Clinicopathologic and MRI features of combined hepatocellular-cholangiocarcinoma in patients with or without cirrhosis.

BACKGROUND AND AIMS: Differences in combined hepatocellular-cholangiocarcinomas (cHCC-CCAs) arising in high-risk patients with or without liver cirrhosis have not been elucidated. This study aimed to compare the clinicopathologic and imaging characteristics of cHCC-CCAs in patients with or without cirrhosis and to determine the prognostic factors for recurrence-free survival (RFS) after curative resections of single cHCC-CCAs. METHODS: This retrospective study included 113 patients with surgically resected single cHCC-CCAs who underwent preoperative magnetic resonance imaging from January 2008 to December 2019 at two tertiary referral centres. Clinical, pathologic and imaging features of tumours were compared in high-risk patients with or without cirrhosis. Imaging features were assessed using the Liver Imaging Reporting and Data System (LI-RADS) version 2018. RFS and associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis and log-rank test. RESULTS: cHCC-CCAs arising from cirrhotic livers had a smaller mean tumour size (2.9 cm vs. 4.5 cm; P < .001) and were more frequently categorized as LR-5 or 4 (41.2% vs. 20.0%; P = .024) than those arising from non-cirrhotic livers. In multivariable analysis, a tumour size of > 3 cm (hazard ratio [HR], 2.081; 95% confidence interval [CI], 1.180-3.668; P = .011) and the LR-M category (HR, 2.302; 95% CI, 1.198-4.424; P = .012) were independent predictors associated with worse RFS. CONCLUSIONS: The tumour size and distribution of LI-RADS categories of cHCC-CCAs differed in high-risk patients with or without cirrhosis. And LR-M category was a worse prognosis predictor after curative resections than LR-5 or 4 category.

SH3YL1 protein as a novel biomarker for diabetic nephropathy in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy. METHODS AND RESULTS: In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis. CONCLUSION: These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy.

SECONDARY WALL ASSOCIATED MYB1 is a positive regulator of secondary cell wall thickening in Brachypodium distachyon and is not found in the Brassicaceae.

Grass biomass is comprised chiefly of secondary walls that surround fiber and xylem cells. A regulatory network of interacting transcription factors in part regulates cell wall thickening. We identified Brachypodium distachyon SECONDARY WALL ASSOCIATED MYB1 (SWAM1) as a potential regulator of secondary cell wall biosynthesis based on gene expression, phylogeny, and transgenic plant phenotypes. SWAM1 interacts with cellulose and lignin gene promoters with preferential binding to AC-rich sequence motifs commonly found in the promoters of cell wall-related genes. SWAM1 overexpression (SWAM-OE) lines had greater above-ground biomass with only a slight change in flowering time while SWAM1 dominant repressor (SWAM1-DR) plants were severely dwarfed with a striking reduction in lignin of sclerenchyma fibers and stem epidermal cell length. Cellulose, hemicellulose, and lignin genes were significantly down-regulated in SWAM1-DR plants and up-regulated in SWAM1-OE plants. There was no reduction in bioconversion yield in SWAM1-OE lines; however, it was significantly increased for SWAM1-DR samples. Phylogenetic and syntenic analyses strongly suggest that the SWAM1 clade was present in the last common ancestor between eudicots and grasses, but is not in the Brassicaceae. Collectively, these data suggest that SWAM1 is a transcriptional activator of secondary cell wall thickening and biomass accumulation in B. distachyon.

Exploratory analysis of neuropsychological and neuroanatomical correlates of progressive mild cognitive impairment in Parkinson's disease.

BACKGROUND: Parkinson's disease with mild cognitive impairment (PD-MCI) is a heterogeneous entity in terms of cognitive profiles and conversion to dementia. However, the risk factors for ongoing cognitive decline in patients with PD-MCI are not clearly defined. METHODS: 51 patients with PD-MCI were prospectively followed-up for a minimum of 2 years. Subjects were classified as MCI converters (n=15) or MCI non-converters (n=36) based on whether they were subsequently diagnosed with PD dementia. We explored cognitive profiles and neuroanatomical characteristics of PD-MCI converters using voxel based morphometry (VBM) of grey matter (GM) density and region of interest based volumetric analysis of the substantia innominata (SI). RESULTS: PD-MCI converters showed more severe cognitive deficits in frontal executive functions, immediate verbal memory and visual recognition memory compared with PD-MCI non-converters. VBM analysis revealed that PD-MCI converters had significantly lower GM density in the left prefrontal areas, left insular cortex and bilateral caudate nucleus compared with that in PD-MCI non-converters. The mean normalised SI volume was significantly smaller in both PD-MCI converters (1.19±0.35, p<0.001) and PD-MCI non-converters (1.52±0.27, p<0.001) compared with that in controls (1.87±0.19). PD-MCI converters had a significantly smaller normalised SI volume than PD-MCI non-converters (p<0.001). CONCLUSIONS: Our data show that atrophy in the frontostriatal areas and cholinergic structures, as well as frontal lobe associated cognitive performance, may act as predictors of dementia in PD-MCI patients, suggesting distinctive patterns of cognitive profiles and a neuroanatomical basis for progressive PD-MCI.

Extramacular drainage of subretinal fluid during vitrectomy for macular hole retinal detachment in high myopia.

PURPOSE: To compare surgical outcomes between subretinal fluid drainage through the macular hole (MH) and through sites other than the MH during vitrectomy for MH retinal detachment in highly myopic eyes. METHODS: Retrospective analysis was performed on the medical records of 41 patients who underwent vitrectomy for MH retinal detachment in highly myopic eyes. Group M included eyes in which subretinal fluid was drained through MH. Group E included eyes in which subretinal fluid was drained through an extramacular break or retinotomy. Pre- and postoperative visual acuity, reattachment rate, and MH closure rate were investigated. RESULTS: Primary retinal reattachment was achieved in 13 of 21 eyes (62%) in Group M and in 19 of 20 eyes (95%) in Group E (P = 0.020). The MH was closed more frequently in Group E (15 eyes) than in Group M (7 eyes; P = 0.012). Ambulatory vision of 20/400 or better was achieved in 16 eyes in Group E and in 10 eyes in Group M (P = 0.033). CONCLUSION: Extramacular drainage of subretinal fluid resulted in better outcomes than the conventional procedure of drainage through the MH.

Mechanically induced localisation of SECONDARY WALL INTERACTING bZIP is associated with thigmomorphogenic and secondary cell wall gene expression.

Plant growth requires the integration of internal and external cues, perceived and transduced into a developmental programme of cell division, elongation and wall thickening. Mechanical forces contribute to this regulation, and thigmomorphogenesis typically includes reducing stem height, increasing stem diameter, and a canonical transcriptomic response. We present data on a bZIP transcription factor involved in this process in grasses. Brachypodium distachyon SECONDARY WALL INTERACTING bZIP (SWIZ) protein translocated into the nucleus following mechanostimulation. Classical touch-responsive genes were upregulated in B. distachyon roots following touch, including significant induction of the glycoside hydrolase 17 family, which may be unique to grass thigmomorphogenesis. SWIZ protein binding to an E-box variant in exons and introns was associated with immediate activation followed by repression of gene expression. SWIZ overexpression resulted in plants with reduced stem and root elongation. These data further define plant touch-responsive transcriptomics and physiology, offering insights into grass mechanotranduction dynamics.

A randomized trial of mesenchymal stem cells in multiple system atrophy.

OBJECTIVE: Neuroprotective or regenerative strategies are invaluable in multiple system atrophy (MSA) due to its rapid progression with fatal prognosis. We evaluated the efficacy of autologous mesenchymal stem cells (MSC) in patients with MSA-cerebellar type (MSA-C). METHODS: Thirty-three patients with probable MSA-C and baseline unified MSA rating scale (UMSARS) scores ranging from 30 to 50 were randomly assigned to receive MSC (4 × 10(7) /injection) via intra-arterial and intravenous routes or placebo. The primary outcome was change in the total UMSARS scores from baseline throughout a 360-day follow-up period between groups. Secondary outcomes were changes in the UMSARS part II scores, cerebral glucose metabolism, gray matter density, and cognitive performance over a 360-day period. RESULTS: The mixed model analysis of neurological deficits revealed a significant interaction effect between treatment group and time, suggesting that the MSC group had a smaller increase in total and part II UMSARS scores compared with the placebo group (p = 0.047 and p = 0.008, respectively). Cerebral glucose metabolism and gray matter density at 360 days relative to the baseline were more extensively decreased in the cerebellum and the cerebral cortical areas, along with greater deterioration of frontal cognition in the placebo group compared with the MSC group. We found no serious adverse effects that were directly related to MSC treatment. However, intra-arterial infusion resulted in small ischemic lesions on magnetic resonance imaging. INTERPRETATION: MSC therapy could delay the progression of neurological deficits in patients with MSA-C, suggesting the potential of MSC therapy as a treatment candidate of MSA.

Subcortical white matter hyperintensities within the cholinergic pathways of Parkinson's disease patients according to cognitive status.

BACKGROUND: White matter hyperintensities (WMH) in the cholinergic pathways show a stronger correlation with cognitive performance than general WMH in Alzheimer's disease. However, the role of WMH within the cholinergic pathways in cognitive dysfunction has not been investigated in Parkinson's disease (PD). METHOD: The severity of WMH within the cholinergic pathways of PD subgroups with intact cognition (PD-IC, n=44), mild cognitive impairment (PD-MCI, n=87) and dementia (PDD, n=40) were compared using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and the correlation between the CHIPS score and performance on individual tests of cognitive subdomains were analysed. RESULTS: The mean CHIPS score was significantly higher in patients with PDD compared with those with PD-IC (p=0.03) or PD-MCI (p=0.015). The CHIPS score in patients with PD was negatively correlated with general cognition assessed using the Mini-Mental State Examination (r=-0.28, p<0.001) and positively with the Unified Parkinson's Disease Rating Scale motor score (r=0.24, p=0.002). The CHIPS score showed a significant correlation with cognitive performance on individual cognitive subdomains and had the highest independent correlations with contrasting programme (ß=-0.33, p<0.001) and forward digit span (ß=-0.17, p=0.04). CONCLUSIONS: This study demonstrated that the burden of WMH within cholinergic pathways was significantly higher in patients with PDD relative to other groups, and that cholinergic WMH was significantly correlated with a decline in frontal executive function and attention.

Cilia in the nervous system: linking cilia function and neurodevelopmental disorders.

PURPOSE OF REVIEW: Ciliopathies are genetic disorders caused by defects of primary ciliary structure and/or function and are characterized by pleiotropic clinical features. The ciliopathies include several partially overlapping syndromes such as Joubert syndrome, Bardet-Biedl syndrome and Meckel-Gruber syndrome, all of which have pronounced neurodevelopmental features. Here we focus on potential roles of cilia in central nervous system function, to explore how impairments may cause brain malformation and neurodevelopmental disease. RECENT FINDINGS: Cilia have long been considered as 'sensory cellular antennae', responding as chemo-sensors, mechano-sensors and thermo-sensors, although their roles in development were not well understood until recently. The surprising finding that disparate syndromes are all due to defects of the primary cilia, along with the recent advances in genetics, has helped elucidate further roles of primary cilia beyond sensory functions. Several molecules that are associated with key signaling pathways have been discovered in primary cilia. These include sonic hedgehog, wingless, planar cell polarity and fibroblast growth factor, which are essential for many cellular processes. Additionally, mutations in 'ciliome' genes have largely shown developmental defects such as abnormal body axis and brain malformation, implying disrupted cilia-related signaling pathways. Accordingly, the emerging theme is that primary cilia may play roles as modulators of signal transduction to help shape cellular responses within the environmental context during both development and homeostasis. SUMMARY: The link between cilia and signal pathways has become a framework for understanding the pathogenesis of ciliopathies. Despite recent progress in ciliary biology, fundamental questions remain about how cilia regulate neuronal function in the central nervous system. Therefore, investigation of ciliary function in the nervous system may reveal cilia-modulating mechanisms in neurodevelopmental processes, as well as suggest new treatments for disease.

Uric acid as a potential disease modifier in patients with multiple system atrophy.

BACKGROUND: Recent studies have suggested that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of multiple system atrophy. METHODS: We evaluated the influence of serum uric acid levels on disease progression in 52 patients with multiple system atrophy using changes in the annualized Unified Multiple System Atrophy Rating Scale scores. RESULTS: The mean annualized Unified Multiple System Atrophy Rating Scale changes were significantly lower in patients with the highest uric acid quartile compared with those with the lowest quartile (8.4 ± 5.1 vs 20.2 ± 16.0, P = .038). Serum uric acid levels had a significant negative correlation with the annualized Unified Multiple System Atrophy Rating Scale changes (r = -0.40, P = .004). Multiple linear regression analysis showed that only serum uric acid concentration was significantly correlated with the annualized Unified Multiple System Atrophy Rating Scale changes (ß = -2.687, P = .011). CONCLUSIONS: These data suggest that serum uric acid may act as a potential disease modifier in multiple system atrophy.

The pattern of cortical atrophy in patients with Parkinson's disease according to cognitive status.

BACKGROUND: Cognitive dysfunction is common in Parkinson's disease (PD), and along with PD with dementia (PDD), the concept of mild cognitive impairment in PD (PD-MCI) has been introduced. METHODS: To identify structural candidates according to cognitive status in PD, we compared gray matter (GM) density across PD-intact cognition (PD-IC, n = 23), PD-MCI (n = 27), and PDD (n = 18) using voxel-based morphometry. RESULTS: The demographic data among PD subjects were similar, however, general cognition and disease duration were more severe in PD-MCI and PDD than in PD-IC. Compared with controls, GM density was significantly decreased in the left occipital area in PD-IC; the bilateral temporal, left prefrontal and insular, and right occipital areas in PD-MCI; and in widespread brain areas in PDD. Compared with PD-IC, patients with PD-MCI had significantly decreased GM density in the right middle frontal area, and those with PDD had decreased GM density in the right parietal, middle frontal, insular, and lentiform areas. GM density in patients with PDD was significantly decreased in the bilateral middle temporal, right inferior temporal, and left middle and superior prefrontal areas. PDD patients with shorter disease duration before dementia (<5 year) showed greater GM atrophy in the posterior cingulate area than did those with longer disease duration (≥5 year). CONCLUSIONS: These data suggest that cortical atrophy in PD exhibits a greater extent with increasing levels of cognitive impairment, and different anatomical substrates would correspond to each cognitive status.

A comparative analysis of cognitive profiles and white-matter alterations using voxel-based diffusion tensor imaging between patients with Parkinson's disease dementia and dementia with Lewy bodies.

BACKGROUND: Despite clinical and neuropsychological similarities between Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. METHODS: 19 patients with probable PDD and 18 patients with probable DLB who had a similar overall severity of dementia and demographic characteristics were examined by a standardised neuropsychological test and voxel-based analysis of fractional anisotropy (FA) using diffusion tensor imaging (DTI). RESULTS: The patients with DLB performed significantly worse in visual recognition memory, semantic fluency and ideomotor praxis than those with PDD (p<0.05). Compared with controls, the FA value in patients with PDD was significantly lower in bilateral frontal, left temporal and left parietal white matter. In patients with DLB, the pattern of FA reduction was similar to that of patients with PDD; however, white-matter abnormalities were more severe and extended into bilateral insular, bilateral posterior cingular and bilateral visual association regions. In a direct comparison between PDD and DLB, the FA value in patients with DLB was significantly decreased in bilateral posterior temporal, posterior cingular and bilateral visual association fibres extending into occipital areas. CONCLUSIONS: Despite global similarities in cognitive performance and white-matter pathology between DLB and PDD patients, those with DLB had more severely impaired frontal and temporal area-associated cognitive subsets, and more severe white-matter pathology in temporal and visual association fibres. These data suggest that differences in the underlying nature of PDD and DLB may exist with global similarities in their cognitive performance and white-matter pathology.

A comparison of gray and white matter density in patients with Parkinson's disease dementia and dementia with Lewy bodies using voxel-based morphometry.

Despite clinical and neuropsychological similarities between Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. We used voxel-based morphometry using a 3-T MRI scanner to compare gray and white matter densities in 20 patients with probable PDD and 18 patients with probable DLB, who had similar overall severity of dementia and similar demographic characteristics. The gray matter density was significantly decreased in the left occipital, parietal, and striatal areas in patients with DLB compared with patients with PDD. The white matter density was significantly decreased in bilateral occipital and left occipito-parietal areas in patients with DLB compared with those with PDD. The degree of white and gray matter atrophy was similar in patients with DLB; in contrast, there was markedly less atrophy in the white matter than in the gray matter in patients with PDD. On analyzing the change of WM density relative to that of GM density in patients with DLB compared to those with PDD, the area of WM atrophy in the occipital areas was more extensive than that of GM atrophy. Our data demonstrate that atrophy of both gray and white matter was more severe in patients with DLB and that white matter atrophy relative to gray matter atrophy was less severe in patients with PDD. These data may reflect a difference in the underlying nature of PDD and DLB.

A case-control study of multiple system atrophy in Korean patients.

A few case-control studies of multiple system atrophy (MSA) have been reported in Western populations. In this study, we included various epidemiological factors to evaluate whether the risk factors for MSA differed in Korean and Western populations. A total of 100 consecutive MSA patients and 104 controls at two referral hospitals participated. Information was obtained through face-to-face interviews using a structured questionnaire: history of living area, occupational history, food habits, alcohol and tobacco consumption, and use of drugs. Odds ratios and 95% confident intervals (OR [95% CI]) were computed using logistic regression. The multivariate logistic regression analysis revealed that use of antihypertensive medication (OR = 0.30 [0.12-0.78]) and vitamins (OR = 0.30 [0.14-0.64]) and consumption of meat and poultry (OR = 0.27 [0.13-0.56]) were associated with decreasing risk for MSA, whereas use of herbal medications (OR = 3.17 [1.28-7.84]) was associated with increasing risk for MSA. In univariate analysis adjusted for age, sex, education level, and recruitment center, use of aspirin (OR = 0.21 [0.07-0.61]) and coffee consumption (OR = 0.44 [0.23-0.84]) were significantly less frequent in MSA patients than in controls, whereas heavy smoking (≥40 pack-years) was significantly more prevalent in MSA patients than in controls (OR = 3.44 [1.05-11.23]). There was no difference in living area, participation in farming, or exposure to agrichemicals and solvents between groups. This study showed that MSA in Korea is characterized by risk factors that are both similar to and different from those affecting Western populations and that herbal medicines constitute a new MSA risk factor for the Korean population.

Factors contributing to the development of restless legs syndrome in patients with Parkinson disease.

Although restless legs syndrome (RLS) commonly accompanies Parkinson disease (PD), the mechanism of RLS development in PD is still unclear. We investigated the prevalence of RLS in Korean patients with PD, and the possible contributing factors to the development of RLS in those patients. Four hundred forty-seven consecutive patients with PD were interviewed and examined. Among them, 73 patients (16.3%) were diagnosed with RLS. PD patients with RLS had a longer duration of PD symptoms, more severe PD disability, a greater degree of cognitive decline, and a longer duration of antiparkinson therapy than those without RLS. Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD. The present results support a higher prevalence of RLS in patients with PD and suggest that long-term antiparkinson therapy, rather than PD itself, may contribute to the development of RLS.

Regulation of Cell-to-Cell Communication and Cell Wall Integrity by a Network of MAP Kinase Pathways and Transcription Factors in Neurospora crassa.

Maintenance of cell integrity and cell-to-cell communication are fundamental biological processes. Filamentous fungi, such as Neurospora crassa, depend on communication to locate compatible cells, coordinate cell fusion, and establish a robust hyphal network. Two MAP kinase (MAPK) pathways are essential for communication and cell fusion in N. crassa: the cell wall integrity/MAK-1 pathway and the MAK-2 (signal response) pathway. Previous studies have demonstrated several points of cross-talk between the MAK-1 and MAK-2 pathways, which is likely necessary for coordinating chemotropic growth toward an extracellular signal, and then mediating cell fusion. Canonical MAPK pathways begin with signal reception and end with a transcriptional response. Two transcription factors, ADV-1 and PP-1, are essential for communication and cell fusion. PP-1 is the conserved target of MAK-2, but it is unclear what targets ADV-1. We did RNA sequencing on Δadv-1, Δpp-1, and wild-type cells and found that ADV-1 and PP-1 have a shared regulon including many genes required for communication, cell fusion, growth, development, and stress response. We identified ADV-1 and PP-1 binding sites across the genome by adapting the in vitro method of DNA-affinity purification sequencing for N. crassa To elucidate the regulatory network, we misexpressed each transcription factor in each upstream MAPK deletion mutant. Misexpression of adv-1 was sufficient to fully suppress the phenotype of the Δpp-1 mutant and partially suppress the phenotype of the Δmak-1 mutant. Collectively, our data demonstrate that the MAK-1/ADV-1 and MAK-2/PP-1 pathways form a tight regulatory network that maintains cell integrity and mediates communication and cell fusion.

Premorbid exercise engagement and motor reserve in Parkinson's disease.

BACKGROUND: Life-long experiences of cognitive activity could enhance cognitive reserve, which may lead individuals to show less cognitive deficits in Alzheimer's disease, despite similar pathological changes. We performed this study to test whether premorbid physical activity may enhance motor reserve in Parkinson's disease (PD) (i.e., less motor deficits despite similar degrees of dopamine depletion). METHODS: We assessed engagement in premorbid leisure-time exercise among 102 drug naive PD patients who had been initially diagnosed at our hospital by dopamine transporter scanning. Patients were classified into tertile groups based on the frequency, duration, and intensity of the exercises in which they participated. RESULTS: Among patients with mild to moderate reductions in striatal dopaminergic activity (above the median dopaminergic activity), the exercise group of the highest tertile showed significantly lower motor scores (i.e., fewer motor deficits, 15.53 ± 6.25), despite similar degrees of dopamine reduction, compared to the combined group of the middle and the lowest tertiles (21.57 ± 8.34, p = 0.01). Nonetheless, the highest tertile group showed a more rapid decline in motor function related to reductions in striatal dopaminergic activity than the other two groups (p = 0.002 with the middle tertile group and p = 0.001 with the lowest tertile group). CONCLUSIONS: These results suggest that engagement in premorbid exercise acts as a proxy for an active reserve in the motor domain (i.e., motor reserve) in patients with PD.

Neuropsychiatric symptoms in Parkinson's disease dementia are associated with increased caregiver burden.

OBJECTIVE: Neuropsychiatric symptoms are common in Parkinson's disease dementia (PDD). Frequent and severe neuropsychiatric symptoms create high levels of distress for patients and caregivers, decreasing their quality of life. The aim of this study was to investigate neuropsychiatric symptoms that may contribute to increased caregiver burden in PDD patients. METHODS: Forty-eight PDD patients were assessed using the 12-item Neuropsychiatric Inventory (NPI) to determine the frequency and severity of mental and behavioral problems. The Burden Interview and Caregiver Burden Inventory were used to evaluate caregiver burden. RESULTS: All but one patient showed one or more neuropsychiatric symptoms. The three most frequent neuropsychiatric symptoms were apathy (70.8%) and anxiety (70.8%), followed by depression (68.7%). More severe neuropsychiatric symptoms were significantly correlated with increased caregiver burden. The domains of delusion, hallucination, agitation and aggression, anxiety, irritability and lability, and aberrant motor behavior were associated with caregiver stress. After controlling for age and other potential confounding variables, total NPI score was significantly associated with caregiver burden. CONCLUSIONS: The results of this study confirm that neuropsychiatric symptoms are frequent and severe in patients with PDD and are associated with increased caregiver distress. A detailed evaluation and management of neuropsychiatric symptoms in PDD patients appears necessary to improve patient quality of life and reduce caregiver burden.