Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown.
Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed (n=11, age 19.5±0.3 yr) and control (n=9, age 19.6±0.5 yr) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range.
There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses.
These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood.
prenatal alcohol exposure; voxel based morphometry; fetal alcohol spectrum disorders; brain volume
Prenatal alcohol exposure has been associated with pre- and postnatal growth restriction, but little is known about the natural history of this restriction throughout childhood or the effects of prenatal alcohol on body composition.
To examine the effects of heavy prenatal alcohol exposure on longitudinal growth and body composition.
85 heavy drinking pregnant women (≥ 2 drinks/day or ≥ 4 drinks/occasion) and 63 abstaining and light-drinking controls (< 1 drink/day, no binging) were recruited at initiation of prenatal care in an urban obstetrical clinic in Cape Town, South Africa, and prospectively interviewed during pregnancy about alcohol, smoking, drug use, and demographics. Among their children, length/height, weight, and head circumference were measured at 6.5 and 12 months and at 5 and 9 years. Percent body fat was estimated at age 9 years using bioelectric impedance analysis.
In multiple regression models with repeated measures (adjusted for confounders), heavy alcohol exposure was associated with reductions in weight (0.6 SD), length/height (0.5 SD), and head circumference (0.9 cm) from 6.5 months to 9 years that were largely determined at birth. These effects were exacerbated by iron deficiency in infancy but were not modified by iron deficiency or measures of food security at 5 years. An alcohol-related postnatal delay in weight gain was seen at 12 months. Effects on head circumference were greater at age 9 than at other age points. Although heavy alcohol exposure was not associated with changes in body composition, children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) had lower % body fat than heavy exposed nonsyndromal and control children.
Heavy prenatal alcohol exposure is related to prenatal growth restriction that persists through age 9 years and an additional delay in weight gain during infancy. FAS and PFAS diagnoses are associated with leaner body composition in later childhood.
fetal alcohol syndrome; intrauterine growth retardation; postnatal growth; body composition; bioelectric impedance analysis; prenatal alcohol exposure; iron deficiency; food security
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
Alzheimer’s disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined. PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (Aβ) peptides compared to SAD, which may play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce uniform increases in the relative proportions of Aβ42 and exhibited substantial variability in total Aβ levels. These observations suggest that neurodegeneration and dementia do not depend solely on enhanced Aβ42 levels. Our data revealed additional complexities in PSEN-FAD individuals. Some direct substrates of γ-secretase, such as Notch, N-cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types. Proteins that were not direct γ-secretase substrates, but play key structural and functional roles in the WM, likewise exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of effective therapeutic interventions for both SAD and FAD.
Sporadic Alzheimer’s disease; familial Alzheimer’s disease; presenilin; γ-secretase; white matter; gray matter; amyloid precursor protein; amyloid-beta
The identification of individuals exposed prenatally to alcohol can be challenging, with only those having the characteristic pattern of facial features, CNS abnormality, and growth retardation receiving a clinical diagnosis of fetal alcohol syndrome (FAS).
17 anthropometric measurements were obtained at 5 and 9 years from 125 Cape Town, South African children, studied since birth. The children were divided into 3 groups: FAS or partial FAS (PFAS), heavily exposed nonsyndromal (HE), and non-alcohol exposed controls (C). Anthropometric measurements were evaluated for mean group differences. Logistic regression models were used to identify the subset of anthropometric measures that best predicted group membership. Anthropometric measurements were examined at the two ages in relation to prenatal alcohol exposure obtained prospectively from the mothers during pregnancy. Correlation of these facial measurements with key neurobehavioral outcomes including WISC-IV IQ and eyeblink conditioning was used to assess their utility as indicators of alcohol-related central nervous system impairment.
Significant group differences were found for the majority of the anthropometric measures, with means of these measures smaller in the FAS/PFAS compared with HE or C. Upper facial widths, ear length, lower facial depth, and eye widths were consistent predictors distinguishing those exposed to alcohol from those who were not. Using longitudinal data, unique measures were identified that predicted facial anomalies at one age but not the other, suggesting the face changes as the individual matures. 41% of the FAS/PFAS group met criteria for microtia at both ages. Three of the predictive anthropometric measures were negatively related to measures of prenatal alcohol consumption, and all were positively related to at least one neurobehavioral outcome.
The analysis of longitudinal data identified a common set of predictors, as well as some that are unique at each age. Prenatal alcohol exposure appears to have its primary effect on brain growth, reflected by smaller forehead widths, and may suppress neural crest migration to the branchial arches, reflected by deficits in ear length and mandibular dimensions. These results may improve diagnostic resolution and enhance our understanding of the relation between the face and the neuropsychological deficits that occur.
fetal alcohol syndrome; fetal alcohol spectrum disorders; prenatal alcohol exposure; anthropometrics; neurobehavior; facial image; 3D photography
Fetal alcohol-related growth restriction persists through infancy but its impact later in life is less clear. Animal studies have demonstrated important roles for maternal nutrition in FASD, but the impact of prenatal maternal body composition has not been studied in humans. This study examined the effects of prenatal alcohol exposure on longitudinal growth from birth through young adulthood and the degree to which maternal weight and body mass index (BMI) moderate these effects.
480 mothers were recruited at their first prenatal clinic visit to over-represent moderate-to-heavy use of alcohol during pregnancy, including a 5% random sample of low-level drinkers and abstainers. They were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach. Their children were examined for weight, length/height, and head circumference at birth, 6.5 and 13 months, and 7.5, 14, and 19 years.
In multiple regression models with repeated measures (adjusted for confounders), prenatal alcohol exposure was associated with longitudinal reductions in weight, height, and weight-for-length/BMI that were largely determined at birth. At low-to-moderate levels of exposure, these effects were more severe in infancy than in later childhood. By contrast, effects persisted among children whose mothers drank at least monthly and among those born to women with alcohol abuse and/or dependence who had consumed ≥4 drinks/occasion. In addition, effects on weight, height, and head circumference were markedly stronger among children born to mothers with lower prepregnancy weight.
These findings confirm prior studies demonstrating alcohol-related reductions in weight, height, weight-for-height/BMI, and head circumference that persist through young adulthood. Stronger effects were seen among children born to mothers with smaller prepregnancy weight, which may have been due to attainment of higher blood alcohol concentrations in smaller mothers for a given amount of alcohol intake or to increased vulnerability in infants born to women with poorer nutrition.
fetal alcohol syndrome; prenatal alcohol exposure; intrauterine growth retardation; postnatal growth; body composition; prepregnancy weight; maternal nutrition
The objective of this report is to estimate the benefits of universal meconium screening for maternal drinking during pregnancy. Fetal alcohol spectrum disorder (FASD), including its most severe manifestation fetal alcohol syndrome (FAS), is preventable and remains a public health tragedy. The incidences of FAS and FASD have been conservatively estimated to be 0.97 and 10 per 1000 births, respectively. Meconium testing has been demonstrated to be a promising at-birth method for detection of drinking during pregnancy.
The current costs of FAS and FASD, alcohol treatment programs, and meconium screening were estimated by literature review. Monetary values were converted roughly to equal dollars in 2006.
Costs of adding meconium analysis to the current newborn screening program and of treatment for the identified mothers were estimated and compared to potential averted costs that may result from identification and intervention for mothers and affected infants. Three potential maternal treatment strategies are analyzed. Depending on the treatment type, the savings may range from $6 to $97 for every $1 spent on screening and treatment.
It needs to be emphasized, however, that such screening is premature and that to be effective this screening can be implemented only if there is a societal willingness to institute prevention and intervention programs to improve both women’s and children’s health. Future research should be directed at improving detection and developing in-depth prevention and remedial intervention programs. A thorough consideration of the ethical issues involved in such a screening program is also needed.
fetal alcohol spectrum disorder; meconium; fatty acid ethyl esters; newborn screening; benefits; maternal alcohol use
Two models of vulnerability to socioenvironmental risk were examined in 337 African American children (M = 7.8 years) recruited to over-represent prenatal alcohol or cocaine exposure: the cumulative risk model predicted synergistic effects from exposure to multiple risk factors, and the fetal patterning of disease model predicted that prenatal insult will increase vulnerability to environmental risk. Four or more risks emerged as a threshold for poorer cognitive and behavioral outcome among the non-substance exposed children, whereas substance-exposed children showed greater vulnerability to lower levels of environmental risk. Cumulative risk was associated with increased delinquent and internalizing behaviors only for the substance-exposed group. Results support the cumulative risk model for non-substance exposed children and increased vulnerability to environmental risk among the substance-exposed group.
Classical eyeblink conditioning (EBC) involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Impairment of EBC has been demonstrated in studies of alcohol-exposed animals and in children exposed prenatally at heavy levels.
Fetal alcohol syndrome (FAS) was diagnosed by expert dysmorphologists in a large sample of Cape Coloured, South African children. Delay EBC was examined in a new sample of 63 children at 11.3 years, and trace conditioning in 32 of the same children at 12.8 years. At each age, two sessions of 50 trials each were administered on the same day; two more sessions the next day, for children not meeting criterion for conditioning.
6 of 34 (17.6%) children born to heavy drinkers were diagnosed with FAS, 28 were heavily exposed nonsyndromal (HE), and 29 were non-exposed controls. Only 33.3% with FAS and 42.9% of HE met criterion for delay conditioning, compared with 79.3% of controls. The more difficult trace conditioning task was also highly sensitive to fetal alcohol exposure. Only 16.7% of the FAS and 21.4% of HE met criterion for trace conditioning, compared with 66.7% of controls. The magnitude of the effect of diagnostic group on trace conditioning was not greater than the effect on short delay conditioning, findings consistent with recent rat studies. Longer latency to onset and peak eyeblink CR in exposed children indicated poor timing and failure to blink in anticipation of the puff. Extended training resulted in some but not all of the children reaching criterion.
These data showing alcohol-related delay and trace conditioning deficits extend our earlier findings of impaired EBC in 5-year-olds to school-age. Alcohol-related impairment in the cerebellar circuitry required for both forms of conditioning may be sufficient to account for the deficit in both tasks. Extended training was beneficial for some exposed children. EBC provides a well-characterized model system for assessment of degree of cerebellar-related learning and memory dysfunction in fetal alcohol exposed children.
Fetal Alcohol Syndrome; Delay Eyeblink Conditioning; Trace Eyeblink Conditioning; Fetal Alcohol Spectrum Disorder; Cerebellar-Mediated Temporal Processing
Carriers of the ApoE ϵ4 allele are at a greater risk for developing Alzheimer’s disease (AD) and those who do develop AD tend to have a much greater neuropathological disease burden. Although several studies have shown significant differences in AD pathology among ϵ4 carriers and non-carriers, few have characterized these differences in terms of brain region and neuropathological score frequency.
566 pathologically-confirmed AD cases who were followed prospectively with antemortem dementia diagnoses (312 ApoE ϵ4 carriers and 254 ApoE ϵ4 non-carriers) were compared on the frequencies of neuropathological frequency scores (none, sparse, moderate, frequent) among several different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal) using the CERAD scoring system. Pathology score frequencies were analyzed by carrier status (ϵ4 carrier vs. ϵ4 non-carrier) and by genotype (2/3, 3/3, 2/4, 3/4, 4/4). Both analyses investigated pathology score frequencies among different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal).
ϵ4 carriers had a significantly lower age at death (p <0.001) and significantly higher Braak scores (p <0.001) than ϵ4 non-carriers. Genotype comparison revealed that plaque and tangle pathologies increased in the following pattern, 2/3<3/3<2/4<3/4<4/4, for several brain regions. When stratified by age and ApoE ϵ4 carrier status, ϵ4 carriers tended to have significantly more frequent scores across most cortical areas. However, non-carriers age 90 and older tended to have greater plaque pathology than carriers. For tangle pathology, ϵ4 carriers tended to have significantly more “frequent” scores than non-carriers, except for the hippocampal and entorhinal areas in individuals age 90 and older.
ApoE ϵ4 carriers had a significantly higher percentage of “frequent” scores for plaques and tangles when compared to ApoE ϵ4 non-carriers for several brain regions. However, ϵ4 non-carriers age 90 and older tended to have less plaque and tangle pathology in certain brain regions. These results demonstrate that AD pathology may manifest itself differently based on ApoE genotype and suggest that ApoE carriers and non-carriers may have different patterns of AD neuropathology location and density.
Background: accurately identifying individuals with cognitive impairment is difficult. Given the time constraints that many clinicians face, assessment of cognitive status is often not undertaken. The intent of this study is to determine the diagnostic accuracy of the Alzheimer's questionnaire (AQ) in identifying individuals with mild cognitive impairment (MCI) and AD.
Methods: utilising a case–control design, 300 [100 AD, 100 MCI, 100 cognitively normal (CN)] older adults between the ages of 53 and 93 from a neurology practice and a brain donation programme had the AQ administered to an informant. Diagnostic accuracy was assessed through receiver-operating characteristic analysis, which yielded sensitivity, specificity and area under the curve (AUC).
Results: the AQ demonstrated high sensitivity and specificity for detecting MCI [89.00 (81.20–94.40)]; [91.00 (83.60–65.80)] and AD [99.00 (94.60–100.00)]; [96.00 (90.10–98.90)]. AUC values also indicated high diagnostic accuracy for both MCI [0.95 (0.91–0.97)] and AD [0.99 (0.96–1.00)]. Internal consistency of the AQ was also high (Cronbach's alpha = 0.89).
Conclusion: the AQ is a valid informant-based instrument for identifying cognitive impairment, which could be easily implemented in a clinician's practice. It has high sensitivity and specificity in detecting both MCI and AD and allows clinicians to quickly and accurately assess individuals with reported cognitive problems.
mild cognitive impairment; Alzheimer's disease; cognitive screening; informant-based assessment
Identifying biomarkers that distinguish Parkinson’s disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer’s disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau181, Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau181/Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau181/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.
Parkinson’s disease; biomarkers; ventricular cerebrospinal fluid; apolipoprotein A-1; p-tau181/Aβ42 ratio
This study compared brain activations during unpaced rhythmic finger tapping in 12-year old children with those of adults. The subject pressed a button at a pace initially indicated by a metronome (12 consecutive tones) and then continued for 16 seconds of unpaced tapping to provide an assessment of his/her ability to maintain a steady rhythm. In particular, the analyses focused on the superior vermis of the cerebellum, which is known to play a key role in timing.
12 adults and 12 children performed this rhythmic finger tapping task in a 3T scanner. Whole-brain analyses were performed in Brain Voyager with a random effects analysis of variance using the general linear model. A dedicated cerebellar atlas was used to localise cerebellar activations.
As in adults, unpaced rhythmic finger tapping in children showed activations in the primary motor cortex, premotor cortex, and cerebellum. However, overall activation was different in that adults showed much more deactivation in response to the task, particularly in the occipital and frontal cortex. The other main differences were additional recruitment of motor and premotor areas in children compared to adults along with increased activity in the vermal region of the cerebellum.
These findings suggest that the timing component of the unpaced rhythmic finger tapping task is less efficient and automatic in children, who needed to recruit the superior vermis more intensively to maintain the rhythm, even though they performed somewhat more poorly than the adults.
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
Background: Prenatal exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) has been associated with impaired performance on attention tasks in previous studies, but the extent to which these cognitive deficits translate into behavioral problems in the classroom and attention deficit/hyperactivity disorder (ADHD) remains unknown. By contrast, lead (Pb) exposure in childhood has been associated with ADHD and disruptive behaviors in several studies.
Objectives: In this study we examined the relation of developmental exposure to MeHg, PCBs, and Pb to behavioral problems at school age in Inuit children exposed through their traditional diet.
Methods: In a prospective longitudinal study conducted in the Canadian Arctic, exposure to contaminants was measured at birth and at school age. An assessment of child behavior (n = 279; mean age = 11.3 years) was obtained from the child’s classroom teacher on the Teacher Report Form (TRF) from the Child Behavior Checklist, and the Disruptive Behavior Disorders Rating Scale (DBD).
Results: Cord blood mercury concentrations were associated with higher TRF symptom scores for attention problems and DBD scores consistent with ADHD. Current blood Pb concentrations were associated with higher TRF symptom scores for externalizing problems and with symptoms of ADHD (hyperactive-impulsive type) based on the DBD.
Conclusions: To our knowledge, this study is the first to identify an association between prenatal MeHg and ADHD symptomatology in childhood and the first to replicate previously reported associations between low-level childhood Pb exposure and ADHD in a population exposed to Pb primarily from dietary sources.
ADHD; attention; children; exposure; externalizing behavior; lead; mercury; methylmercury; polychlorinated biphenyls
Normal pressure hydrocephalus (NPH) is considered potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. Yet, the procedure has had variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic co-morbidities, particularly Alzheimer's Disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co-occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during life would elucidate the frequency of such co-morbidities.
We conducted a search of the Sun Health Research Institute Brain Donation Program database between 1/1/1997 and 4/1/09 to identify all cases with neuropathologic evidence of dementia as well as those cases of clinically diagnosed NPH. We reviewed the medical records and brain findings of each NPH case.
Of the 761 cases autopsied over the study interval, 563 cases were found to have neuropathological evidence meeting criteria for a dementing illness. AD was found exclusively in 313/563 (56%) cases with 94/563 cases having a secondary diagnosis of dementia.
We identified 9/761 cases with a clinical diagnosis of NPH, all nine cases were among the 563 cases with neuropathology of dementing illness at autopsy, representing 1.6% (9/563). Upon review of brain autopsy reports, 8/9 (89%) cases were found to have AD and 1/9 (11%) had progressive supranuclear palsy. Review of the medical records of the nine NPH cases revealed the following clinical co-morbidities: 5/9 with AD; 1/9 with Parkinson's Disease (PD); 1/9 with Mild Cognitive Impairment (MCI); 1/9 with seizure disorder.
Given the findings of our study, we support the AD-NPH theory and posit that AD is a common pathological co-morbidity in the setting of NPH and may preclude cognitive improvement post-shunt placement. This may have influence on selection of cases for shunting in the future.
normal pressure hydrocephalus; Alzheimer's disease; cerebrospinal fluid shunt; autopsy study; dementia
Use three-dimensional (3D) facial laser scanned images from children with fetal alcohol syndrome (FAS) and controls to develop an automated diagnosis technique that can reliably and accurately identify individuals prenatally exposed to alcohol.
A detailed dysmorphology evaluation, history of prenatal alcohol exposure, and 3D facial laser scans were obtained from 149 individuals (86 FAS; 63 Control) recruited from two study sites (Cape Town, South Africa and Helsinki, Finland). Computer graphics, machine learning, and pattern recognition techniques were used to automatically identify a set of facial features that best discriminated individuals with FAS from controls in each sample.
An automated feature detection and analysis technique was developed and applied to the two study populations. A unique set of facial regions and features were identified for each population that accurately discriminated FAS and control faces without any human intervention.
Our results demonstrate that computer algorithms can be used to automatically detect facial features that can discriminate FAS and control faces.
fetal alcohol syndrome; geometric feature extraction; image analysis; machine learning; pattern classification
Although an extensive literature has documented a broad range of cognitive performance deficits in children with prenatal alcohol exposure, little is known about how the neurophysiological processes underlying these deficits may be affected. Event-related potentials (ERPs), which reflect task-specific changes in brain electrical activity, provide a method for examining multiple constituents of cognitive processing at the neural level.
We recorded ERPs in 217 children from Inuit communities in Arctic Quebec (M age = 11.3 yr) during two different tasks—Go/No-go response inhibition and continuous recognition memory. Children were classified as either alcohol-exposed (ALC) or controls (CON) depending on whether the mother reported binge drinking during pregnancy.
Both groups performed comparably in terms of accuracy and reaction time on the tasks, and both tasks elicited the expected effects on ERPs when responses were compared across conditions. However, the ALC group showed slower P2 latencies on Go/No-go, suggesting an altered neurophysiological response associated with initial visual processing of the stimuli. On the memory task, the ALC group showed reduced FN400 amplitude to new items, known as the familiarity effect, and reduced amplitude for the late positive component, possibly reflecting impairment in memory retrieval.
These findings show that, even in tasks in which alcohol-exposed children exhibit behavioral performance that is comparable to controls, fetal alcohol exposure is associated with altered neurophysiological processing of response inhibition and recognition memory. The data suggest that fetal alcohol exposure is associated with reduced efficiency in the initial extracting of the meaning of a stimulus, reduced allocation of attention to the task, and poorer conscious, explicit recognition memory processing.
Prenatal alcohol exposure; fetal alcohol spectrum disorders; event-related potentials; response inhibition; recognition memory
Poor arithmetic performance is among the most sensitive outcomes associated with prenatal alcohol exposure and is also common in individuals with attention deficit hyperactivity disorder (ADHD). We hypothesized that prenatal alcohol exposure would be associated with deficits in the most fundamental aspects of number processing, representation of quantity and distance; whereas ADHD would be associated with deficits in calculation, the form of number processing most dependent on attention and memory.
262 inner-city, African American adolescents, who had been evaluated prospectively for prenatal alcohol exposure and ADHD, were assessed on a number processing test comprised of 7 subtests.
More heavily alcohol-exposed adolescents were four times more likely to meet diagnostic criteria for ADHD than those whose mothers abstained from alcohol use during pregnancy. Two dimensions of number processing were identified in a factor analysis—magnitude comparison and calculation. As hypothesized, prenatal alcohol exposure was more strongly related to the former; ADHD, to the latter. Moreover, the relation of prenatal alcohol to calculation was fully mediated by magnitude comparison, whereas the relation of ADHD to calculation was mediated by IQ but not by magnitude comparison.
These data confirm findings from previous studies identifying arithmetic as a particularly sensitive developmental endpoint for prenatal alcohol exposure. Whereas difficulties with arithmetic in ADHD are mediated by domain-general deficits in overall cognitive ability, fetal alcohol-related arithmetic difficulties are mediated primarily by a specific deficit in the core quantity system involving the ability to mentally represent and manipulate number. These data suggest that different interventions are likely to be effective for remediating arithmetic problems in children with prenatal alcohol exposure than in non-exposed children with ADHD.
Fetal alcohol spectrum disorder; prenatal alcohol exposure; arithmetic; number processing; magnitude comparison; attention deficit hyperactivity disorder
Compare the frequency of REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD), restless legs syndrome (RLS), essential tremor (ET), and control subjects.
Subjects enrolled in a longitudinal clinicopathologic study, and when available an informant, completed the Mayo Sleep Questionnaire, which asks “Have you ever been told that you act out your dreams?”, and the Epworth Sleepiness Scale (ESS).
Probable RBD (based on informant response to the questionnaire) was much more frequent in PD (34/49, 69%, p<0.001) than in RLS (6/30, 20%), ET (7/53, 13%), or control subjects (23/175, 13%), with an odds ratio of 11 for PD compared to controls. The mean ESS and the number of subjects with an ESS ≥ 10 was higher in PD (29/60, 48%, p<0.001) and RLS (12/39, 31%, p<0.001) compared with ET (12/93, 13%) and Controls (34/296, 11%).
Probable RBD is much more frequent in PD with no evidence to suggest an increase in either RLS or ET. Given the evidence that RBD is a synucleinopathy, the lack of an increased frequency of RBD in subjects with ET or RLS suggests the majority of ET and RLS subjects are unlikely to be at increased risk for developing PD.
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
Alcohol consumption during pregnancy, a known teratogen often associated with drug use and smoking, is a well-known public health concern.
This study provides prevalence data for alcohol, smoking, and illicit drug use before, during, and after pregnancy among Inuit. Factors associated with alcohol use are also identified.
248 Inuit women from Arctic Quebec were interviewed at mid-pregnancy, and at 1 and 11 months postpartum to provide descriptive data on smoking, alcohol, and drug use during pregnancy, and the year before and after pregnancy. Sociodemographic and family characteristics potentially associated with alcohol use were documented.
92% of the women reported smoking and 61% reported drinking during pregnancy. Episodes of binging during pregnancy were reported by 62% of the alcohol users, which corresponds to 38% of pregnant women. 36% of the participants reported using marijuana during pregnancy. Alcohol use and binge drinking during pregnancy were more likely to be reported by women who lived in less crowded houses, had a better knowledge of a second language, drank alcohol more often and in larger amounts prior to pregnancy, and used illicit drugs. Binge drinkers were more likely to be single women and to have had fewer previous pregnancies. Postpartum distress and violence were more likely to be experienced by women who used alcohol during pregnancy. Binge drinking during pregnancy was best predicted by drinking habits before pregnancy, maternal symptoms of depression, the use of illicit drugs during pregnancy and the number of young children living with the mother.
These results confirm that alcohol is a major risk factor to maternal and child health in this population, underscoring the need for culturally relevant and effective prevention programs.
alcohol; drug use; pregnancy; Inuit; fetal alcohol spectrum disorder
Identification of children with fetal alcohol spectrum disorders (FASD) is difficult because information regarding prenatal exposure is often lacking, a large proportion of affected children do not exhibit facial anomalies, and no distinctive behavioral phenotype has been identified. Castellanos and Tannock have advocated going beyond descriptive symptom-based approaches to diagnosis to identify biomarkers derived from cognitive neuroscience. Classical eyeblink conditioning and magnitude comparison are particularly promising biobehavioral markers of FASD—eyeblink conditioning because a deficit in this elemental form of learning characterizes a very large proportion of alcohol-exposed children; magnitude comparison because it is a domain of higher order cognitive function that is among the most sensitive to fetal alcohol exposure. Because the neural circuitry mediating both these biobehavioral markers is well understood, they have considerable potential for advancing understanding of the pathophysiology of FASD, which can contribute to development of treatments targeted to the specific deficits that characterize this disorder.
Fetal alcohol syndrome; Eyeblink conditioning; Arithmetic; Fetal alcohol spectrum disorders; Biomarkers; Behavioral phenotype; Prenatal alcohol exposure
Background: Lead (Pb) and polychlorinated biphenyls (PCBs) are neurotoxic contaminants that have been related to impairment in response inhibition.
Objectives: In this study we examined the neurophysiological correlates of the response inhibition deficits associated with these exposures, using event-related potentials (ERPs) in a sample of school-age Inuit children from Arctic Québec exposed through their traditional diet.
Methods: In a prospective longitudinal study, we assessed 196 children (mean age, 11.3 years) on a visual go/no-go response inhibition paradigm. Pb, PCB, and mercury (Hg) concentrations were analyzed in cord and current blood samples. Hierarchical multiple regression analyses were conducted to examine the associations of contaminant levels to go/no-go performance (mean reaction time, percent correct go, percent correct no-go) and five ERPs [N2, P3, error-related negativity, error positivity (Pe), and correct response positivity (Pc)] after control for confounding variables.
Results: Current blood Pb concentrations were associated with higher rates of false alarms and with decreased P3 amplitudes to go and no-go trials. Current plasma PCB-153 concentrations were associated with slower reaction times and with reduced amplitudes of the Pe and Pc response-related potentials. Hg concentrations were not related to any outcome on this task but showed significant interactions with other contaminants on certain outcomes.
Conclusions: These results suggest that Pb exposure during childhood impairs the child’s ability to allocate the cognitive resources needed to correctly inhibit a prepotent response, resulting in increased impulsivity. By contrast, postnatal PCB exposure appears to affect processes associated with error monitoring, an aspect of behavioral regulation required to adequately adapt to the changing demands of the environment, which results in reduced task efficiency.
event-related potentials; error monitoring; executive function; lead; methylmercury; neurotoxicity; polychlorinated biphenyls; response inhibition
Differentiating amnestic mild cognitive impairment (aMCI) from normal cognition is difficult in clinical settings. Self-reported and informant-reported memory complaints occur often in both clinical groups, which then necessitates the use of a comprehensive neuropsychological examination to make a differential diagnosis. However, the ability to identify cognitive symptoms that are predictive of aMCI through informant-based information may provide some clinical utility in accurately identifying individuals who are at risk for developing Alzheimer's disease (AD).
The current study utilized a case-control design using data from an ongoing validation study of the Alzheimer's Questionnaire (AQ), an informant-based dementia assessment. Data from 51 cognitively normal (CN) individuals participating in a brain donation program and 47 aMCI individuals seen in a neurology practice at the same institute were analyzed to determine which AQ items differentiated aMCI from CN individuals.
Forward stepwise multiple logistic regression analysis which controlled for age and education showed that 4 AQ items were strong indicators of aMCI which included: repetition of statements and/or questions [OR 13.20 (3.02, 57.66)]; trouble knowing the day, date, month, year, and time [OR 17.97 (2.63, 122.77)]; difficulty managing finances [OR 11.60 (2.10, 63.99)]; and decreased sense of direction [OR 5.84 (1.09, 31.30)].
Overall, these data indicate that certain informant-reported cognitive symptoms may help clinicians differentiate individuals with aMCI from those with normal cognition. Items pertaining to repetition of statements, orientation, ability to manage finances, and visuospatial disorientation had high discriminatory power.