplantation to clarify the therapeutic potential of intramedullary transplanted BM-MNCs and their protective effects in acute SCI. Sprague-Dawley rats were subjected to traumatic SCI and received intramedullary transplantation of EGFP(+)BM-MNCs (n=6), BM-MNCs (n=10), or solvent (n=10) immediately after injury. To evaluate the transplanted BM-MNCs and their therapeutic effects, immunohistochemical evaluations were performed at 3 and 7days post-injury (DPI). BM-MNCs were observed at the injected site at both 3 (683±83 cells/mm(2)) and 7 DPI (395±64 cells/mm(2)). The expression of hepatocyte growth factor was observed in approximately 20% transplanted BM-MNCs. Some BM-MNCs also expressed monocyte chemotactic protein-1 or vascular endothelial growth factor. The demyelinated area and number of cleaved caspase-3-positive cells were significantly smaller in the BM-MNC-transplanted group at 3 DPI. Hindlimb locomotor function was significantly improved in the BM-MNC-transplanted group at 7 DPI. These results suggest that intramedullary transplantation of BM-MNCs is an efficient method for introducing a large number of growth factor-producing cells that can induce neuroprotective effects in the acute stage of SCI.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout.

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease.

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.

BACKGROUND: Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes. METHODS: We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. FINDINGS: We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48-4·24; p=0·0004) and 4·69 (1·59-13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96-1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. INTERPRETATION: CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease. FUNDING: Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients.

Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

Abscisic acid metabolism and anthocyanin synthesis in grape skin are affected by light emitting diode (LED) irradiation at night.

The effects of blue and red light irradiation at night on abscisic acid (ABA) metabolism and anthocyanin synthesis were examined in grape berries. The expressions of VlMYBA1-2, VlMYBA2, UDP-glucose-flavonoid 3-O-glucosyltransferase (VvUFGT), 9-cis-epoxycarotenoid dioxygenase (VvNCED1), and ABA 8'-hydroxylase (VvCYP707A1) were also investigated. Endogenous ABA, its metabolite phaseic acid (PA), and the expressions of VvNCED1 and VvCYP707A1 were highest in red light-emitting diode (LED)-treated skin. In contrast, anthocyanin concentrations were highest in blue LED-treated skin, followed by red LED treatment. However, the expressions of VlMYBA1-2, VlMYBA2, and VvUFGT did not necessarily coincide with anthocyanin concentrations. The quality of coloring may depend on the amount of malvidin-based anthocyanin, which increased toward harvest in blue and red LED-treated skin, unlike in untreated controls. An increase in sugars was also observed in blue and red LED-treated skin. These results suggest that blue LED irradiation at night may be effective in increasing anthocyanin and sugar concentrations in grape berries. However, there is evidence that another factor may influence anthocyanin concentrations in grape berry skin significantly more than endogenous ABA: ABA concentrations were highest in red LED-treated skin, which had lower anthocyanin concentrations than blue LED-treated skin.

Evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease.

We evaluated the contributions of various polyglutamine (polyQ) disease genes to Parkinson's disease (PD). We compared the distributions of polyQ repeat lengths in 8 common genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1, and HTT) in 299 unrelated patients with autosomal dominant PD (ADPD) and 329 normal controls. We also analyzed the possibility of genetic interactions between ATXN1 and ATXN2, ATXN2 and ATXN3, and ATXN2 and CACNA1A. Intermediate-length polyQ expansions (>24 Qs) of ATXN2 were found in 7 ADPD patients and no controls (7/299 = 2.34% and 0/329 = 0%, respectively; p = 0.0053 < 0.05/8 after Bonferroni correction). These patients showed typical L-DOPA-responsive PD phenotypes. Conversely, no significant differences in polyQ repeat lengths were found between the ADPD patients and the controls for the other 7 genes. Our results may support the hypothesis that ATXN2 polyQ expansion is a specific predisposing factor for multiple neurodegenerative diseases.

A preliminary diffusional kurtosis imaging study of Parkinson disease: comparison with conventional diffusion tensor imaging.

INTRODUCTION: Diffusional kurtosis imaging (DKI) is a more sensitive technique than conventional diffusion tensor imaging (DTI) for assessing tissue microstructure. In particular, it quantifies the microstructural integrity of white matter, even in the presence of crossing fibers. The aim of this preliminary study was to compare how DKI and DTI show white matter alterations in Parkinson disease (PD). METHODS: DKI scans were obtained with a 3-T magnetic resonance imager from 12 patients with PD and 10 healthy controls matched by age and sex. Tract-based spatial statistics were used to compare the mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) maps of the PD patient group and the control group. In addition, a region-of-interest analysis was performed for the area of the posterior corona radiata and superior longitudinal fasciculus (SLF) fiber crossing. RESULTS: FA values in the frontal white matter were significantly lower in PD patients than in healthy controls. Reductions in MK occurred more extensively throughout the brain: in addition to frontal white matter, MK was lower in the parietal, occipital, and right temporal white matter. The MK value of the area of the posterior corona radiata and SLF fiber crossing was also lower in the PD group. CONCLUSION: DKI detects changes in the cerebral white matter of PD patients more sensitively than conventional DTI. In addition, DKI is useful for evaluating crossing fibers. By providing a sensitive index of brain pathology in PD, DKI may enable improved monitoring of disease progression.

Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease.

The glucocerebrosidase gene (GBA) is a known risk factor of Parkinson's disease (PD). We sequenced entire coding exons and exon/intron boundaries of GBA in 147 Japanese familial PD (FPD) patients from 144 families and 100 unrelated control subjects. Twenty-seven of 144 (18.8%) of index patients were heterozygous for known Gaucher disease mutations, suggesting that GBA heterozygous mutations are strongly associated with FPD (odds ratio = 22.9, 95% confidence interval = 3.1-171.2). The frequency was significantly higher in autosomal dominant PD (ADPD) compared with autosomal recessive PD. According to clinical assessments, PD patients with GBA mutations exhibited typical manifestations of PD or dementia with Lewy bodies (DLB), such as L-dopa responsive parkinsonism with psychiatric problems and/or cognitive decline. Interestingly, they also presented with reduced myocardial (123)I-metaiodobenzylguanidine uptake. Our findings suggest that heterozygous GBA mutations are strong risk factors in FPD, especially for autosomal dominant PD. Some patients with GBA heterozygous mutations develop clinical features of DLB. We speculate that GBA dysfunction may promote Lewy body formation, resulting in more severe PD or DLB phenotypes that are inherited in families.