In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TDP-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
Neuroserpin encephalopathy is an autosomal-dominant degenerative disease associated with mutations in the Proteinase Inhibitor 12 (PI12) gene. A 26-year-old male presented with progressive myoclonus epilepsy and declining mental status. He had failed in university studies because of impaired attention, memory and concentration. Generalized seizures started to occur approximately once a month, and he developed myoclonus and progressive gait disturbances. Neuroimaging revealed mild atrophy and multiple periventricular white matter lesions, consistent with demyelination. He progressively declined and died at age 34. Neuropathologic examination revealed widespread involvement of the cerebral cortex by numerous round eosinophilic inclusions in neuronal perikarya and neuropil, predominantly within the deep cortical layers. Numerous inclusions were also found in the basal ganglia, thalamus, hippocampus, brain stem, spinal gray matter, and dorsal root ganglia. They were essentially absent from the cerebellum. The inclusions were immunopositive for antibodies raised against neuroserpin. The white matter lesions showed histologic features compatible with multiple sclerosis. Genetic analysis revealed a nucleotide substitution in codon 47 in one allele of the PI12 gene, resulting in a proline for leucine amino acid substitution (L47P). In summary, we report a case of neuroserpin encephalopathy associated with a novel PI12 mutation and complicated by coexistent multiple sclerosis.
dementia; mutation; neurodegeneration; neuroserpin; progressive myoclonus epilepsy; seizures
Normative information is important for appropriate interpretation of cognitive test scores as a critical component of dementia diagnosis in the elderly population. A cross-sectional evaluation of 1826 participants aged 65 years and older from four rural counties in China was conducted using six cognitive instruments including tests of global cognitive function (the Community Screening Instrument for Dementia), Memory (Word List Learning and Recall tasks from the Consortium to Establish a Registry for Alzheimer’s Disease, IU Story), Language (Animal Fluency Test), and executive function (IU Token). Multiple regression models adjusting for demographic variables were used to provide standardized residuals z-scores and corresponding percentile ranking for each cognitive test. In all cognitive tests, older age was associated with worse test performance while exposure to education was related to better cognitive test performance. We also detected a significant gender difference with men scoring better than women and a significant gender by education interaction on two tests. The interaction indicates that gender difference in test scores was much smaller in participants with more education than those who had less or no education. These demographically adjusted, regression-based norms can be a useful tool to clinicians involved with differential diagnosis of cognitive and memory disorders in older adults in rural China.
Normative Study; Neuropsychological Test; Age; Gender; Education; Regression- Based Norms
Selenium is considered a protective agent against free radicals through the maintenance of better enzyme activity. The few studies examining the relationship between selenium and depression have yielded inconsistent results and none of these studies considered the role of cognitive function in this context.
A cross-sectional evaluation of 1737 rural Chinese age 65 and over from two provinces in China was conducted. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cognitive function was assessed using various cognitive instruments. Selenium measures were obtained from nail samples. Other information collected included demographic characteristics and medical history. Analysis of covariance models were used to identify factors associated with GDS score.
Higher selenium levels were associated with lower GDS scores adjusting for demographic and medical conditions (p = 0.0321). However, the association between selenium and depressive symptoms was no longer significant when cognitive function score was adjusted in the model (p = 0.2143).
Higher selenium level was associated with lower depressive symptoms without adjusting for cognition in this cohort. However, after cognition was adjusted in the model the association between selenium and depressive symptoms was no longer significant, suggesting that selenium’s association with depressive symptoms may be primarily through its association with cognitive function.
The literature on the association between apolipoprotein E (ApoE) and mortality across ethnic and age groups has been inconsistent. No studies have looked at this association in developing countries. We used data from the Indianapolis-Ibadan Dementia study to examine this association between APOE and mortality in 354 African-Americans from Indianapolis and 968 Yoruba from Ibadan, Nigeria. Participants were followed up to 9.5 years for Indianapolis and 8.7 years for Ibadan. Subjects from both sites were divided into 2 groups based upon age at baseline. A Cox proportional hazards regression model adjusting for age at baseline, education, hypertension, smoking history and gender in addition to time-dependent covariates of cancer, diabetes, heart disease, stroke, and dementia was fit for each cohort and age group. Having ApoE ε4 alleles significantly increased mortality risk in Indianapolis subjects under age 75 ( hazard ratio: 2.00; 95% CI: 1.19–3.35; p = 0.0089). No association was found in Indianapolis subjects 75 and older (hazard ratio: 0.71; 95% CI: 0.45–1.10; p = 0.1238), Ibadan subjects under 75 (hazard ratio: 1.04; 95% CI: 0.78 to 1.40; p = 0.7782), or Ibadan subjects over 75 (hazard ratio: 1.21; 95% CI: 0.83 to 1.75; p = 0.3274).
Apolipoprotein E; survival analysis; African-Americans
Alzheimer disease (AD) is the most frequent cause of dementia. Even though the incidence of AD in the African American population is similar to or higher than that in persons of European descent, AD in African Americans is understudied. Identification of genetic risk factors in African Americans is essential for understanding the etiology of AD.
To determine the effect of apolipoprotein E (APOE) genotype on the risk of AD in elderly African Americans.
Population-based longitudinal study of AD.
African Americans 65 years and older.
Main Outcome Measures
APOE genotype and diagnosis of AD.
The APOE genotype was determined in 1822 samples. Of these, 690 were clinically evaluated: 318 were normal, and 162 had a diagnosis of AD. The presence of APOE ε4 was significantly associated with increased risk of AD (ε3/ε4: OR, 2.32; 95% confidence interval [CI], 1.41–3.82; and ε4/ε4: OR, 7.19; 95% CI, 3.00–17.29, compared with the ε3/ε3 genotype). There was also a significant protective effect with APOE ε2 (ε2/ε2 and ε2/ε3: OR, 0.42; 95% CI, 0.20–0.89).
These findings are in marked contrast to the lack of association between APOE and AD in the Ibadan, Nigeria, sample of this project. These results suggest that other genetic factors and different environmental influences may play a role in the risk for AD in individuals of African ancestry.
The relationship between weight and dementia risk has not been investigated in populations with relatively low body mass index (BMI) such as the Yoruba. This study set out to achieve this objective using a prospective observational design.
The setting was Idikan Ward in Ibadan City, Nigeria. The participants were all aged 65 years or older and were enrolled in the Indianapolis-Ibadan Dementia Project. Repeated cognitive assessments and clinical evaluations were conducted to identify participants with dementia or MCI during 10 years of follow-up (mean duration: 5.97 years). BMI measures, information on alcohol, smoking history, cancer, hypertension, diabetes, heart attack, stroke and depression were collected at each follow-up evaluation. Mixed effect models adjusted for covariates were used to examine the differences in BMI among participants who developed dementia or MCI and those who remained cognitively normal during the follow-up.
This analysis included 1559 participants who had no dementia at their first BMI measurements. There were 136 subjects with incident dementia, 255 with MCI and 1168 with normal cognition by the end of the study. The mean BMI at baseline was higher for female participants (22.31; SD = 4.39) than for male (21.09; SD = 3.61, p < 0.001). A significantly greater decline in BMI was found in those with either incident dementia (p < 0.001) or incident MCI (p < 0.001) compared to normal subjects.
Decline in BMI is associated with incident MCI and dementia in elderly Yoruba. This observation calls for close monitoring of weight loss in elderly individuals which may indicate future cognitive impairment for timely detection and tailored interventions.
body mass index; dementia; mild cognitive impairment; normal cognition
Since 1992, research teams from Indiana University and the University of Ibadan have been collecting and comparing data from two diverse, elderly populations to identify risk factors for dementia and Alzheimer’s disease. Apolipoprotein E (APOE) was genotyped in 2,245 Nigerian samples. Of these, 830 had a diagnosis: 459 were normal, and 140 had dementia including 123 diagnosed with Alzheimer’s disease. In contrast with other populations, the APOE ε4 allele was not significantly associated with Alzheimer’s disease or dementia. This lack of association in the Yoruba might reflect genetic variation, environmental factors, as well as genetic/environmental interactions.
To examine the association between hypertension and cognitive decline in older adults.
Prospective observational study.
Four rural counties in China.
Two thousand rural Chinese aged 65 and older (median age 70, range 65–92) participated in a baseline evaluation. A follow-up evaluation of 1,737 subjects was conducted 2.5 years after baseline.
Cognitive function was assessed using the Community Screening Instrument for Dementia (CSID), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning and Recall Tests, Indiana University (IU) Story Recall Test, Animal Fluency Test, and IU Token Test. Hypertension was defined as the mean of two readings of systolic blood pressure (BP) of 140 mmHg or greater, diastolic BP of 90 mmHg or greater, or according to self-report. Cognitive decline was derived as the difference between baseline and follow-up scores. Analysis of covariance models were used to estimate the association between hypertension, BP, and cognitive decline, adjusting for other covariates.
Greater decline was found on the CERAD 10-Word List Learning (P<.001) and Recall (P =.01) scores for subjects with hypertension than for those without. In particular, significantly greater decline was seen in the group with hypertension that was not taking medication than in the group without hypertension. No significant difference on cognitive decline was found between subjects with hypertension who were taking medication and those without hypertention.
Untreated hypertension was associated with greater cognitive decline in this Chinese cohort. Better hypertension detection and treatment in elderly people, especially in developing countries, may offer protection against cognitive decline
cognitive aging; cardiovascular risk factor; elderly
Se is an essential trace element in human nutrition associated with antioxidant activity. Previous studies on predictors of toenail Se or serum Se have mostly concentrated on demographic factors such as age and gender. The present paper examines the association between apoE genotype and Se levels in nail samples in a rural elderly Chinese cohort.
Two thousand Chinese aged 65 years and over from four counties in China were enrolled in a cohort to study the association of Se with cognitive decline. Nail samples were collected from each participant and analysed for Se levels. Dietary Se intake was estimated from an FFQ using Se contents measured in food items collected from each village. Blood samples on filter cards were collected and analysed for apoE genotype. Mixed-effect models were constructed with nail Se level as the dependent variable and each village as the random effect, which controlled for the potential confounding effect from correlation in Se measures obtained from participants residing in the same village.
In this elderly Chinese cohort, carriers of the apoE ε4 allele had significantly lower Se levels measured in nail samples than non-carriers after adjusting for other significant covariates and controlling for estimated dietary Se intake. There was no significant difference between the two genotypes on estimated Se dietary intake (P=0·6451).
Future studies are needed to examine the mechanism underlying the association between the apoE ε4 allele and Se levels, including the role of oxidative stress and that of reduced lipid metabolism in the apoE ε4 carriers.
Selenium; Nail samples; Dietary intake; apoE ε4
Late life depression has been studied in many populations around the world. However, findings on risk factors for late life depression have remained inconsistent.
A cross-sectional survey of 1737 rural Chinese age 65 and over from two provinces in China was conducted assessing cognitive functions using various cognitive instruments and collecting information on demographic characteristics and medical history. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Analysis of covariance and logistic regression models were used to identify factors associated with the continuous GDS score, mild or severe depression.
In this cohort, 26.5% (95% CI: 24.4–28.6%) met the criteria for mild depression and 4.3% (95% CI: 3.4–5.4%) for severely depression. Living alone, history of heart attack, head injury, and fracture were associated with higher depressive symptoms. Alcohol consumption and higher cognitive function were associated with lower depressive symptoms. Living alone, not attended school, history of head injury, fracture, and low cognitive function were associated with increased probability of mild depression. Living alone, history of stroke or heart attack, and low cognitive function were associated with severe depression.
Depression, particularly mild depression, is common in rural elderly Chinese. Among a number of factors identified in this cohort as being significantly associated with depressive symptoms, living alone and lower cognitive function were the most consistent factors associated with depressive symptoms, mild and severe depression. History of stroke, heart attack, and fracture were also risk factors for depressive symptoms.
depressive symptoms; Geriatric Depression Scale; Elderly Chinese
Frontotemporal lobar degenerations are a group of disorders characterized by circumscribed degeneration of the frontal and temporal lobes and diverse histopathological features. We report clinical, neuropathological, ultrastructural, biochemical and genetic data on seven individuals with a four-repeat (4R) tauopathy characterized by the presence of globular glial inclusions (GGIs) in brain white matter. Clinical manifestations were compatible with the behavioral variant of frontotemporal dementia (FTD) and included motor neuron symptoms; there was prominent neuronal loss in the frontal and temporal cortex, subiculum and amygdala. The surrounding white matter showed abundant GGIs composed of abnormal filaments present mostly in oligodendrocytes. The severity of white matter tau abnormalities correlated with a reduction in myelin and axons and with microglial activation. Western blotting of sarkosyl-insoluble tau demonstrated the presence of two major tau bands of 64 and 68 kDa. No mutations in the microtubule-associated protein tau (MAPT) gene were detected in two affected individuals. We propose that 4R tau-immunoreactive GGIs are the neuropathologic hallmark of a distinct sporadic tauopathy with variable clinical presentations that include FTD and occasionally upper motor neuron disease. This type of tauopathy with GGIs expands the group of neurodegenerative disorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders.
Dementia; Frontotemporal lobar degeneration; Tau; Tauopathy; White matter
Selenium is a trace element associated with antioxidant activity and is considered to be a protective agent against free radicals through enhanced enzyme activity. Studies on selenium and cognitive function or Alzheimer’s disease have yielded inconsistent results. A cross-sectional survey of 2,000 rural Chinese aged 65 years or older from two provinces in the People’s Republic of China was conducted from December 2003 to May 2005 by use of the Community Screening Instrument for Dementia, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning Test, the Indiana University Story Recall Test, the Animal Fluency Test, and the Indiana University Token Test. Over 70% of the study participants have lived in the same village since birth. Nail samples were collected and analyzed for selenium contents. Analysis-of-covariance models were used to estimate the association between quintile selenium levels measured in nail samples and cognitive test scores, with adjustment for other covariates. Lower selenium levels measured in nail samples were significantly associated with lower cognitive scores (p < 0.0087 for all tests) except the Animal Fluency Test (p = 0.4378). A dose-response effect of selenium quintiles was also seen for those significant associations. Results in this geographically stable cohort support the hypothesis that a lifelong low selenium level is associated with lower cognitive function.
aged; Asian continental ancestry group; cognition; selenium
Trace elements are involved in metabolic processes and oxidation-reduction reactions in the central nervous system and could have a possible effect on cognitive function. The relationship between trace elements measured in individual biological samples and cognitive function in an elderly population had not been investigated extensively.
The participant population is part of a large cohort study of 2000 rural elderly Chinese persons. Six cognitive assessment tests were used to evaluate cognitive function in this population, and a composite score was created to represent global cognitive function. Trace element levels of aluminum, calcium, cadmium, copper, iron, lead, and zinc were analyzed in plasma samples of 188 individuals who were randomly selected and consented to donating fasting blood. Analysis of covariance models were used to assess the association between each trace element and the composite cognitive score adjusting for demographics, medical history of chronic diseases, and the apolipoprotein E (APOE) genotype.
Three trace elements—calcium, cadmium, and copper—were found to be significantly related to the composite cognitive score. Increasing plasma calcium level was associated with higher cognitive score (p < .0001). Increasing cadmium and copper, in contrast, were significantly associated with lower composite score (p = .0044 and p = .0121, respectively). Other trace elements did not show significant association with the composite cognitive score.
Our results suggest that calcium, cadmium, and copper may be associated with cognitive function in the elderly population.
Trace element; Cognitive function; Calcium; Copper; Cadmium
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
Frontotemporal dementia and parkinsonism linked to chromosome 17; Tau; Ubiquitin; TDP-43; Neuropathology
Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.
frontotemporal dementia; progressive supranuclear palsy; hippocampus; voxel-based morphometry; Tau haplotype
Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
Results 1-19 (19)
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