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1.  GWAS of cerebrospinal fluid tau levels identifies novel risk variants for Alzheimer’s disease 
Neuron  2013;78(2):256-268.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau) and Aβ42 are established biomarkers for Alzheimer’s Disease (AD), and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n=1,269), identifying three novel genome-wide significant loci for CSF tau and ptau: rs9877502 (P=4.89×10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (P=1.07×10−8 and P=3.22×10−9 for tau and ptau respectively), located at 9p24.2 within GLIS3 and rs6922617 (P = 3.58×10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent datasets rs9877502 showed a strong association with risk for AD, tangle pathology and global cognitive decline (P=2.67×10−4, 0.039, 4.86×10−5 respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
doi:10.1016/j.neuron.2013.02.026
PMCID: PMC3664945  PMID: 23562540
2.  Cerebrocerebellar Hypometabolism Associated With Repetitive Blast Exposure Mild Traumatic Brain Injury in 12 Iraq War Veterans With Persistent Post-Concussive Symptoms 
Neuroimage  2010;54(Suppl 1):S76-S82.
Disagreement exists regarding the extent to which persistent post-concussive symptoms (PCS) reported by Iraq combat Veterans with repeated episodes of mild traumatic brain injury (mTBI) from explosive blasts represent structural or functional brain damage or an epiphenomenon of comorbid depression or posttraumatic stress disorder (PTSD). Objective assessment of brain function in this population may clarify the issue. To this end, twelve Iraq war Veterans (32.0 ±8.5 [mean ± standard deviation (SD)] years of age) reporting one or more blast exposures meeting American College of Rehabilitation Medicine criteria for mTBI and persistent PCS and 12 cognitively normal community volunteers (53.0 ±4.6 years of age) without history of head trauma underwent brain fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological assessments and completed PCS and psychiatric symptom rating scales. Compared to controls, Veterans with mTBI (with or without PTSD) exhibited decreased cerebral metabolic rate of glucose in the cerebellum, vermis, pons, and medial temporal lobe. They also exhibited subtle impairments in verbal fluency, cognitive processing speed, attention, and working memory, similar to those reported in the literature for patients with cerebellar lesions. These FDG-PET imaging findings suggest that regional brain hypometabolism may constitute a neurobiological substrate for chronic PCS in Iraq combat Veterans with repetitive blast-trauma mTBI. Given the potential public health implications of these findings, further investigation of brain function in these Veterans appears warranted.
doi:10.1016/j.neuroimage.2010.04.008
PMCID: PMC3264671  PMID: 20385245
Positron emission tomography; mild traumatic brain injury; post-concussive symptoms; cerebellum; blast; Veterans; cognition
3.  The Role of Norepinephrine in Differential Response to Stress in an Animal Model of Posttraumatic Stress Disorder 
Biological psychiatry  2011;70(5):441-448.
Background
Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system.
Methods
An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2mA, 10sec) followed by exposure to six contextual1-minute reminders of the shock overa 25-dayperiod. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice).
Results
Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic α1-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice.
Conclusions
These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress.
doi:10.1016/j.biopsych.2010.11.029
PMCID: PMC3740168  PMID: 21251647
Amygdala; bed nucleus of stria terminalis; clonidine; locus coeruleus; norepinephrine; posttraumatic stress disorder; prazosin; resilience; stress; ventral tegmental area
4.  A Luminex Assay Detects Amyloid β Oligomers in Alzheimer’s Disease Cerebrospinal Fluid 
PLoS ONE  2013;8(7):e67898.
Amyloid beta (aβ) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer’s disease (AD) and there is increasing evidence that soluble aβ oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased aβ42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric aβ in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized aβ42 and sAPPα fragments. We evaluated oligomeric aβ reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and aβ42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated aβ oligomers compared to control subjects (p < 0.05) and the ratio of aβ oligomers to aβ42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric aβ becomes a routine diagnostic assay for the evaluation of late onset AD patients.
doi:10.1371/journal.pone.0067898
PMCID: PMC3699502  PMID: 23844122
5.  Tau Phosphorylation Pathway Genes and Cerebrospinal Fluid Tau Levels in Alzheimer’s Disease 
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
doi:10.1002/ajmg.b.32094
PMCID: PMC3626266  PMID: 22927204
FYN; PPP2R4; MAPT; AD; CSF
6.  Elevated Plasma MCP-1 Concentration Following Traumatic Brain Injury as a Potential “Predisposition” Factor Associated with an Increased Risk for Subsequent Development of Alzheimer’s Disease 
We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer’s disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer’s disease.
doi:10.3233/JAD-2012-120598
PMCID: PMC3576700  PMID: 22543850
Alzheimer’s disease; biomarker; long-term clinical TBI phenotypes; mild cognitive impairment; monocyte chemotactic protein-1; plasma; traumatic brain injury
7.  DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease 
Scientific Reports  2012;2:954.
DJ-1 is a multifunctional protein that plays an important role in oxidative stress, cell death, and synucleinopathies, including Parkinson disease. Previous studies have demonstrated that total DJ-1 levels decrease in the cerebrospinal fluid, but do not change significantly in human plasma from patients with Parkinson disease when compared with controls. In this study, we measured total DJ-1 and its isoforms in whole blood of patients with Parkinson disease at various stages, Alzheimer disease, and healthy controls to identify potential peripheral biomarkers of PD. In an initial discovery study of 119 subjects, 7 DJ-1 isoforms were reliably detected, and blood levels of those with 4-hydroxy-2-nonenal modifications were discovered to be altered in late-stage Parkinson disease. This result was further confirmed in a validation study of another 114 participants, suggesting that, unlike total DJ-1 levels, post-translationally modified isoforms of DJ-1 from whole blood are candidate biomarkers of late-stage Parkinson disease.
doi:10.1038/srep00954
PMCID: PMC3518819  PMID: 23233873
8.  Temporal relationship between depression and dementia – findings from a large community-based 15 year follow-up study 
Archives of General Psychiatry  2011;68(9):970-977.
Context
Late-life depression is associated with increased risk of dementia but the temporal relationship between depression and development of dementia remains unclear.
Objectives
To examine the association between risk of dementia and 1) baseline depressive symptoms ; 2) past history of depression, particularly early-life (< 50 years) versus late-life depression; and 3) individual domains of the Center for Epidemiologic Studies Depression Scale (CESD).
Design
A large cohort with initially non-demented participants was followed biennially for up to 15 years for incident dementia. Baseline depressive symptoms were assessed using the 11-item version of CESD (CESD-11), and defined as CESD-11 score ≥ 11. Self-reported history of depression was collected at the baseline interview. Cox proportional hazards regression was used to assess the association between depression and the dementia risk.
Setting
Population-based cohort drawn from members of Group Health Cooperative in Seattle, Washington.
Participants
A cohort of 3,410 participants without dementia aged ≥ 65 years.
Results
Over an average of 7.1 years follow-up, 658 participants (19%) developed dementia. At baseline, 9% of participants had depressive symptoms (CESD-11 ≥ 11) and 21% reported a past history of depression. The adjusted hazard ratio (aHR) for dementia associated with baseline depressive symptoms was 1.71 (95% confidence interval 1.37, 2.13), after adjusting for age-at-entry, gender, education, and wave of enrollment. Compared to participants without depression history, those with late-life depression were at increased dementia risk (aHR =1.46 [1.16, 1.84]), but early-life depression had no association with dementia risk (aHR=1.10 [0.83, 1.47]). Depressed mood (aHR 1.48 [1.25, 1.76]) and perceived performance difficulty (aHR 1.39 [1.15, 1.67]) were independently associated with dementia.
Conclusions
This study confirmed previous observations of an association between late-life depression and increased risk of dementia and provided additional evidence that late-life depression may be an early manifestation of dementia rather than increasing risk for dementia.
doi:10.1001/archgenpsychiatry.2011.86
PMCID: PMC3289582  PMID: 21893662
9.  Phosphorylated α-Synuclein in Parkinson’s Disease 
Science Translational Medicine  2012;4(121):121ra20.
Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129, along withtotal α-synuclein, in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein CSF concentrations, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether PS-129 CSF concentrations will be useful for diagnosing PD and for monitoring PD severity and progression.
doi:10.1126/scitranslmed.3002566
PMCID: PMC3302662  PMID: 22344688
10.  Changes In Adrenoreceptors In The Prefrontal Cortex Of Subjects With Dementia: Evidence Of Compensatory Changes 
Neuroscience  2007;146(1):471-480.
In Alzheimer’s disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC α2-adrenoreceptor (AR) binding site density, as determined by 3H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic α1-AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of α1-AR subtypes (α1A- and α1D-AR) and α2C-AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of α1A-AR mRNA. The expression of the α1A-AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of α1A-, α1D- and α2C-AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.
doi:10.1016/j.neuroscience.2007.01.031
PMCID: PMC3399726  PMID: 17324522
norepinephrine; RX 821002; prazosin; α1-adrenoreceptor; α2-adrenoreceptor; sprouting; Alzheimer’s disease
11.  Salivary tau species are potential biomarkers of Alzheimer disease 
Journal of Alzheimer's Disease  2011;27(2):299-305.
Phosphorylation of tau protein is a critical event in the pathogenesis of Alzheimer disease (AD). Increased phosphorylated tau and total tau levels, combined with reduced concentrations of amyloid beta 1–42 (Aβ42) in cerebrospinal fluid (CSF), but not in plasma or serum, have been generally accepted as sensitive AD diagnostic markers. However, obtaining CSF is a relatively invasive procedure that requires participation of specially trained medical professionals, i.e., CSF is not an ideal sample source for screening or early diagnosis of AD, which is essential to current and future neuroprotective treatments for the disease. Here, we identified tau, but not Aβ species, with mass spectrometry in human saliva, a body fluid that is much more accessible compared to CSF or even blood. Quantitative assessment of salivary levels of total tau, phosphorylated tau, and Aβ42 using highly sensitive Luminex assays revealed that, while Aβ42 was not detectable, the phosphorylated tau/tau ratio significantly increased in patients with AD compared to healthy controls. These results suggest that salivary tau species could be ideal biomarkers for AD diagnosis, especially at early stages of the disease or even screening asymptomatic subjects, allowing for a much larger therapeutic window for AD patients.
doi:10.3233/JAD-2011-110731
PMCID: PMC3302350  PMID: 21841250
Alzheimer disease; Amyloid beta-Peptide; Biomarkers; Saliva; Tau protein
12.  Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression 
Annals of neurology  2011;69(3):570-580.
Background
There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for PD diagnosis, but not for PD severity.
Methods
Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ1-42), Flt3 ligand and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these five markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally.
Findings
The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ1-42 that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples.
Interpretation
We have demonstrated that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression.
doi:10.1002/ana.22311
PMCID: PMC3117674  PMID: 21400565
13.  Increased Cerebrospinal Fluid F2-Isoprostanes are Associated with Aging and Latent Alzheimer’s Disease as Identified by Biomarkers 
Neuromolecular medicine  2010;13(1):37-43.
Alzheimer’s disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F2-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) β42 and tau, we defined normality using results from 28 clinically normal individuals < 50 years old, and then stratified 74 clinically normal subjects ≥ 60 years into those with CSF that had normal CSF Aβ42 and tau (n=37); abnormal CSF Aβ42 and tau, the biomarker signature of AD (n=24); decreased Aβ42 only (n=4); or increased tau only (n=9). Increased CSF F2-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F2-IsoPs for those clinically normal adults with normal CSF (n=37) and those with abnormal CSF Aβ42 and/or tau (n=37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F2-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.
doi:10.1007/s12017-010-8126-6
PMCID: PMC3000441  PMID: 20632131
Alzheimer’s disease; cerebrospinal fluid; biomarkers; Aβ42; tau; F2-isoprostanes
14.  The aging systemic milieu negatively regulates neurogenesis and cognitive function 
Nature  2011;477(7362):90-94.
Summary
In the central nervous system (CNS), aging results in a precipitous decline in adult neural stem/progenitor cells (NPCs) and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Accordingly, exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines - including CCL11/Eotaxin – whose plasma levels correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and whose levels are increased in plasma and cerebral spinal fluid of healthy aging humans. Finally, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis, and cognitive impairments, observed during aging can be in part attributed to changes in blood-borne factors.
doi:10.1038/nature10357
PMCID: PMC3170097  PMID: 21886162
15.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
16.  High Prevalence of Chronic Pituitary and Target-Organ Hormone Abnormalities after Blast-Related Mild Traumatic Brain Injury 
Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25–50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.
doi:10.3389/fneur.2012.00011
PMCID: PMC3273706  PMID: 22347210
traumatic brain injury; hypopituitarism; blast; concussion; growth hormone; pituitary
17.  CSF Aβ42 and tau in Parkinson’s disease with cognitive impairment 
We tested the hypothesis that the CSF biomarker signature associated with Alzheimer’s disease (AD) is present in a subset of individuals with Parkinson’s disease and Dementia (PD-D) or with PD and Cognitive Impairment, Not Dementia (PD-CIND). We quantified CSF Aβ42, total tau (T-tau), and phospho-tau (P181-Tau) using commercially available kits. Samples were from 345 individuals in seven groups (n): Controls ≤ 50 years (35), Controls > 50 years (115), amnestic Mild Cognitive Impairment (aMCI) (24), AD (49), PD (49), PD-CIND (62), and PD-D (11). We observed expected changes in AD or aMCI compared with age-matched or younger controls. CSF Aβ42 was reduced in PD-CIND (P < 0.05) and PD-D (P < 0.01) while average CSF T-Tau and P181-Tau were unchanged or decreased. One-third of PD-CIND and one-half of PD-D patients had the biomarker signature of AD. Abnormal metabolism of Aβ42 may be a common feature of PD-CIND and PD-D.
doi:10.1002/mds.23287
PMCID: PMC2978754  PMID: 20818673
Parkinson’s disease; cognitive impairment; CSF biomarkers; Aβ42; tau
18.  YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer’s Disease 
Biological psychiatry  2010;68(10):903-912.
Background
Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design.
Methods
2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40.
Results
In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition.
Conclusions
These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.
doi:10.1016/j.biopsych.2010.08.025
PMCID: PMC3011944  PMID: 21035623
YKL-40; Alzheimer’s disease; biomarkers; cerebrospinal fluid; chitinase-3 like-1; inflammation
19.  Multiple SNPs Within and Surrounding the Apolipoprotein E Gene Influence Cerebrospinal Fluid Apolipoprotein E Protein Levels 
The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer’s disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age (n = 134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.
PMCID: PMC3192652  PMID: 18430993
Apolipoprotein E gene; apolipoprotein E protein; cerebroshinal fluid; enhancer; promoter; SNP
20.  Age-Varying Association Between Statin Use and Incident Alzheimer Disease 
Objectives
Our earlier post hoc analysis suggested possible benefits of statins in reducing risk of Alzheimer’s disease (AD) in younger participants (< age 80 years) with the APOE ε4 allele. We further investigated these findings with more follow-up time and more recently enrolled participants.
Design
A cohort of cognitively intact elderly was assessed biennially for dementia and AD.
Setting
Community based.
Participants
3,392 non-demented member of a health maintenance organization (HMO) aged ≥ 65 years.
Measurements
We identified statin use from the HMO pharmacy database and applied proportional hazards models with statin use as a time-dependent covariate to assess the statin-AD association and the modifying effects of age and the APOE ε4 allele.
Results
Over an average of 6.1 years of follow-up of 3099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval [CI], 0.40 – 0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the statin-AD association diminished with age (statin × age-at-entry interaction p = 0.04); the aHR in those younger than 80 was 0.44 (CI 0.25 – 0.78) vs. 1.22 (CI 0.61 – 2.42) for those older than 80. The interaction term for statin use × APOE ε4 was not significant (p = 0.65).
Conclusion
This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with reduced risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.
doi:10.1111/j.1532-5415.2010.02906.x
PMCID: PMC3176730  PMID: 20533968
Statin; Old age; APOE genotype; Alzheimer disease
21.  Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson disease 
Neuroscience letters  2010;480(1):78-82.
DJ-1 and α-synuclein are leading biomarkers for Parkinson disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and α-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and α-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects (~300 cases) whose cerebrospinal fluid DJ-1 and α-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and α-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (≤1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and α-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and α-synuclein in patients with Parkinson or Alzheimer disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or α-synuclein and Parkinson disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or α-synuclein in plasma alone is not useful as biomarkers for Parkinson disease diagnosis or progression/severity.
doi:10.1016/j.neulet.2010.06.009
PMCID: PMC2943649  PMID: 20540987
Biomarker; DJ-1; α-synuclein; plasma; Parkinson disease; Alzheimer disease
22.  DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease 
Brain  2010;133(3):713-726.
Biomarkers are urgently needed for the diagnosis and monitoring of disease progression in Parkinson’s disease. Both DJ-1 and α-synuclein, two proteins critically involved in Parkinson’s disease pathogenesis, have been tested as disease biomarkers in several recent studies with inconsistent results. These have been largely due to variation in the protein species detected by different antibodies, limited numbers of patients in some studies, or inadequate control of several important variables. In this study, the nature of DJ-1 and α-synuclein in human cerebrospinal fluid was studied by a combination of western blotting, gel filtration and mass spectrometry. Sensitive and quantitative Luminex assays detecting most, if not all, species of DJ-1 and α-synuclein in human cerebrospinal fluid were established. Cerebrospinal fluid concentrations of DJ-1 and α-synuclein from 117 patients with Parkinson’s disease, 132 healthy individuals and 50 patients with Alzheimer’s disease were analysed using newly developed, highly sensitive Luminex technology while controlling for several major confounders. A total of 299 individuals and 389 samples were analysed. The results showed that cerebrospinal fluid DJ-1 and α-synuclein levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid. Both DJ-1 and α-synuclein levels were decreased in Parkinson’s patients versus controls or Alzheimer’s patients when blood contamination was controlled for. In the population aged ≥65 years, when cut-off values of 40 and 0.5 ng/ml were chosen for DJ-1 and α-synuclein, respectively, the sensitivity and specificity for patients with Parkinson’s disease versus controls were 90 and 70% for DJ-1, and 92 and 58% for α-synuclein. A combination of the two markers did not enhance the test performance. There was no association between DJ-1 or α-synuclein and the severity of Parkinson’s disease. Taken together, this represents the largest scale study for DJ-1 or α-synuclein in human cerebrospinal fluid so far, while using newly established sensitive Luminex assays, with controls for multiple variables. We have demonstrated that total DJ-1 and α-synuclein in human cerebrospinal fluid are helpful diagnostic markers for Parkinson’s disease, if variables such as blood contamination and age are taken into consideration.
doi:10.1093/brain/awq008
PMCID: PMC2842513  PMID: 20157014
cerebrospinal fluid; Parkinson’s disease; biomarker; DJ-1; α-synuclein
23.  Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease 
PLoS ONE  2011;6(1):e16032.
Background
Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.
Methods and Findings
CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively.
Conclusions
Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.
doi:10.1371/journal.pone.0016032
PMCID: PMC3020224  PMID: 21264269
24.  Glycoproteomics in Neurodegenerative Diseases 
Mass spectrometry reviews  2010;29(1):79-125.
Protein glycosylation regulates protein function and cellular distribution. Additionally, aberrant protein glycosylations have been recognized to play major roles in human disorders, including neurodegenerative diseases. Glycoproteomics, a branch of proteomics that catalogs and quantifies glycoproteins, provides a powerful means to systematically profile the glycopeptides or glycoproteins of a complex mixture that are highly enriched in body fluids, and therefore, carry great potential to be diagnostic and/or prognostic markers. Application of this mass spectrometry-based technology to the study of neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease) is relatively new, and is expected to provide insight into the biochemical pathogenesis of neurodegeneration, as well as biomarker discovery. In this review, we have summarized the current understanding of glycoproteins in biology and neurodegenerative disease, and have discussed existing proteomic technologies that are utilized to characterize glycoproteins. Some of the ongoing studies, where glycoproteins isolated from cerebrospinal fluid and human brain are being characterized in Parkinson's disease at different stages versus controls, are presented, along with future applications of targeted validation of brain specific glycoproteins in body fluids.
doi:10.1002/mas.20221
PMCID: PMC2799547  PMID: 19358229
glycoproteomics; mass spectrometry; Alzheimer's diseases; Parkinson's disease; biomarkers; cerebrospinal fluids
25.  Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers 
Neurobiology of aging  2007;29(7):981-991.
The apolipoprotein ε4 allele (APOE*4) is a major genetic risk factor for Alzheimer’s disease (AD) and has been associated with altered cortical activation as assessed by functional neuroimaging in cognitively normal younger and older carriers. We chose to evaluate medial temporal lobe (MTL) activation during encoding and recognition using a perspective dependent (route or survey) visuospatial memory task by monitoring the blood-oxygen-level-dependent (BOLD) fMRI response in older, non-demented APOE*4 carriers (APOE*4+) and non-carriers (APOE*4−). During encoding, the APOE*4− group had greater average task-associated BOLD responses in ventral visual pathways, including the MTLs, as compared to the APOE*4+ group. Furthermore, MTL activation was greater during route encoding than survey encoding on average in APOE*4−, but not APOE*4+, subjects. During recognition, both groups performed similarly and no BOLD signal differences were found. Finally, within-group analysis revealed MTL activation during encoding was correlated with recognition performance in APOE*4−, but not APOE*4+ subjects. Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers.
doi:10.1016/j.neurobiolaging.2007.01.012
PMCID: PMC2943631  PMID: 17350142
Alzheimer; Apolipoprotein; Hippocampus; APOE*4; Perspective; Visuospatial learning; Encoding; Recognition; fMRI; Route; Survey

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