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Approximately 14% of military personnel and veterans who have deployed to the combat theater are at risk for combat-related posttraumatic stress disorder (PTSD). The treatment of combat-related PTSD in active duty service members and veterans is challenging. Combat trauma may involve multiple high levels of exposure to different types of traumatic events (e.g., human carnage after explosive blasts, life threat/injuries to self/others, etc.). Many service members and veterans are unable or unwilling to receive treatment in government facilities due to avoidance, scheduling difficulties, transportation or parking problems, concerns about career advancement, or stigma associated with seeking treatment. Innovative treatment-delivery approaches are needed to help overcome these barriers. The present study is a randomized clinical trial to evaluate three versions of Cognitive Processing Therapy (CPT; [54]) for the treatment of combat-related PTSD in active duty military service members and veterans: (1) standard In-Office CPT, (2) In-Home Telebehavioral Health CPT from the provider's office to the participant's home, and (3) In-Home CPT in which the provider delivers treatment in the participant's home. Use of an equipoise-stratified randomization design allows participants to decline one of the treatment arms. This research design partly overcomes the problems active duty military and veterans face when receiving PTSD treatment by allowing them to opt out of one inappropriate or unacceptable treatment modality and still permitting randomization to the two remaining treatment modalities. This manuscript provides an overview of the research design and methods for the study.

When systemic lupus erythematosus (SLE) patients exhibit central nervous system (CNS) signs or symptoms, the prognosis is poorer, the mortality higher (1), and the quality of life is reduced (2). The increased mortality and poor quality of life accompanying CNS involvement highlights the importance of detecting SLE-mediated effects on the brain as early as possible. The best estimate for the prevalence rate of SLE in the United States is approximately 350,000 (3) with CNS involvement in as many as 80% (2, 4, 5). Within the first two years of disease, approximately 20% of patients report neuropsychiatric (NP) symptoms that are attributed to SLE (2). However, many patients (28–40%) report at least one neuropsychiatric episode before or within the first year of diagnosis (2). The primary pathophysiology of SLE is inflammation secondary to autoantibody-mediated effects on tissue, degeneration of small vessels and vasculopathy (6). Inflammation is initiated by circulating autoantibodies generating inflammatory mediators and ends with cell dysfunction, apoptosis and tissue loss (1, 6, 7). Neuroimaging studies in SLE have supplied ample evidence of chronic changes indicative of late-stage pathology. PET studies have reported decreased blood flow (hypoperfusion) and decreased glucose metabolism (hypometabolism), chiefly in frontal and parietal grey matter. T1- and T2-weighted MRI studies have reported white matter volume loss and small punctate lesions. Diffusion tensor MRI and magnetization transfer imaging (MTI) studies show reduced myelination, even in SLE patients with no clear structural damage (8). No neuroimaging methods used to date have detected the inciting pathology, i.e., inflammation. Here, we used PET imaging to detect and localize both brain markers of inflammation (incipient pathology) and tissue failure and apoptosis (late-stage pathology) in persons with newly diagnosed, neurologically asymptomatic SLE. This was done using 18F-fluoro-deoxy-glucose (18FDG) PET to index both inflammation (detected as increased 18FDG uptake) and cell failure (detected as decreased 18FDG uptake). 18FDG is commonly used to detect grey matter dysfunction and atrophy, because the glucose metabolic rate decreases as tissue fails. 18FDG, however, can also be used to detect inflammation (e.g., vasculitis (9)) given that inflammatory cells demonstrate increased glucose transporter expression and that cytokines increase the affinity of glucose transporters for deoxyglucose (10). Similar methods to ours have been used to detect early evidence of white matter hypermetabolism in schizophrenia (11) and attention-deficit/hyperactivity disorder (12). PET data can be analyzed either by visual inspection, or more objectively by using regression methods to quantify covariance of regional 18FDG uptake with a clinical measure (13). The Safety of Estrogens in Lupus Erythematosus National Assessment modified version of the SLE Disease Activity Index (SELENA SLEDAI, SS) is a clinical measure used regularly in the evaluation of SLE (14). It is an index of disease activity in multiple organs, including the brain. Its score correlates with the presence of punctate white matter lesions in the brain of SLE patients without CNS signs or neuropsychiatric (NP) symptoms (15). The imaging analysis we utilized allows for the use of SS as a pattern vector to determine covariance of 18FDG uptake with disease activity. We hypothesized that combining the in vivo assessment of inflammation or tissue failure in the brain and the SS would provide a potential window into the CNS pathophysiology in SLE.

Objective.Cognitive impairment is present in 80% of patients with systemic lupus erythematosus (SLE) 10 years after diagnosis. The natural history of cognitive dysfunction in newly diagnosed SLE is unknown. We examined the association of depression and cognitive performance in newly diagnosed SLE.Methods.A multicenter cohort of 111 patients newly diagnosed (within 9 months) with SLE underwent cognitive function testing using an automated battery [Automated Neuropsychological Assessment Metrics (ANAM)] with 9 subtests. Depression was measured using the Calgary Depression Scale (CDS).Results.The patient cohort was 97.3% female, 55.9% white, 15.3% African American, 20.7% Hispanic, mean age 37.8 years, mean education 15.2 years. CDS score ranged from 0 to 18 (mean 5.0 ± 4.6). CDS score did not differ by age, sex, ethnicity, or prednisone dose. Higher Krupp Fatigue Severity Scale scores and presence of fibromyalgia were significantly associated with higher CDS score (p < 0.001; p = 0.006, respectively). Depressed patients, defined by a CDS score > 6, had significantly poorer performance on 5 ANAM throughput measures: code substitution (p = 0.03), continuous performance (p = 0.02), matching-to-sample (p = 0.04), simple reaction time (p = 0.02), and the Sternberg memory test (p = 0.04). Adjusting for age, sex, ethnicity, education, and prednisone dose, a higher CDS score remained significantly associated with poorer performance on 3 measures, but the association was slightly attenuated for code substitution and matching-to-sample. Depression was not associated with mathematical or spatial processing.Conclusion.Depression, a modifiable risk factor, is associated with significantly poorer function in several cognitive domains in patients newly diagnosed with SLE. Treatment of depression when the CDS score is greater than 6 may improve cognitive functioning and should be further studied.

ObjectiveWe wished to determine the prevalence of cerebral atrophy and focal lesions in a cohort of patients with newly diagnosed systemic lupus erythematosus (SLE) and the association of these brain abnormalities with clinical characteristics.MethodsA total of 97 patients with SLE, within 9 months of diagnosis, with 4 or more American College of Rheumatology classification criteria, were enrolled. Brain magnetic resonance imaging was performed.ResultsThe patients were 97% female, mean age 38.1 (SD 12.2) years, education 15.1 (2.8) years; 59 Caucasian, 11 African American, 19 Hispanic, 5 Asian, and 3 other ethnicity. Cerebral atrophy was prevalent in 18% (95% CI 11%–27%): mild in 12%, moderate in 5%. Focal lesions were prevalent in 8% (95% CI 4%–16%): mild in 2%, moderate in 5%, severe in 1%. Patients with cerebral atrophy were more likely to have anxiety disorder (p = 0.04). Patients with focal lesions were more likely to be African American (p = 0.045) and had higher Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI scores (p = 0.02) and anti-dsDNA (p = 0.05).ConclusionIn this population with newly diagnosed SLE, brain abnormalities were prevalent in 25% of patients. These findings suggest that the brain may be affected extremely early in the course of SLE, even before the clinical diagnosis of SLE is made. Followup of these patients is planned, to determine the reversibility or progression of these abnormalities and their association with and potential predictive value for subsequent neuropsychiatric SLE manifestations.

Objectives There is an enrichment of immune response genes that are subject to copy number variations (CNVs). However, there is limited understanding of their impact on susceptibility to human diseases. CC chemokine ligand 3 like-1 (CCL3L1) is a potent ligand for the HIV coreceptor, CC chemokine receptor 5 (CCR5), and we have demonstrated previously an association between CCL3L1- gene containing segmental duplications and polymorphisms in CCR5 and HIV/AIDS susceptibility. Here, we determined the association between these genetic variations and risk of developing systemic lupus erythaematosus (SLE), differential recruitment of CD3+ and CD68+ leukocytes to the kidney, clinical severity of SLE reflected by autoantibody titres and the risk of renal complications in SLE. Methods We genotyped 1084 subjects (469 cases of SLE and 615 matched controls with no autoimmune disease) from three geographically distinct cohorts for variations in CCL3L1 and CCR5. Results Deviation from the average copy number of CCL3L1 found in European populations increased the risk of SLE and modified the SLE-influencing effects of CCR5 haplotypes. The CCR5 human haplogroup (HH)E and CCR5-Δ32-bearing HHG*2 haplotypes were associated with an increased risk of developing SLE. An individual’s CCL3L1–CCR5 genotype strongly predicted the overall risk of SLE, high autoantibody titres, and lupus nephritis as well as the differential recruitment of leukocytes in subjects with lupus nephritis. The CCR5 HHE/HHG*2 genotype was associated with the maximal risk of developing SLE. Conclusion CCR5 haplotypes HHE and HHG*2 strongly influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. These findings implicate a key role of the CCL3L1–CCR5 axis in the pathogenesis of SLE. COL0000962

Objective: To evaluate predictors of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). Methods: The authors evaluated 123 patients enrolled in the San Antonio Lupus Study of Neuropsychiatric Disease (SALUD) who had completed at least 3 years of follow-up. Study visits occurred every 4 months and included a standard medical history, physical examination, and cognitive testing. Blood was obtained at each study visit for autoantibody testing. Results: There were 116 (94.3%) women and 7 (5.7%) men (mean age = 41.5 [±12.0] years). Patients had the following vascular risk factors: hypercholesterolemia (17.1%), diabetes (21.1%), and hypertension (48.0%). Consistent medication use included aspirin (21.1%), prednisone (65.0%), nonsteroidal anti-inflammatories (42.3%), and hydroxychloroquine (58.5%). The numbers of patients with consistently positive autoantibody levels were as follows: antiphospholipid, 54%; anti-beta-2-glycoprotein 1, 73%; and anti-ribosomal P, 17%. Factors significantly associated with declining cognitive function were consistently positive antiphospholipid antibodies, consistent prednisone use, diabetes, higher depression scores, and less education. The association of prednisone and poorer cognitive function was seen primarily in the middle age group and could not be totally explained by SLE-associated disease activity. Consistent aspirin use was associated with improved cognitive function, primarily in the oldest age group, especially if diabetes was also present. Conclusions: Regular aspirin use is associated with improved cognitive function in older patients with systemic lupus erythematosus (SLE) in conjunction with the presence of other vascular risk factors. Regular prednisone use is associated with decreased cognitive functioning in middle-aged patients with SLE. Although this prednisone effect was independent of measures of SLE-associated disease activity, the authors cannot exclude the possibility that consistent prednisone use is a surrogate for more severe disease.

Paraphasias on the Cognistat (Northern California Neurobehavioral Group, 1995) memory subtest were examined in a sample of geriatric veterans (average age = 77). “Robert” and “parrot” were the most frequently occurring paraphasias for the target words robin, carrot, piano, and green. Paraphasias were also common (35%) for patients with no deficits on Cognistat. Paraphasia production could not be explained by differences in hearing ability, education level, or neuropsychological deficits. Paraphasia frequency and type varied by ethnic group: European-Americans were less likely to have a paraphasia, Hispanic-Americans were more likely to have a “Robert” or “parrot” paraphasia, and African-Americans were more likely to have a paraphasia other than “Robert” or “parrot.” Additional research is needed to determine the cause of paraphasias on the Cognistat and the clinical significance of paraphasias for each ethnic group.

Patients with systemic lupus erythematosus (SLE) often show cognitive impairment on traditional neuropsychological tests; however, many of these tests are unsuitable for use with mixed ethnic populations. Computer-administered cognitive tests are promising, but have not been validated against traditional tests or with predominantly Hispanic samples. We gave 67 lupus patients a computer-administered test battery (Automated Neuropsychological Assessment Metrics--ANAM) and a battery of traditional neuropsychological tests. The two batteries were compared using correlation and multiple regression analyses. All patients were fluent in English, 54% were Hispanic and 13% were bilingual. Non-Hispanic patients were predominantly European American (37%). About 80% of patients were rated as impaired on traditional tests. Hispanics were younger, had less education and more current SLE disease activity than non-Hispanics; but did not differ in lifetime SLE-related organ damage or current steroid use. Hispanics and younger patients were more impaired on many of the traditional tests, while ANAM was not affected by Hispanic ethnicity or education. ANAM tests were moderately correlated with analogous traditional tests. Age and selected ANAM scores accounted for about 60% of the variance in the traditional battery. These results replicate the high prevalence of cognitive deficits in SLE found by others and suggest that computer-administered tests like ANAM may be useful for assessment of cognitive impairment in mixed-ethnic samples. Confounding variables such as age, education, English language fluency and prior experience with tests were identified and need to be controlled statistically or with comparison groups in future studies.

Objective: The San Antonio Lupus Study of Neuropsychiatric Disease is a longitudinal study designed to characterize the spectrum of and important risk factors for specific neuropsychiatric systemic lupus erythematosus (NPSLE) syndromes.Methods: Subjects must meet criteria for SLE and must be at least 18 years of age. A standardized medical history, neurologic, rheumatologic, and psychiatric examinations, computerized neuropsychological evaluation, and serologic testing are performed.Results: This report is based on the first 128 subjects (120 women and 8 men) who completed the initial study visit. Data from this initial study visit were evaluated for the prevalence of NPSLE using the American College of Rheumatology case definitions for 19 NPSLE syndromes. One or more NPSLE syndromes were present in 80% of subjects: cerebrovascular disease (2, 2%; ischemic stroke); headaches (73, 57%); mononeuropathy (9, 8%; median 8, ulnar 1); movement disorder (1, 1%; chorea); neuropathy, cranial (2, 2%; trigeminal); polyneuropathy (29, 22%; sensorimotor); seizures (21, 16%; partial); anxiety disorder (27, 24%); major depressive-like episode (37, 28%); mood disorder with depressive features (21, 19%); mood disorder with manic features (3, 3%); mood disorder with mixed features (1, 1%); psychosis (6, 5%). In a subset of 67 patients who received standardized neuropsychological testing, 21% had normal results. In the remainder, the following levels of impairment were seen: 43% mild, 30% moderate, and 6% severe.Conclusions: The prevalence of NPSLE was high in this cohort of unselected patients with SLE. Headaches, cognitive dysfunction, and psychiatric disorders were the most common NPSLE syndromes seen. These results will be easily comparable to other studies also using standardized diagnostic criteria. However, the lack of ethnicity and language-matched normative neuropsychological data may make comparisons of cognitive dysfunction in SLE populations difficult.

Surgery is performed on some patients with epilepsy. This treatment is usually considered when standard medical treatment is not effective in controlling seizures, when the area of the brain from which the seizures are coming (also called “seizure focus”) can be identified, and when seizures are restricted to only one side of the brain. Approximately 80% of adult epilepsy patients who undergo this surgery have significant improvement in seizure control. More information about epilepsy surgery can be found on the next page. ### Memory Problems After Epilepsy Surgery One of the side effects of epilepsy surgery can be memory problems. From prior studies, the risk of this seems greater when the surgery is performed on the left side of the brain. It is unclear whether these memory problems after epilepsy surgery are any worse than in patients with poorly controlled seizures who do not have epilepsy surgery. In this issue of Neurology , Rausch et al. report a study of memory function 9 to 19 years after epilepsy surgery in patients who had left vs right-sided surgery. Both groups were compared to epilepsy patients who had similar seizure disorders and were followed for the same time period, but did not have surgery. There were 21 patients who had epilepsy surgery on the left side of the brain, 23 who had epilepsy surgery on the right side of the brain, and 8 patients who did not have surgery. Memory function and seizure control was measured in each group 1 year after the surgery, or 1 year after the surgical evaluation in the group who did not have epilepsy surgery. All groups were evaluated again at an average of 12 years later. ### Patients With Epilepsy Surgery on the Left Side of the Brain Have More Memory Problems The 1st year after …

Objective: Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients. Methods: All English-speaking participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (National Clinical Trial 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z scores using published norms. Those with impairment (z ≤ −1.5) in memory and/or nonmemory domains were classified as having mild cognitive impairment (MCI). Results: Among the 1,636 participants, average z scores on all tests were

Methods TNPB, Ped-ANAM, quality of life (PedsQL), and depression scales (CDI-S) were administered by psychology associates blinded to clinical status at two research visits. Differences in mean TNPB standardized scores, PedANAM throughput scores (raw Throughput=correct responses/minute), and clinical variables between visits were compared using paired Student t-tests. Multi-variable linear regression analysis was used to assess the influence of initial test performance, aPL/LAC status, disease duration, and cumulative prednisone dosing on composite TNPB or Ped-ANAM scores at a second visit.

The neurovascular consequences of collagen vascular diseases are due in large part to two major causes: atherosclerosis and prothrombotic effects of antiphospholipid (aPL) antibodies. Patients with systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) can both develop premature atherosclerosis, and the study of patients with these disorders has been quite informative in understanding the relationship between inflammation, atherosclerosis, and cardioand cerebrovascular disease outcomes (Manzi et al. 1997; Abou-Raya & Abou-Raya, 2006; Rhew & Ramsey-Goldman, 2006). In this chapter, we will discuss the evidence for the role of inflammation-induced atherosclerosis and aPL antibodies in neurovascular consequences of SLE, a prototypic collagen vascular disease. Systemic lupus erythematosis is an autoimmune inflammatory disorder affecting multiple organ systems, which affects women nine times more frequently than men (Ward, 2004). The prevalence is approximately 130/100,000 in the United States, with African Americans, Hispanics, and Asians more frequently affected than non-Hispanic Whites (Danchenko, Satia, & Anthony, 2006). The nervous system is commonly affected in people with SLE (Ainiala, Loukkola, Peltola, Korpela, & Hietaharju, 2001; Brey, Holliday et al., 2002). TheAmerican College of Rheumatology ((ACR) established case definitions for 19CNS and PNS syndromes observed in SLE patients, which collectively are referred to as neuropsychiatric systemic lupus erythematosus (NPSLE) syndromes (Table 1) (The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes, 1999).

Measurable cognitive impairment occurs in 30-75% of patients with systemic lupus erythematosus (SLE). We compared cognitive functioning in recently-diagnosed SLE patients and normal controls.The Automated Neuropsychological Assessment Metrics (ANAM), a repeatable computerized cognitive battery assessing cognitive processing speed and efficiency, was administered to 111 recently diagnosed SLE patients and 79 normal controls. Throughput scores on ANAM subtests were compared using linear regression.After adjusting for age, gender, ethnicity, and education, SLE patients scored significantly lower than controls on throughput measures of 4 ANAM subtests: code substitution immediate recall (p = 0.02), continuous performance (p = 0.02), matching to sample (p = 0.02), and Sternberg subtest (p = 0.0002).Recently diagnosed SLE patients performed significantly worse than normal controls on 4 of 9 ANAM subtests. ANAM subtests of cognitive efficiency requiring sustained attention/vigilance, visuospatial span of attention/working memory, and simple reaction time showed the greatest impairment. These cognitive deficits were particularly striking, because the SLE patients in this sample were not selected for the presence of neuropsychiatric manifestations, had mild SLE-related disease/damage, and were recently diagnosed with SLE. This suggests that deficits in cognitive efficiency and sustained attention are present early in the course of SLE and in the absence of other significant neuropsychiatric manifestations.