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1.  Low clinical diagnostic accuracy of early vs advanced Parkinson disease 
Neurology  2014;83(5):406-412.
Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard.
Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard.
Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia.
Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced.
Classification of evidence:
This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%.
PMCID: PMC4132570  PMID: 24975862
2.  Prenatal Tobacco Exposure and Response Inhibition in School-Aged Children: An Event-Related Potential Study 
Prenatal cigarette smoke exposure (PCSE) has been linked to problems in behavioral inhibition and attention deficit hyperactivity disorder in children in several epidemiological studies. We used event-related potentials (ERPs) to examine the effects of PCSE on neural correlates of inhibitory control of behavior. In a prospective longitudinal study on child development in the Canadian Arctic, we assessed 186 Inuit children (mean age = 11.3 years) on a visual Go/No-go response inhibition paradigm. PCSE was assessed through maternal recall. Potential confounders were documented from a maternal interview, and exposure to neurotoxic environmental contaminants was assessed from umbilical cord and child blood samples. PCSE was not related to behavioral performance on this simple response inhibition task. Nevertheless, this exposure was associated with smaller amplitudes of the N2 and P3 components elicited by No-go stimuli, suggesting an impairment in the neural processes underlying response inhibition. Amplitude of the No-go P3 component was also inversely associated with behavioral measures of externalizing problems and hyperactivity/impulsivity in the classroom. This study is the first to report neurophysiological evidence of impaired response inhibition in school-aged children exposed to tobacco smoke in utero. Effects were found on ERP components associated with conflict processing and inhibition of a prepotent response, indicating neurophysiological deficits that may play a critical role in the attention and behavior problems observed in children with PCSE.
PMCID: PMC4112075  PMID: 24946039
Cigarette; Event-related potentials; Go/No-go; Inhibition; Nicotine; Pregnancy
3.  A comparison of spectral quality in magnetic resonance spectroscopy data acquired with and without a novel EPI-navigated PRESS sequence in school-aged children with fetal alcohol spectrum disorders 
Metabolic brain disease  2014;29(2):323-332.
Single voxel spectroscopy (SVS) can generate useful information regarding metabolite concentrations provided that the MR signal can be averaged over several minutes during which the subject remains stationary. This requirement can be particularly challenging for children who cannot otherwise be scanned without sedation. To address this problem we developed an EPI volume navigated (vNav) SVS PRESS sequence, which applies real-time head pose (location and orientation), frequency, and first-order B0 shim adjustments. A water-independent preprocessing algorithm removes residual frequency and phase shifts resulting from within-TR movements. We compare results and performance of the standard and vNav PRESS sequences in a sample of 9- to 10-year-olds from a South African cohort of children with fetal alcohol spectrum disorders (FASD) and healthy controls. Magnetic resonance spectroscopy (MRS) data in the deep cerebellar nuclei were initially acquired with the standard PRESS sequence. The children were re-scanned 1 year later with the vNav PRESS sequence. Good quality data were acquired in 73% using the vNav PRESS sequence, compared to only 50% for the standard PRESS sequence. Additionally, tighter linewidths and smaller variances in the measured concentrations were observed. These findings confirm previous reports demonstrating the efficacy of our innovative vNav sequence with healthy volunteers and young children with HIV and expand its application to a school-aged population with FASD—disorders often associated with attention problems and hyperactivity. This study provides the most direct evidence to date regarding degree to which these new methods can improve data quality in research studies employing MRS.
PMCID: PMC4024336  PMID: 24488204
magnetic resonance spectroscopy; motion correction; B0 correction; EPI navigator; fetal alcohol spectrum disorders; South Africa
4.  Concomitant Pathologies among a Spectrum of Parkinsonian Disorders 
Parkinsonism & related disorders  2014;20(5):525-529.
Many clinicopathological studies do not specify the presence of other pathologies located within the brain, so disease heterogeneity may be under appreciated.
The purpose of this study was to determine the frequencies of concomitant pathologies among parkinsonian disorders.
Data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), an ongoing longitudinal clinical-neuropathological study, was used to analyze concomitant pathologies, including Alzheimer’s disease (AD), argyrophilic grains (Arg), cerebral amyloid angiopathy (CAA), cerebral white matter rarefaction (CWMR) and overlap of each parkinsonian disorder in clinico-pathologically defined Parkinson’s disease (PD; N=140), dementia with Lewy bodies (DLB; N=90), progressive supranuclear palsy (PSP; N=64), multiple system atrophy (MSA; N=6), corticobasal degeneration (CBD; N=7); and normal elderly (controls; N=166).
Of the neuropathologically-confirmed PD cases, 38% had a concomitant diagnosis of AD, 9% PSP, 25% Arg, and 44% CWMR, and 24% CAA. For DLB, 89% had AD, 1% PSP, 21% Arg, and 51% CWMR, and 50% CAA. For PSP cases, 36% had AD, 20% PD, 1% DLB, 44% Arg, 52% CWMR and 25% CAA. Similar heterogeneity was seen for MSA and CBD cases. Many cases had more than one of the above additional diagnoses.
These data demonstrate a great deal of concomitant pathologies among different types of parkinsonian disorders; this may help explain the heterogeneity of clinical findings.
PMCID: PMC4028418  PMID: 24637124
Argyrophilic grains; White Matter Rarefaction; Alzheimer’s disease; cerebral amyloid angiopathy; neoplasms; vascular dementia; Parkinson’s disease
5.  An in vivo 1H Magnetic Resonance Spectroscopy Study of the Deep Cerebellar Nuclei in Children with Fetal Alcohol Spectrum Disorders 
Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo 1H magnetic resonance spectroscopy (MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region.
MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa.
Increased maternal alcohol consumption around time of conception was associated with lower N-acetylaspartate (NAA) levels in the deep nuclei (r=−0.33, p<0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites (r=−0.37, p<0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception (r=0.35, p<0.01) and during pregnancy (r=0.38, p<0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders.
The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate–glutamine cycling involved in glutamatergic excitatory neurotransmission.
PMCID: PMC4171650  PMID: 24655149
fetal alcohol spectrum disorders (FASD); prenatal alcohol exposure; magnetic resonance spectroscopy (MRS); N-acetylaspartate (NAA); choline (Cho); glutamate (Glu)
The Journal of pediatrics  2003;143(4):463-469.
To test the sensitivity and specificity of fatty acid ethyl esters (FAEEs) extracted from meconium to identify alcohol-using pregnant women with a sensitive and specific methodology, gas chromatography-tandem mass spectroscopy (GC/MS/MS).
Study design
Twenty-seven samples of meconium were obtained from infants from the mixed race community in Cape Town, South Africa, who were enrolled in a longitudinal neurobehavioral study. Maternal alcohol use was reported prospectively during pregnancy. FAEEs were isolated from meconium and quantitated by GC/MS/MS.
Ethyl oleate was the FAEE that correlated most strongly with maternal self-reported drinking, especially with the average ounces of absolute alcohol ingested per drinking day. Ethyl oleate was most strongly related to drinking in the second and third trimesters (Pearson r = .55 and .40, respectively). At a threshold of 1.5 average ounces of absolute alcohol ingested per drinking day, the area under the receiving operator characteristic curve was .92 (95% confidence interval, 0.74–0.97). Using a cut-off value of 32 ng/g, sensitivity was 84.2% and specificity was 83.3%.
Ethyl oleate concentration in meconium assayed by GC/MS/MS provides a highly sensitive and specific indicator of maternal alcohol use during pregnancy.
PMCID: PMC4362510  PMID: 14571221
7.  Clinicopathological Outcomes of Prospectively Followed Normal Elderly Brain Bank Volunteers 
Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively-assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were female, median age of study entry was 83.5 years (range 67 to 99), and median duration from first visit until death was 4.3 years (range 0-10). At autopsy a clinico-neuropathological diagnosis was made in 30 cases (25%). Clinicopathological diagnoses included 20 (17%) with Alzheimer's disease (AD), 7 (6%) with vascular dementia, 4 (3%) with progressive supranuclear palsy, (1; 0.8%) with dementia with Lewy bodies, (1; 0.8%) with corticobasal degeneration and (1; 0.8%) with multiple system atrophy. Of those 87 subjects (73%) still clinically normal at death, 33 (38%) had extensive AD pathology (pre-clinical AD), 17 (20%) had incidental Lewy bodies and 4 (5%) had incidental pathology consistent with progressive supranuclear palsy. Diagnoses are not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.
PMCID: PMC4066814  PMID: 24487796
Alzheimer's disease; progressive supranuclear palsy; vascular dementia; Parkinson's disease; dementia with Lewy bodies; pathology; epidemiology
8.  Protective Effects of the Alcohol Dehydrogenase-ADH1B*3 Allele on Attention and Behavior Problems in Adolescents Exposed to Alcohol during Pregnancy 
Alcohol dehydrogenase is a critical enzyme in the metabolism of alcohol. Expression of three alleles at the ADH1B locus results in enzymes that differ in turnover rate and affinity for alcohol. The ADH1B*3 allele, which appears to be unique to individuals of African descent, is associated with more rapid alcohol metabolism than the more prevalent ADH1B*1 allele. It has been previously demonstrated that the presence of at least one maternal ADH1B*3 allele confers a protective effect against alcohol teratogenicity in infants and children. This study was conducted to determine whether the presence of the ADH1B*3 allele in the mother or child continues to be protective in alcohol-exposed individuals during adolescence. 186 adolescents and 167 mothers participating in a 14-year follow-up of the Detroit Longitudinal Cohort were genotyped for ADH1B alleles. Behavioral reports were obtained from classroom teachers. Frequencies of the ADH1B*3 allele were 17.6% in the mothers and 21.0% in the adolescents, which are consistent with the 15-20% expected for African Americans. Prenatal alcohol exposure was associated with increased attention problems and externalizing behaviors in adolescents born to mothers with two ADH1B*1 alleles but not in those whose mothers had at least one ADH1B*3 allele. A similar pattern was seen in relation to the presence or absence of an ADH1B*3 allele in the adolescent, which may have reflected the presence/absence of the maternal variant. This study is the first to demonstrate that the protective effects of the maternal ADH1B*3 allele continue to be evident during adolescence. These persistent individual differences in vulnerability of offspring to the behavioral effects of fetal alcohol exposure are likely attributable to more rapid metabolism of alcohol that the ADH1B*3 variant confers on the mother, leading to a reduction of the peak blood alcohol concentration to which the fetus is exposed during each drinking episode.
PMCID: PMC3943945  PMID: 24263126
fetal alcohol spectrum disorders; prenatal alcohol exposure; alcohol dehydrogenase; ADH1B*3 allele; adolescent externalizing behavior
9.  Neural correlates of cerebellar-mediated timing during finger tapping in children with fetal alcohol spectrum disorders 
NeuroImage : Clinical  2014;7:562-570.
Classical eyeblink conditioning (EBC), an elemental form of learning, is among the most sensitive indicators of fetal alcohol spectrum disorders. The cerebellum plays a key role in maintaining timed movements with millisecond accuracy required for EBC. Functional MRI (fMRI) was used to identify cerebellar regions that mediate timing in healthy controls and the degree to which these areas are also recruited in children with prenatal alcohol exposure.
Experimental design
fMRI data were acquired during an auditory rhythmic/non-rhythmic finger tapping task. We present results for 17 children with fetal alcohol syndrome (FAS) or partial FAS, 17 heavily exposed (HE) nonsyndromal children and 16 non- or minimally exposed controls.
Principal observations
Controls showed greater cerebellar blood oxygen level dependent (BOLD) activation in right crus I, vermis IV–VI, and right lobule VI during rhythmic than non-rhythmic finger tapping. The alcohol-exposed children showed smaller activation increases during rhythmic tapping in right crus I than the control children and the most severely affected children with either FAS or PFAS showed smaller increases in vermis IV–V. Higher levels of maternal alcohol intake per occasion during pregnancy were associated with reduced activation increases during rhythmic tapping in all four regions associated with rhythmic tapping in controls.
The four cerebellar areas activated by the controls more during rhythmic than non-rhythmic tapping have been implicated in the production of timed responses in several previous studies. These data provide evidence linking binge-like drinking during pregnancy to poorer function in cerebellar regions involved in timing and somatosensory processing needed for complex tasks requiring precise timing.
•Identified 4 cerebellar regions activated more during rhythmic tapping in controls•These regions are right crus I, vermis IV–V, vermis VI and right lobule VI•Fetal alcohol exposed children activated right crus I less than control children•Children with FAS and PFAS activated vermis IV–V less than the other children•Activity in all 4 regions is reduced with higher levels of alcohol exposure
PMCID: PMC4377649  PMID: 25844307
Functional magnetic resonance imaging (fMRI); Cerebellum; Finger tapping; Prenatal alcohol exposure; Fetal alcohol syndrome; Eyeblink conditioning
10.  Neuropathological and biochemical assessments of an Alzheimer’s disease patient treated with the γ-secretase inhibitor semagacestat 
Amyloid deposition has been implicated as the key determinant of Alzheimer’s disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhibitor, semagacestat. This patient received a daily oral dose of 140 mg of semagacestat for approximately 76 weeks. Levels of brain amyloid-β (Aβ) peptides were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot/scanning densitometry was performed to reveal BACE1, presenilin1, amyloid precursor protein (APP) and its proteolysis-produced C-terminal peptides APP-CT99 and APP-CT83 as well as several γ-secretase substrates. To serve as a frame of reference, the ELISA and Western analyses were performed in parallel on samples from neuropathologically confirmed non-demented control (NDC) and AD subjects who did not receive semagacestat. Neuropathology findings confirmed a diagnosis of AD with frequent amyloid deposits and neurofibrillary tangles in most areas of the cortex and subcortical nuclei as well as cerebellar amyloid plaques. Mean levels of Tris-soluble Aβ40 and glass-distilled formic acid (GDFA)/guanidine hydrochloride (GHCl)-extractable Aβ40 in the frontal lobe and GDFA/GHCl-soluble Aβ40 in the temporal lobe were increased 4.2, 9.5 and 7.7-fold, respectively, in the semagacestat-treated subject compared to those observed in the non-treated AD group. In addition, GDFA/GHCl-extracted Aβ42 was increased 2-fold in the temporal lobe relative to non-treated AD cases. No major changes in APP, β- and γ-secretase and CT99/CT83 were observed between the semagacestat-treated subject compared to either NDC or AD cases. Furthermore, the levels of γ-secretase substrates in the semagacestat-treated subject and the reference groups were also similar. Interestingly, there were significant alterations in the levels of several γ-secretase substrates between the NDC and non-treated AD subjects. This is the first reported case study of an individual enrolled in the semagacestat clinical trial. The subject of this study remained alive for ~7 months after treatment termination, therefore it is difficult to conclude whether the outcomes observed represent a consequence of semagacestat therapy. Additional evaluations of trial participants, including several who expired during the course of treatment, may provide vital clarification regarding the impacts and aftermath of γ-secretase inhibition.
PMCID: PMC4299724  PMID: 25628963
Alzheimer’s disease; semagacestat immunotherapy; Alzheimer’s clinical trial; γ-secretase; γ-secretase inhibitors; γ-secretase substrates; amyloid-β
11.  Prevalence of Hippocampal Sclerosis in a Clinicopathologically Characterized Cohort 
Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized.
Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples.
The age range of the sample was 43 to 106 years, with a mean of 81.49±8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59±2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies.
The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases.
PMCID: PMC4196704  PMID: 25324686
hippocampal sclerosis; dementia; neuropathology; TDP-43; Alzheimer's disease; Parkinson's disease
12.  Associations Between Prenatal Cigarette Smoke Exposure and Externalized Behaviors at School Age Among Inuit Children Exposed to Environmental Contaminants 
Neurotoxicology and teratology  2013;39:10.1016/
Smoking during pregnancy is common among Inuit women from the Canadian Arctic. Yet, prenatal cigarette smoke exposure (PCSE) is seen as a major risk factor for childhood behavior problems. Recent data also suggest that co-exposure to neurotoxic environmental contaminants can exacerbate the effects of PCSE on behavior. This study examined the association between PCSE and behavior at school age in a sample of Inuit children from Nunavik, Québec, where co-exposure to environmental contaminants is also an important issue. Interactions with lead (Pb) and mercury (Hg), two contaminants associated with behavioral problems, were also explored.
Participants were 271 children (mean age = 11.3 years) involved in a prospective birth-cohort study. PCSE was assessed through maternal recall. Assessment of child behavior was obtained from the child’s classroom teacher on the Teacher Report Form (TRF) and the Disruptive Behavior Disorders Rating Scale (DBD). Exposure to contaminants was assessed from umbilical cord and child blood samples. Other confounders were documented by maternal interview.
After control for contaminants and confounders, PCSE was associated with increased externalizing behaviors and attention problems on the TRF and higher prevalence of attention deficit hyperactivity disorder (ADHD) assessed on the DBD. No interactions were found with contaminants.
This study extends the existing empirical evidence linking PCSE to behavioral problems in school-aged children by reporting these effects in a population where tobacco use is normative rather than marginal. Co-exposure to Pb and Hg do not appear to exacerbate tobacco effects, suggesting that these substances act independently.
PMCID: PMC3812672  PMID: 23916943
attention deficit hyperactivity disorder; prenatal smoking; tobacco smoke; child behavior; environmental contaminants; externalizing behaviors; attention problems; Teacher Report Form
13.  Biochemical Assessment of Precuneus and Posterior Cingulate Gyrus in the Context of Brain Aging and Alzheimer’s Disease 
PLoS ONE  2014;9(8):e105784.
Defining the biochemical alterations that occur in the brain during “normal” aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer’s disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.
PMCID: PMC4148328  PMID: 25166759
14.  Commentary on Day and colleagues (2013): The association between prenatal alcohol exposure and behavior at 22 years of age—Adverse effects of risky patterns of drinking among low to moderate alcohol-using pregnant women 
Day and colleagues have presented the first data showing that the behavioral effects of low to moderate prenatal alcohol exposure seen in childhood and adolescence persist into adulthood. Using the Achenbach Adult Self Report, they found dose-dependent effects of prenatal exposure on Internalizing, Externalizing, and Attention problems that persist in young adults and, thus, appear to be permanent. To date, few studies have attempted to identify thresholds at which prenatal alcohol exposure is harmful, although the animal literature suggests that even 1–2 binge episodes can result in adverse effects in the offspring. Four prospective longitudinal studies have reported adverse effects at what can be characterized as moderate exposure levels based on NIAAA criteria, but moderate drinking women often concentrate their alcohol use on 1–2 days per week, thereby engaging in binge drinking. In this study binge drinking was not a strong predictor of adverse outcome when average daily dose was held constant, a conclusion that the authors note runs “counter to studies that have reported that binge drinking has a greater effect.” This inconsistency may be due to the difficulty of allocating variance that is shared (overlapping) between average daily dose and binge drinking (i.e., dose/occasion). Data from laboratory animal studies, in which dosage can be manipulated experimentally, demonstrate that a higher dose per occasion, the key feature of binge drinking, leads to more severe adverse effects. Day et al.’s findings of adverse effects at low levels of exposure provides clear evidence that there is no safe level of drinking during pregnancy and that, even at low levels, drinking results in irreversible behavioral impairment. On the other hand, given the evidence from the animal and most human studies, it is important for all women who drink during pregnancy, even at light to moderate levels, to recognize that minimizing their intake per occasion and refraining from binge drinking can reduce risk to the fetus.
PMCID: PMC3703854  PMID: 23822873
light to moderate prenatal alcohol exposure; fetal alcohol spectrum disorders; binge drinking; adult behavior; prospective longitudinal studies; internalizing and externalizing behavior; attention
15.  Neurochemical Profile of Dementia Pugilistica 
Journal of Neurotrauma  2013;30(11):981-997.
Dementia pugilistica (DP), a suite of neuropathological and cognitive function declines after chronic traumatic brain injury (TBI), is present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD). Some biochemical alterations observed in AD and PD may be recapitulated in DP and other TBI persons. In this report, we investigate long-term biochemical changes in the brains of former boxers with neuropathologically confirmed DP. Our experiments revealed biochemical and cellular alterations in DP that are complementary to and extend information already provided by histological methods. ELISA and one-dimensional and two dimensional Western blot techniques revealed differential expression of select molecules between three patients with DP and three age-matched non-demented control (NDC) persons without a history of TBI. Structural changes such as disturbances in the expression and processing of glial fibrillary acidic protein, tau, and α-synuclein were evident. The levels of the Aβ–degrading enzyme neprilysin were reduced in the patients with DP. Amyloid-β levels were elevated in the DP participant with the concomitant diagnosis of AD. In addition, the levels of brain-derived neurotrophic factor and the axonal transport proteins kinesin and dynein were substantially decreased in DP relative to NDC participants. Traumatic brain injury is a risk factor for dementia development, and our findings are consistent with permanent structural and functional damage in the cerebral cortex and white matter of boxers. Understanding the precise threshold of damage needed for the induction of pathology in DP and TBI is vital.
PMCID: PMC3684215  PMID: 23268705
adult brain injury; axonal injury; immunoblots; neurodegenerative disorders; traumatic brain injury
16.  Can platelet BACE1 levels be used as a biomarker for Alzheimer’s disease? Proof-of-concept study 
Platelets  2012;24(3):235-238.
To date there is no validated peripheral biomarker to assist with the clinical diagnosis of Alzheimer’s disease (AD). Platelet proteins have been studied as AD biomarkers with relative success. In the present study we investigated whether platelet BACE1 levels differ between AD and cognitively normal (CN) control patients. Using a newly developed ELISA method, we found that BACE1 levels were significantly lower in AD compare to CN subjects. These data were supported by the observation that several BACE1 isoforms, identified by Western blotting, were also lower in AD platelets. This proof-of-concept study provides evidence for testing platelet BACE1 levels as a peripheral AD biomarker using a novel, sensitive and inexpensive method.
PMCID: PMC4000702  PMID: 22775589
Alzheimer’s disease; BACE1; Biomarker; Peripheral; Platelets
17.  Exposure to organochlorines and mercury through fish and marine mammal consumption: associations with growth and duration of gestation among Inuit newborns 
Environment international  2013;54:85-91.
Several studies have reported negative associations of polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and mercury (Hg) with duration of gestation and foetal growth in fish eating populations. Docosahexaenoic acid (DHA) from fish, seafood and marine mammal intake has been reported to be positively related with pregnancy duration and foetal growth. So far, it remains unclear, however, if the associations of environmental contaminants (ECs) with growth are direct or mediated through their relation with the duration of gestation and the degree to which DHA intake during pregnancy attenuates the negative association of ECs with fetal growth.
To investigate direct and indirect associations of in utero exposure to ECs with foetal growth and pregnancy duration while taking into account the possible positive effects of DHA.
Pregnant Inuit women (N = 248) from Arctic Quebec were recruited and cord blood samples were analyzed for PCBs, HCB, Hg and DHA. Anthropometric measurements were assessed at birth. Path models were used to evaluate direct and indirect associations.
Cord concentrations of PCB 153, HCB and Hg were significantly associated with shorter duration of pregnancy (β varying from −0.17 to −0.20, p < 0.05). Path models indicated that the associations of PCBs, HCB and Hg with reduced foetal growth (β varying from −0.09 to −0.13, p < 0.05) were mediated through their relations with shorter gestation duration. Cord DHA was indirectly related to greater growth parameters (β varying from 0.17 to 0.20, p < 0.05) through its positive association with gestation duration.
Prenatal exposure to ECs was associated with reduced gestation duration, which is a recognized determinant of foetal growth. DHA intake during pregnancy appeared to have independent positive association with foetal growth by prolonging gestation. Whether these associations are causal remains to be elucidated.
PMCID: PMC3632409  PMID: 23422685
Gestation; growth; mercury; organochlorines; polyunsaturated fatty acids; prenatal exposure
18.  Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults 
Human brain mapping  2013;35(4):1390-1403.
This study characterized human cerebellar activity during eyeblink classical conditioning (EBC) in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps, and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired. Although all participants demonstrated significant conditioning, the adults produced more conditioned responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex (Crus I– II, lateral lobules IV–IX, and vermis IV–VI) in all participants, suggesting multiple sites of associative learning-related plasticity. Despite their less optimal behavioral performance, the children showed greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning. Correlation analyses relating brain activations to behavioral CRs showed a positive association of activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children versus adults during eyeblink classical conditioning.
PMCID: PMC3823743  PMID: 23674498
cerebellum; development; learning; memory; neuroimaging
19.  Fetal alcohol-related growth restriction from birth through young adulthood and moderating effects of maternal prepregnancy weight 
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.
PMCID: PMC3743666  PMID: 23013325
fetal alcohol syndrome; prenatal alcohol exposure; intrauterine growth retardation; postnatal growth; body composition; prepregnancy weight; maternal nutrition
20.  Facial Dysmorphism Across the Fetal Alcohol Spectrum 
Pediatrics  2013;131(3):e779-e788.
Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics.
Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior.
Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97–1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics.
Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment.
PMCID: PMC3581841  PMID: 23439907
facial dysmorphism; fetal alcohol spectrum disorders; fetal alcohol syndrome; dense surface modeling; signature graphs; prenatal alcohol exposure; alcohol-related neurodevelopmental disorder
21.  Domain-Specific Effects of Prenatal Exposure to PCBs, Mercury, and Lead on Infant Cognition: Results from the Environmental Contaminants and Child Development Study in Nunavik 
Environmental Health Perspectives  2014;122(3):310-316.
Background: Polychlorinated biphenyls (PCBs), methylmercury (MeHg), and lead (Pb) are environmental contaminants known for their adverse effects on cognitive development.
Objectives: In this study we examined the effects of prenatal exposure to PCBs, MeHg, and Pb on cognitive development in a sample of Inuit infants from Arctic Québec.
Methods: Mothers were recruited at local prenatal clinics. PCBs, mercury (Hg), Pb, and two seafood nutrients—docosahexaenoic acid (DHA) and selenium (Se)—were measured in umbilical cord blood. Infants (n = 94) were assessed at 6.5 and 11 months of age on the Fagan Test of Infant Intelligence (FTII), A-not-B test, and Bayley Scales of Infant Development–2nd Edition (BSID-II).
Results: Multiple regression analyses revealed that higher prenatal PCB exposure was associated with decreased FTII novelty preference, indicating impaired visual recognition memory. Prenatal Hg was associated with poorer performance on A-not-B, which depends on working memory and is believed to be a precursor of executive function. Prenatal Pb was related to longer FTII fixation durations, indicating slower speed of information processing.
Conclusions: PCBs, MeHg, and Pb each showed specific and distinct patterns of adverse associations with the outcomes measured during infancy. By contrast, none of these exposures was associated with performance on the BSID-II, a global developmental measure. The more focused, narrow band measures of cognitive function that appeared to be sensitive to these exposures also provide early indications of long-term impairment in specific domains that would otherwise not likely be evident until school age.
Citation: Boucher O, Muckle G, Jacobson JL, Carter RC, Kaplan-Estrin M, Ayotte P, Dewailly É, Jacobson SW. 2014. Domain-specific effects of prenatal exposure to PCBs, mercury, and lead on infant cognition: results from the Environmental Contaminants and Child Development Study in Nunavik. Environ Health Perspect 122:310–316;
PMCID: PMC3948023  PMID: 24441767
22.  Persistent Dose-dependent Changes in Brain Structure in Young Adults with Low-to-Moderate Alcohol Exposure in Utero 
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.
PMCID: PMC3424348  PMID: 22594302
prenatal alcohol exposure; voxel based morphometry; fetal alcohol spectrum disorders; brain volume
23.  Effects of heavy prenatal alcohol exposure and iron deficiency anemia on child growth and body composition through age 9 years 
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.
PMCID: PMC3697011  PMID: 22897691
fetal alcohol syndrome; intrauterine growth retardation; postnatal growth; body composition; bioelectric impedance analysis; prenatal alcohol exposure; iron deficiency; food security
24.  SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA Screening 
PLoS ONE  2013;8(10):e77711.
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.
PMCID: PMC3813773  PMID: 24204929
25.  Subjects harboring presenilin familial Alzheimer’s disease mutations exhibit diverse white matter biochemistry alterations 
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.
PMCID: PMC3783832  PMID: 24093083
Sporadic Alzheimer’s disease; familial Alzheimer’s disease; presenilin; γ-secretase; white matter; gray matter; amyloid precursor protein; amyloid-beta

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