[Show abstract][Hide abstract] ABSTRACT: The growing public threat of Alzheimer's disease (AD) has raised the urgency to discover and validate prognostic biomarkers in order to predicting time to onset of AD. It is anticipated that both whole genome single nucleotide polymorphism (SNP) data and high dimensional whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. The aim of this paper is to test whether both whole genome SNP data and whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. In 343 subjects with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI-1), we extracted high dimensional MR imaging (volumetric data on 93 brain regions plus a surface fluid registration based hippocampal subregion and surface data), and whole genome data (504,095 SNPs from GWAS), as well as routine neurocognitive and clinical data at baseline. MCI patients were then followed over 48 months, with 150 participants progressing to AD. Combining information from whole brain MR imaging and whole genome data was substantially superior to the standard model for predicting time to onset of AD in a 48-month national study of subjects at risk. Our findings demonstrate the promise of combined imaging-whole genome prognostic markers in people with mild memory impairment.
[Show abstract][Hide abstract] ABSTRACT: A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p < 0.01), entorhinal cortex (p < 0.01), hippocampus (p < 0.053) and cortical gray matter (p < 0.009). However, when E4 genotype was added as a covariate, none of the FH effects remained significant. Analyses by ApoE genotype showed that the effect of FH on amygdala atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH− subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.
[Show abstract][Hide abstract] ABSTRACT: Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having offspring with an inherited debilitating or fatal neurological disorder who wish to conceive a healthy child. PGD has been carried out for conditions with various modes of inheritance, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal or mitochondrial disorders, and for susceptibility genes for cancers with nervous system involvement. Most couples at risk of transmitting a genetic mutation would opt for PGD over prenatal testing and possible termination of a pregnancy. The aim of this Perspectives article is to assist neurologists in counselling and treating patients who wish to explore the option of PGD to enable conception of an unaffected child. PGD can be accomplished for most disorders in which the genetic basis is known, and we argue that it is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology.
[Show abstract][Hide abstract] ABSTRACT: This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66±1.47 vs -0.71±1.09, P=0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P<0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P<0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.Molecular Psychiatry advance online publication, 11 March 2014; doi:10.1038/mp.2014.9.
[Show abstract][Hide abstract] ABSTRACT: Case reports suggest a relationship between cholinesterase inhibitors (ChEIs) and Pisa syndrome (PS), also known as pleurothotonus, a form of dystonia, but this relationship has not been systematically examined. Our objective was to estimate the adjusted reporting ratios of PS with donepezil, rivastigmine, and galantamine in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.
Retrospective analysis of adverse event reports in the FAERS database.
Patients with drug-related adverse events in the FAERS database.
The Gamma Poisson Shrinker algorithm was used to estimate the empirical Bayes geometric mean (EBGM) along with the lower and upper 90% confidence interval (CI) limits (EB05 and EB95, respectively), as measures of the adjusted reporting ratio of PS in patients taking ChEIs. EB05 > 2.0 was used as the cutoff for significance for the signals. The EBGM (EB05) was 37.9 (30) for all ChEIs, 25.6 (17.6) for donepezil, 76.4 (50.3) for galantamine, and 33.7 (21.2) for rivastigmine. All adverse event signals were strongly significant based on the a priori set EB05 cutoff. The female:male ratio in the reported cases was 2:1. No significant signals were found between ChEIs and other dystonias. About half of the ChEI users were also taking concomitant antipsychotics.
Although FAERS data cannot establish causality due to reporting biases, our findings support a potential dopaminergic-cholinergic imbalance as an underlying mechanism for PS and may help increase clinician awareness, early identification, and treatment of ChEI-related dystonias.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE To describe the first case of preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF) performed for the prevention of genetic prion disease in the children of a 27-year-old asymptomatic woman with a family history of Gerstmann-Sträussler-Sheinker syndrome (GSS). OBSERVATIONS PGD and fertilization cycles resulted in detection of 6 F198S mutation-free embryos. Of these, 2 were selected for embryo transfer to the patient's uterus, yielding a clinical twin pregnancy and birth of healthy but slightly premature offspring with normal development at age 27 months. CONCLUSION AND RELEVANCE IVF with PGD is a viable option for couples who wish to avoid passing the disease to their offspring. Neurologists should be aware of PGD to be able to better consult at-risk families on their reproductive choices.
[Show abstract][Hide abstract] ABSTRACT: Subjects with higher cognitive reserve (CR) may be at a lower risk for Alzheimer's disease (AD), but the neural mechanisms underlying this are not known. Hippocampal volume loss is an early event in AD that triggers cognitive decline.
Regression analyses of the effects of education on MRI-measured baseline HV in 675 subjects (201 normal, 329 with mild cognitive impairment (MCI), and 146 subjects with mild AD), adjusting for age, gender, APOE ɛ4 status and intracranial volume (ICV). Subjects were derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large US national biomarker study.
The association between higher education and larger HV was significant in AD (P=0.014) but not in cognitively normal or MCI subjects. In AD, HV was about 8% larger in a person with 20 years of education relative to someone with 6 years of education. There was also a trend for the interaction between education and APOE ɛ4 to be significant in AD (P=0.056).
A potential protective association between higher education and lower hippocampal atrophy in patients with AD appears consistent with prior epidemiologic data linking higher education levels with lower rates of incident dementia. Longitudinal studies are warranted to confirm these findings.
Journal of Neuroradiology 01/2014; 8. DOI:10.1016/j.neurad.2013.11.004 · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To evaluate differences in the structural connectome among patients with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer disease (AD) and to determine associations between the structural connectome and cortical amyloid deposition. Materials and Methods: Patients enrolled in a multicenter biomarker study (Alzheimer's Disease Neuroimaging Initiative [ADNI] 2) who had both baseline diffusion-tensor (DT) and florbetapir positron emission tomography (PET) data at the time of data analyses in November 2012 were studied. All institutions received institutional review board approval. There were 102 patients in ADNI 2 who met criteria for analysis. Patients' T1-weighted images were automatically parcellated into cortical regions of interest. Standardized uptake value ratio (SUVr) was calculated from florbetapir PET images for composite cortical regions (frontal, cingulate, parietal, and temporal). Structural connectome graphs were created from DT images, and connectome topology was analyzed in each region by using graph theoretical metrics. Analysis of variance of structural connectome metrics and florbetapir SUVr across diagnostic group was performed. Linear mixed-effects models were fit to analyze the effect of florbetapir SUVr on structural connectome metrics. Results: Diagnostic group (NC, MCI, or AD) was associated with changes in weighted structural connectome metrics, with decreases from the NC group to the MCI group to the AD group shown for (a) strength in the bilateral frontal, right parietal, and bilateral temporal regions (P < .05); (b) weighted local efficiency in the left temporal region (P < .05); and (c) weighted clustering coefficient in the bilateral frontal and left temporal regions (P < .05). Increased cortical florbetapir SUVr was associated with decreases in weighted structural connectome metrics; namely, strength (P = .00001), weighted local efficiency (P = .00001), and weighted clustering coefficient (P = .0006), independent of brain region. For every 0.1-unit increase in florbetapir SUVr, there was a 14% decrease in strength, an 11% decrease in weighted local efficiency, and a 9% decrease in weighted clustering coefficient, regardless of the analyzed cortical region or, in the case of weighted local efficiency and clustering coefficient, diagnostic group. Conclusion: Increased amyloid burden, as measured with florbetapir PET imaging, is related to changes in the topology of the large-scale cortical network architecture of the brain, as measured with graph theoretical metrics of DTI tractography, even in the preclinical stages of AD.
[Show abstract][Hide abstract] ABSTRACT: Social cognition refers to the brain mechanisms by which we process social information about other humans and ourselves. Alterations in interpersonal and social functioning are common in major depressive disorder, though only poorly addressed by current pharmacotherapies. Further standardized tests, such as depression ratings or neuropsychologic tests, used in routine practice provide very little information on social skills, schemas, attributions, stereotypes and judgments related to social interactions. In this article, we review recent literature on how healthy human brains process social decisions and how these processes are altered in major depressive disorder. We especially focus on interactive paradigms (e.g., game theory based tasks) that can reproduce daily life situations in laboratory settings. The evidences we review, together with the rich literature on the protective role of social networks in handling stress, have implications for developing more ecologically-valid biomarkers and interventions in order to optimize functional recovery in depressive disorders
[Show abstract][Hide abstract] ABSTRACT: Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological β-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p < 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
[Show abstract][Hide abstract] ABSTRACT: Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78weeks (18months). Eighty DEP-CI outpatients (age 55 to 95years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
The hypothesis of the current study is that relationships between the structural connectome and cortical amyloid burden may provide complementary information about pathologic changes in Alzheimer's Disease (AD).
METHOD AND MATERIALS
Subjects were those newly enrolled in the ADNI2 study. Baseline data was used. T1 anatomical images were parcellated using FreeSurfer. DTI scans were registered to the T1 images using FSL. Structural connectomes were created using the Connectome Mapper Toolkit. Node degree, local efficiency, and clustering coefficient were calculated for the precuneus, posterior cingulate, inferior temporal, superior parietal, and superior frontal connectome nodes. The FreeSurfer parcellations were registered to the florbetapir PET scans. The global SUVR and four local SUVRs (frontal, cingulate, parietal, and temporal) were calculated. Clinical cognitive assessments included MMSE, ADAS-Cog, and Rey AVLT. Statistical analyses were performed between structural connection metrics, amyloid status, and clinical cognitive scores.
There were 102 ADNI2 subjects (64 males, 38 females) available at the time of the analysis. There were 37 normal control, 19 early mild cognitive impairment (MCI), 25 late MCI, and 21 AD subjects. All global and local AV45 amyloid burden measures were significantly associated with RAVLT, MMSE, and ADAS-Cog (p < 0.05). The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05). The strongest associations between structural connection metrics and clinical dementia scores were in the precuneus, superior parietal, and superior temporal regions (node degree vs. MMSE and ADAS-cog; p < 0.05).
Brain amyloid burden has significant associations with clinical cognitive status in all regions analyzed, consistent with globally increased amyloid burden as an important condition for AD. The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05), suggesting that these regions are most likely to have structural changes related to amyloid deposition in AD.
The combination of quantitative amyloid PET and DTI tractography can provide information about global and local structural changes in AD, aiding in diagnosis and disease tracking.
Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
[Show abstract][Hide abstract] ABSTRACT: Understanding negative consequences of heavy Internet use on mental health is a topic that is gaining significant traction recently. A number of studies have investigated heavy Internet usage, especially among young adults in relation to online games, social media and email. While such studies do provide valuable insights, Internet usage so far has been characterized by means of self-reported surveys only that may suffer from errors and biases. In this paper, we report the findings of a two month empirical study on heavy Internet usage among students conducted at a college campus. The novelty of the study is that it is believed to be the first to use real Internet data that is collected continuously, passively and preserving privacy. A total of 69 Computer Science freshman students were surveyed for symptoms of heavy Internet usage, using the Internet Related Problem Scale, and their campus Internet usage was monitored (after appropriate anonymization procedures to maintain subject privacy). Statistical analysis revealed that several Internet usage features, such as instant messaging, entropy, gaming, web browsing, peer-to-peer usage, remote usage, and email usage exhibit significant correlations with symptoms of Internet addiction like introversion, craving, loss of control and tolerance. Although the study found that Facebook and Twitter usage did not show significant statistical correlations with symptoms of heavier Internet usage, it was found that students tending towards heavier Internet usage used those websites less. We believe that this study provides critical new insights into symptoms of heavier (possibly addictive) Internet usage among young adults, which is now a topic of significant concern to the mental health community today.
2013 IEEE International Conference on Advanced Networks and Telecommuncations Systems (ANTS); 12/2013