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.
Positron emission tomography; mild traumatic brain injury; post-concussive symptoms; cerebellum; blast; Veterans; cognition
The current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including β-amyloid 1–42 (Aβ1–42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults.
One hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55–100 years) underwent blood pressure assessment for determination of PP (systolic − diastolic blood pressure) and lumbar puncture for measurement of CSF Aβ1–42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers.
PP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aβ1–42 (r = −0.19, p = 0.01), and increased P-tau to Aβ1–42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (β = 0.18, p = 0.0196) and P-tau to Aβ1–42 ratio (β = 0.0016, p < 0.001) but was no longer associated with Aβ1–42 (β = −0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55–70 years) (Aβ1–42: p = 0.050; P-tau: p = 0.003; P-tau to Aβ ratio: p = 0.0007) but not older participants (aged 70–100 years).
PP elevation is associated with increased CSF P-tau and decreased Aβ1–42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.
Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21–100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.
Noradrenergic system; Norepinephrine; Cognition; Aging
This study investigates the association between TOMM40 poly-T length, age-at-onset, and neuropathology in Alzheimer’s disease (AD) individuals with the APOE ε3/ε3 allele.
Thirty-two PSEN1 mutation carriers with AD, 27 PSEN2 mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 participants with autopsies from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays.
Among AD patients with PSEN2 mutations, the presence of a long poly-T was associated with an earlier age-at-onset, whereas there were no such associations for patients with PSEN1 mutations or LOAD. In community-based participants, the presence of a long poly-T was associated with increased neuritic tangles and a higher likelihood of pathologically diagnosed AD.
TOMM40 intron 6 poly-T length may explain some of the variation in age-at-onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ε3/ε3.
Alzheimer’s disease; age-at-onset; genetic; APOE; TOMM40; PSEN1 mutation; PSEN2 mutation; neuropathology
Mild traumatic brain injury (mTBI) is considered the ‘signature injury’ of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phosphor- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes.
Blast-induced neurotrauma; brain trauma; cerebellum; mitochondrial oxidative stress; neurodegeneration; tauopathy
MicroRNA (miRNA) may be potential biomarkers of Alzheimer’s disease (AD). The objective of this investigation was to demonstrate that miRNAs in human brain or biofluids are differentially expressed according to disease status, tissue type, neuritic plaque score or Braak stage. Post-mortem brain (PMB) miRNA were profiled using arrays and validated using quantitative RT-PCR (qRT-PCR). Five qRT-PCR-validated miRNAs were measured in an independent sample of PMB, cerebrospinal fluid and plasma from the same subjects. Plasma miR-15a was found to be associated with plaque score in the independent sample. In conclusion, miRNA present in human biofluids may offer utility as biomarkers of AD.
Amyloid; biomarker; Braak stage; miR-15a; miR-370; miR-328; miR-138; miR 132; plaque
Olfactory dysfunction is an early feature of Alzheimer disease. This study used multimodal imaging of PET and 18F-FDG combined with diffusion tensor imaging (DTI) to investigate the association of fiber tract integrity in the olfactory tract with cortical glucose metabolism in subjects with mild cognitive impairment (MCI) and normal controls. We hypothesized that MCI subjects would show loss of olfactory tract integrity and may have altered associations with glucose metabolism.
Subjects diagnosed with amnestic MCI (n = 12) and normal controls (n = 23) received standard brain 18F-FDG PET and DTI with 32 gradient directions on a 3-T MR imaging scanner. Fractional anisotropy (FA) maps were generated. Voxelwise correlation analysis of olfactory tract FA values with 18F-FDG PET images was performed.
Integrated analysis over all subjects indicated a positive correlation between white matter integrity in the olfactory tract and metabolic activity in olfactory processing structures, including the rostral prefrontal cortex, dorsomedial thalamus, hypothalamus, orbitofrontal cortex, and uncus, and in the superior temporal gyrus, insula, and anterior cingulate cortex. Subjects with MCI, compared with normal controls, showed differential associations of olfactory tract integrity with medial temporal lobe and posterior cortical structures.
These findings indicate that impairment of axonal integrity or neuronal loss may be linked to functional metabolic changes and that disease-specific neurodegeneration may affect this relationship. Multimodal imaging using 18F-FDG PET and DTI may provide better insights into aging and neurodegenerative processes.
olfactory tract; Alzheimer’s disease; fiber tract integrity; glucose metabolism; 18F-FDG PET; DTI
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.
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.
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).
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.
These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress.
Amygdala; bed nucleus of stria terminalis; clonidine; locus coeruleus; norepinephrine; posttraumatic stress disorder; prazosin; resilience; stress; ventral tegmental area
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.
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.
FYN; PPP2R4; MAPT; AD; CSF
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.
Alzheimer’s disease; biomarker; long-term clinical TBI phenotypes; mild cognitive impairment; monocyte chemotactic protein-1; plasma; traumatic brain injury
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.
Late-life depression is associated with increased risk of dementia but the temporal relationship between depression and development of dementia remains unclear.
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).
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.
Population-based cohort drawn from members of Group Health Cooperative in Seattle, Washington.
A cohort of 3,410 participants without dementia aged ≥ 65 years.
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.
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.
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.
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.
norepinephrine; RX 821002; prazosin; α1-adrenoreceptor; α2-adrenoreceptor; sprouting; Alzheimer’s disease
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.
Alzheimer disease; Amyloid beta-Peptide; Biomarkers; Saliva; Tau protein
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.
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.
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.
We have demonstrated that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression.
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.
Alzheimer’s disease; cerebrospinal fluid; biomarkers; Aβ42; tau; F2-isoprostanes
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.
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).
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.
Academic medical centers
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
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.
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.
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.
traumatic brain injury; hypopituitarism; blast; concussion; growth hormone; pituitary
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.
Parkinson’s disease; cognitive impairment; CSF biomarkers; Aβ42; tau
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.
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.
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.
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.
YKL-40; Alzheimer’s disease; biomarkers; cerebrospinal fluid; chitinase-3 like-1; inflammation
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.
Apolipoprotein E gene; apolipoprotein E protein; cerebroshinal fluid; enhancer; promoter; SNP