Effect of blast-related mTBI on the working memory system: a resting state fMRI study.

Reduced working memory is frequently reported by Veterans with a history of blast-related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory.

Retrospective and Prospective Memory Among OEF/OIF/OND Veterans With a Self-Reported History of Blast-Related mTBI.

OBJECTIVES: To evaluate prospective and retrospective memory abilities in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans with and without a self-reported history of blast-related mild traumatic brain injury (mTBI). METHODS: Sixty-one OEF/OIF/OND Veterans, including Veterans with a self-reported history of blast-related mTBI (mTBI group; n=42) and Veterans without a self-reported history of TBI (control group; n=19) completed the Memory for Intentions Test, a measure of prospective memory (PM), and two measures of retrospective memory (RM), the California Verbal Learning Test-II and the Brief Visuospatial Memory Test-Revised. RESULTS: Veterans in the mTBI group exhibited significantly lower PM performance than the control group, but the groups did not differ in their performance on RM measures. Further analysis revealed that Veterans in the mTBI group with current PTSD (mTBI/PTSD+) demonstrated significantly lower performance on the PM measure than Veterans in the control group. PM performance by Veterans in the mTBI group without current PTSD (mTBI/PTSD-) was intermediate between the mTBI/PTSD+ and control groups, and results for the mTBI/PTSD- group were not significantly different from either of the other two groups. CONCLUSIONS: Results suggest that PM performance may be a sensitive marker of cognitive dysfunction among OEF/OIF/OND Veterans with a history of self-reported blast-related mTBI and comorbid PTSD. Reduced PM may account, in part, for complaints of cognitive difficulties in this Veteran cohort, even years post-injury. (JINS, 2018, 24, 324-334).

Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.

OBJECTIVE: To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. METHODS: Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aß42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. RESULTS: Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aß42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group. CONCLUSIONS: Simvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.

Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults.

BACKGROUND: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. METHODS: CSF amyloid beta1-42 (Aß42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. RESULTS: CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aß42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × Îµ4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). CONCLUSIONS: Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

Higher Pretreatment Blood Pressure Is Associated With Greater Posttraumatic Stress Disorder Symptom Reduction in Soldiers Treated With Prazosin.

BACKGROUND: In a previously reported positive randomized controlled trial of the α1-adrenoreceptor (α1AR) antagonist prazosin for combat posttraumatic stress disorder (PTSD) in 67 active duty soldiers, baseline symptoms did not predict therapeutic response. If increased brain α1AR activation in PTSD is the target of prazosin treatment action, higher brain α1AR activation should predict greater prazosin efficacy. Although brain α1AR activation is not measurable, coregulated peripheral α1AR activation could provide an estimate of brain α1AR activation. Standing blood pressure (BP) is an accessible biological parameter regulated by norepinephrine activation of α1ARs on peripheral arterioles. METHODS: Effects of baseline standing systolic and other BP parameters on PTSD outcome measures from the previously reported randomized controlled trial were analyzed using linear mixed-effects models. Prazosin participants (n = 32) and placebo participants (n = 35) were analyzed separately. RESULTS: In prazosin participants, each 10-mm Hg higher baseline standing systolic BP increment resulted in an additional 14-point reduction (improvement) of Clinician-Administered PTSD Scale total score at end point (p = .002). All other combinations of baseline BP parameters and PTSD outcome measures were similarly significant or demonstrated trends in the predicted direction. In placebo participants, there was no signal for a baseline BP effect on PTSD outcome measures. CONCLUSIONS: These findings suggest that higher standing BP is a biomarker that helps identify persons with combat PTSD who are likely to benefit from prazosin. These results also are consistent with α1AR activation contributing to PTSD pathophysiology in a subgroup of patients.

Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction.

Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose-response relationship between the number of blast-related mild TBIs and uptake of (18)F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast-related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans.

Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans.

Abstract Whether persisting cognitive complaints and postconcussive symptoms (PCS) reported by Iraq and Afghanistan war veterans with blast- and/or combined blast/impact-related mild traumatic brain injuries (mTBIs) are associated with enduring structural and/or functional brain abnormalities versus comorbid depression or posttraumatic stress disorder (PTSD) remains unclear. We sought to characterize relationships among these variables in a convenience sample of Iraq and Afghanistan-deployed veterans with (n=34) and without (n=18) a history of one or more combined blast/impact-related mTBIs. Participants underwent magnetic resonance imaging of fractional anisotropy (FA) and macromolecular proton fraction (MPF) to assess brain white matter (WM) integrity; [(18)F]-fluorodeoxyglucose positron emission tomography imaging of cerebral glucose metabolism (CMRglu); structured clinical assessments of blast exposure, psychiatric diagnoses, and PTSD symptoms; neurologic evaluations; and self-report scales of PCS, combat exposure, depression, sleep quality, and alcohol use. Veterans with versus without blast/impact-mTBIs exhibited reduced FA in the corpus callosum; reduced MPF values in subgyral, longitudinal, and cortical/subcortical WM tracts and gray matter (GM)/WM border regions (with a possible threshold effect beginning at 20 blast-mTBIs); reduced CMRglu in parietal, somatosensory, and visual cortices; and higher scores on measures of PCS, PTSD, combat exposure, depression, sleep disturbance, and alcohol use. Neuroimaging metrics did not differ between participants with versus without PTSD. Iraq and Afghanistan veterans with one or more blast-related mTBIs exhibit abnormalities of brain WM structural integrity and macromolecular organization and CMRglu that are not related to comorbid PTSD. These findings are congruent with recent neuropathological evidence of chronic brain injury in this cohort of veterans.

Blast exposure causes early and persistent aberrant phospho- and cleaved-tau expression in a murine model of mild blast-induced traumatic brain injury.

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 phospho- 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.

A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan.

OBJECTIVE: The authors conducted a 15-week randomized controlled trial of the alpha-1 adrenoreceptor antagonist prazosin for combat trauma nightmares, sleep quality, global function, and overall symptoms in active-duty soldiers with posttraumatic stress disorder (PTSD) returned from combat deployments to Iraq and Afghanistan. METHOD: Sixty-seven soldiers were randomly assigned to treatment with prazosin or placebo for 15 weeks. Drug was titrated based on nightmare response over 6 weeks to a possible maximum dose of 5 mg midmorning and 20 mg at bedtime for men and 2 mg midmorning and 10 mg at bedtime for women. Mean achieved bedtime doses were 15.6 mg of prazosin (SD=6.0) and 18.8 mg of placebo (SD=3.3) for men and 7.0 mg of prazosin (SD=3.5) and 10.0 mg of placebo (SD=0.0) for women. Mean achieved midmorning doses were 4.0 mg of prazosin (SD=1.4) and 4.8 mg of placebo (SD=0.8) for men and 1.7 mg of prazosin (SD=0.5) and 2.0 mg of placebo (SD=0.0) mg for women. Primary outcome measures were the nightmare item of the Clinician-Administered PTSD Scale (CAPS), the Pittsburgh Sleep Quality Index, and the change item of the Clinical Global Impressions Scale anchored to functioning. Secondary outcome measures were the 17-item CAPS, the Hamilton Depression Rating Scale, the Patient Health Questionnaire-9, and the Quality of Life Index. Maintenance psychotropic medications and supportive psychotherapy were held constant. RESULTS: Prazosin was effective for trauma nightmares, sleep quality, global function, CAPS score, and the CAPS hyperarousal symptom cluster. Prazosin was well tolerated, and blood pressure changes did not differ between groups. CONCLUSIONS: Prazosin is effective for combat-related PTSD with trauma nightmares in active-duty soldiers, and benefits are clinically meaningful. Substantial residual symptoms suggest that studies combining prazosin with effective psychotherapies might demonstrate further benefit.

Loss of olfactory tract integrity affects cortical metabolism in the brain and olfactory regions in aging and mild cognitive impairment.

UNLABELLED: Olfactory dysfunction is an early feature of Alzheimer disease. This study used multimodal imaging of PET and (18)F-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. METHODS: Subjects diagnosed with amnestic MCI (n = 12) and normal controls (n = 23) received standard brain (18)F-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 (18)F-FDG PET images was performed. RESULTS: 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. CONCLUSION: 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 (18)F-FDG PET and DTI may provide better insights into aging and neurodegenerative processes.

Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span.

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.

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.

Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms.

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 Congress 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.

Adrenocortical responsiveness to infusions of physiological doses of ACTH is not altered in posttraumatic stress disorder.

Early studies of posttraumatic stress disorder (PTSD) reported that abnormal function of the hypothalamic-pituitary-adrenocortical (HPA) system was associated with the disorder. However, subsequent studies attempting to identify a specific aspect of HPA dysfunction that characterizes PTSD have been marked by considerable inconsistency of results. A facet of HPA regulation that has been considered but not definitively investigated is the possibility that the responsiveness of the adrenal cortex to physiological concentrations of adrenocorticotropin (ACTH) is diminished in PTSD. Relationships between PTSD and the adrenal androgen dehydroepiandrosterone (DHEA) have also been postulated. In this study we investigated the magnitude and time course of changes in concentrations of plasma cortisol and DHEA in response to bolus infusions of physiological doses of ACTH (1-24) in PTSD patients and control subjects. We found no evidence for PTSD-related alterations in cortisol or DHEA secretion in response to stimulation by low doses of ACTH and conclude that adrenocortical responsiveness is normal in PTSD. Results from this and other studies suggest that the occurrence of defects in HPA function in PTSD may be specific responses to particular combinations of trauma type, genetic susceptibility, and individual history.

Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid biomarker and fluorodeoxyglucose positron emission tomography findings.

BACKGROUND: Alterations in cerebrospinal fluid (CSF) tau and beta-amyloid peptide 1-42 (Abeta(42)) levels and rates of cerebral glucose metabolism (CMRglu) on fluorodeoxyglucose positron emission tomography (FDG-PET) occur years before clinical symptoms of Alzheimer disease (AD) become manifest, but their relationship remains unclear. OBJECTIVE: To determine whether CSF AD biomarker levels and CMRglu in healthy individuals correlate in brain structures affected early in AD. DESIGN: Cohort study. SETTING: Alzheimer disease research center. PARTICIPANTS: Twenty individuals without dementia aged 46 to 83 years. INTERVENTIONS: Lumbar CSF sampling and FDG-PET imaging of CMRglu. The CSF Abeta(42), tau, and tau phosphorylated at threonine 181 (ptau(181)) levels were measured using immunobead-based multiplex assays. MAIN OUTCOME MEASURES: Correlations between CMRglu and CSF biomarker levels were analyzed via voxel-based and volume-of-interest approaches. RESULTS: Voxel-based analyses demonstrated significant negative correlations between CSF tau and ptau(181) levels and CMRglu in the posterior cingulate, precuneus, and parahippocampal regions. In contrast, a limited positive correlation was found between CSF Abeta(42) levels and CMRglu in the inferior temporal cortex. Volume-of-interest analyses confirmed negative associations between CSF tau and ptau(181) levels and CMRglu in the parietal and medial parietal lobes and a positive association between CSF Abeta(42) levels and CMRglu in the parahippocampal gyrus. CONCLUSIONS: In healthy individuals, higher CSF tau and ptau(181) concentrations were associated with more severe hypometabolism in several brain regions affected very early in AD, whereas lower CSF Abeta(42) concentrations were associated with hypometabolism only in the medial temporal lobe. This suggests that early tau and Abeta abnormalities may be associated with subtle synaptic changes in brain regions vulnerable to AD. A longitudinal assessment of CSF and FDG-PET biomarkers is needed to determine whether these changes predict cognitive impairment and incipient AD.

Apolipoprotein E highly correlates with AbetaPP- and tau-related markers in human cerebrospinal fluid.

We assessed cerebrospinal fluid (CSF) levels of apolipoprotein E (apoE), phospholipid transfer protein (PLTP) activity, cholesterol, secreted amyloid-beta protein precursor alpha and beta (sAbetaPPalpha, sAbetaPPbeta), amyloid-beta peptides 1-40 (Abeta_{40}) and 1-42 (Abeta_{42}), total tau and tau phosphorylated at threonine 181 (pTau) in neurologically healthy, cognitively intact adults. ApoE significantly correlated with sAbetaPPalpha (r = 0.679), sAbetaPPbeta (r = 0.634), Abeta_{40} (r = 0.609), total and pTau (r = 0.589 and r = 0.673, respectively, all p < 0.001), PLTP activity (r = 0.242, p = 0.002) and cholesterol (r = 0.194, p < 0.01). PLTP activity significantly correlated with sAbetaPPalpha (r = 0.292), sAbetaPPbeta (r = 0.281), total and pTau (r = 0.265 and 0.258, respectively; all p

Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid.

BACKGROUND: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-beta (Abeta) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). METHODS: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. RESULTS: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Abeta42, Abeta40, soluble amyloid beta protein precursor (sAbetaPP) alpha or beta, or F2-isoprostanes. CONCLUSIONS: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.

Lewy body pathology in late-onset familial Alzheimer's disease: a clinicopathological case series.

BACKGROUND: Lewy body pathology (LBP) is a common finding in Alzheimer's disease (AD), but the pathophysiology for this coexistent pathology remains unclear. METHODS: We ascertained late-onset dementia (mean age > 60 years old) families with at least 3 autopsies. We then conducted systematic alpha-synuclein (SNCA) immunostaining to determine the frequency and distribution of LBP in families with late-onset AD. RESULTS: All 32 subjects met NIA-Reagan neuropathological criteria for "high likelihood" of having AD. Hematoxylin and eosin staining detected LBP in the substantia nigra (SN) in 8 (25%) individuals. SNCA immunostaining detected LBP in 21 individuals (66%). While all subjects with SN LBP had co-existent amygdala LBP, many (9/21, 43%) of the cases with amygdala LBP did not have coexistent SN LBP (McNemar's chi-square test, p=0.008). Each family had at least two cases with LBP, but no family had LBP in all autopsied cases. CONCLUSIONS: Presence of significant AD pathology in one family member was highly predictive of similar pathology in other family members. However, despite the use of more sensitive SNCA immunohistochemistry, the presence of LBP was variable within all 7 families. Consistent with previous studies in sporadic and familial AD, the amygdala appeared to be the most vulnerable region for LBP in AD. Additional clinical, neuropathologic, and genetic studies are necessary to determine the clinical and pathological significance of LBP in AD.

Salivary cortisol and memory function in human aging.

OBJECTIVE: To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition. METHODS: Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually. RESULTS: The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall. CONCLUSION: These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study.

OBJECTIVE: Prazosin is a centrally active alpha(1) adrenergic antagonist. The authors' goal was to evaluate prazosin efficacy for nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) in combat veterans. METHOD: Ten Vietnam combat veterans with chronic PTSD and severe trauma-related nightmares each received prazosin and placebo in a 20-week double-blind crossover protocol. RESULTS: Prazosin (mean dose=9.5 mg/day at bedtime, SD=0.5) was superior to placebo for the three primary outcome measures: scores on the 1) recurrent distressing dreams item and the 2) difficulty falling/staying asleep item of the Clinician-Administered PTSD Scale and 3) change in overall PTSD severity and functional status according to the Clinical Global Impression of change. Total score and symptom cluster scores for reexperiencing, avoidance/numbing, and hyperarousal on the Clinician-Administered PTSD Scale also were significantly more improved in the prazosin condition, and prazosin was well tolerated. CONCLUSIONS: These data support the efficacy of prazosin for nightmares, sleep disturbance, and other PTSD symptoms.