Structural connectome disruption at baseline predicts 6-months post-stroke outcome.

In this study, models based on quantitative imaging biomarkers of post-stroke structural connectome disruption were used to predict six-month outcomes in various domains. Demographic information and clinical MRIs were collected from 40 ischemic stroke subjects (age: 68.1 ± 13.2 years, 17 female, NIHSS: 6.8 ± 5.6). Diffusion-weighted images were used to create lesion masks, which were uploaded to the Network Modification (NeMo) Tool. The NeMo Tool, using only clinical MRIs, allows estimation of connectome disruption at three levels: whole brain, individual gray matter regions and between pairs of gray matter regions. Partial Least Squares Regression models were constructed for each level of connectome disruption and for each of the three six-month outcomes: applied cognitive, basic mobility and daily activity. Models based on lesion volume were created for comparison. Cross-validation, bootstrapping and multiple comparisons corrections were implemented to minimize over-fitting and Type I errors. The regional disconnection model best predicted applied cognitive (R(2) = 0.56) and basic mobility outcomes (R(2) = 0.70), while the pairwise disconnection model best predicted the daily activity measure (R(2) = 0.72). These results demonstrate that models based on connectome disruption metrics were more accurate than ones based on lesion volume and that increasing anatomical specificity of disconnection metrics does not always increase model accuracy, likely due to statistical adjustments for concomitant increases in data dimensionality. This work establishes that the NeMo Tool's measures of baseline connectome disruption, acquired using only routinely collected MRI scans, can predict 6-month post-stroke outcomes in various functional domains including cognition, motor function and daily activities. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Two Novel Psychomotor Tasks in Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (INPH) is a neurological disorder presenting with gait, cognitive, and bladder symptoms in the context of ventricular enlargement. Although gait is the primary indicator for treatment candidacy and outcome, additional monitoring tools are needed. Line Tracing Test (LTT) and Serial Dotting Test (SDT), two psychomotor tasks, have been introduced as potential outcome measures but have not been widely studied. This preliminary study examined whether LTT and SDT are sensitive to motor dysfunction in INPH and determined if accuracy and time are important aspects of performance. METHODS: Eighty-four INPH subjects and 36 healthy older adults were administered LTT and SDT. Novel error scoring procedures were developed to make scoring practical and efficient; interclass correlation showed good reliability of scoring procedures for both tasks (0.997; p<.001). RESULTS: The INPH group demonstrated slower performance on SDT (p<.001) and made a greater number of errors on both tasks (p<.001). Combined Time/Error scores revealed poorer performance in the INPH group for original-LTT (p<.001), modified-LTT (p ≤ .001) and SDT (p<.001). CONCLUSIONS: These findings indicate LTT and SDT may prove useful for monitoring psychomotor skills in INPH. While completion time reflects impaired processing speed, reduced accuracy may suggest planning and self-monitoring difficulties, aspects of executive functioning known to be compromised in INPH. This is the first study to underscore the importance of performance accuracy in INPH and introduce practical/reliable error scoring for these tasks. Future work will establish reliability and validity of these measures and determine their utility as outcome tools.

Exploring the brain's structural connectome: A quantitative stroke lesion-dysfunction mapping study.

The aim of this work was to quantitatively model cross-sectional relationships between structural connectome disruptions caused by cerebral infarction and measures of clinical performance. Imaging biomarkers of 41 ischemic stroke patients (72.0 ± 12.0 years, 20 female) were related to their baseline performance in 18 cognitive, physical and daily life activity assessments. Individual estimates of structural connectivity disruption in gray matter regions were computed using the Change in Connectivity (ChaCo) score. ChaCo scores were utilized because they can be calculated using routinely collected clinical magnetic resonance imagings. Partial Least Squares Regression (PLSR) was used to predict various acute impairment and activity measures from ChaCo scores and patient demographics. Statistical methods of cross-validation, bootstrapping and multiple comparisons correction were implemented to minimize over-fitting and Type I errors. Multiple linear regression models based on lesion volume and lateralization information were constructed for comparison. All models based on connectivity disruption had lower Akaike Information Criterion and almost all had better goodness-of-fit values (R(2) : 0.26-0.92) than models based on lesion characteristics (R(2) : 0.06-0.50). Confidence intervals of PLSR coefficients identified brain regions important in predicting each clinical assessment. Appropriate mapping of eloquent functions, that is, language and motor, and replication of results across pathologies provided validation of this method. Models of complex functions provided new insights into brain-behavior relationships. In addition to the potential applications in prognostication and rehabilitation development, this quantitative approach provides insight into the structural networks underlying complex functions like activities of daily living and cognition. Quantitative analysis of big data will be invaluable in understanding complex brain-behavior relationships.

A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease.

INTRODUCTION: Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. METHODS: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. RESULTS: Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P < .001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. CONCLUSIONS: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

Clinical trials of intravenous immunoglobulin for Alzheimer's disease.

The human polyclonal IgG antibody preparation known as Intravenous Immunoglobulin (IVIG) has been under study as a potential treatment for Alzheimer's disease (AD) since 2002. Preclinical and clinical studies have shown that IVIG has anti-amyloid and immune modulatory properties relevant to treating neurodegenerative disorders. In early stage AD clinical trials, IVIG was found to reduce cognitive decline and increase brain glucose metabolism. Unfortunately, IVIG failed to meet primary outcome objectives in the North American Phase 3 clinical trial in mild to moderate AD. However, positive cognitive signals were observed in pre-planned subgroup analyses among APOE-ε4 carriers and moderately impaired AD patients. Biomarker studies revealed dose dependent increases in plasma and CSF immunoglobulins and decreases in beta amyloid-42 levels. In addition, IVIG treatment was generally safe and well-tolerated. These findings suggest that naturally occurring human anti-amyloid antibodies may play a physiologic role in the clearance of aggregated amyloid proteins. While the results of clinical trials to date do not provide support for the use of IVIG to treat AD at the doses tested, additional studies of IVIG's mechanisms are warranted and may guide the development of more effective therapies for AD in the future.

Longitudinal effects of intravenous immunoglobulin on Alzheimer's cerebrospinal fluid proteome.

Intravenous immunoglobulin (IVIg) therapy has shown promise in the treatment of Alzheimer's disease (AD). In this study, serial cerebrospinal fluid (CSF) samples from a group of subjects with AD undergoing IVIg immunotherapy are analyzed to identify IVIg-related changes. CSF samples from eight subjects were collected before therapy, after 6 months of therapy, and after a 3-month drug washout period. Samples were analyzed using a gel-based proteomics strategy and IVIg-related changes were determined by gel spot percent volumes. An initial assessment of the data revealed consistent and considerable change in 69 spots. A statistical analysis revealed 79 protein spots with a significant change after 6 months; furthermore, in a subset of these (25), the percent volume change was either maintained or reversed in the washout samples. The proteins that showed a significant change during IVIg therapy, including Ig molecules, gelsolin, transferrin, and transthyretin, have been previously implicated in AD. This study provides preliminary findings regarding a group of CSF proteins that may be associated with the treatment of AD, as well as the potential use of IVIg as an AD immunotherapy.

Disclosure of APOE genotype for risk of Alzheimer's disease.

BACKGROUND: The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial. METHODS: We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. RESULTS: There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7, respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE epsilon4 allele (which is associated with increased risk) also revealed no significant differences. However, the epsilon4-negative subgroup had a significantly lower level of test-related distress than did the epsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the epsilon4-positive and epsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). CONCLUSIONS: The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE epsilon4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number, NCT00571025.)

Longitudinal analysis of novel Alzheimer's disease proteomic cerebrospinal fluid biomarkers during intravenous immunoglobulin therapy.

Intravenous immunoglobulin (IVIg) therapy has shown promising results in treating Alzheimer's disease (AD). In this study, a Random Forest (RF) classification model was used to identify possible effects of IVIg on a group of eight subjects who underwent immunotherapy. Cerebrospinal fluid (CSF) samples from eight AD subjects who underwent IVIg therapy were collected before therapy, after 6 months of therapy, and after a 3-month drug washout period. Samples were analyzed using 2DE and further studied using a RF classification model to identify effects of IVIg on a panel of 23 putative diagnostic AD biomarkers previously identified. Six of the eight subjects showed improvements with respect to the 23 AD diagnostic biomarkers after 6 months of therapy compared to the samples taken at the outset of the trial. All subjects reverted back to baseline during drug washout. These results are also consistent with clinical observations. The observed improvements in subjects during 6 months of IVIg therapy and the reversion back to baseline during drug washout provides preliminary evidence regarding the potential use of IVIg as an AD immunotherapy.

Salmonella Typhimurium biofilm disruption by a human antibody that binds a pan-amyloid epitope on curli.

Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S. Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms.

The clinical spectrum of hydrocephalus in adults: report of the first 517 patients of the Adult Hydrocephalus Clinical Research Network registry.

OBJECTIVE: The authors describe the demographics and clinical characteristics of the first 517 patients enrolled in the Adult Hydrocephalus Clinical Research Network (AHCRN) during its first 2 years. METHODS: Adults ≥ 18 years were nonconsecutively enrolled in a registry at 6 centers. Four categories of adult hydrocephalus were defined: transition (treated before age 18 years), unrecognized congenital (congenital pattern, not treated before age 18 years), acquired (secondary to known risk factors, treated or untreated), and suspected idiopathic normal pressure hydrocephalus (iNPH) (≥ age 65 years, not previously treated). Data include etiology, symptoms, examination findings, neuropsychology screening, comorbidities, treatment, complications, and outcomes. Standard evaluations were administered to all patients by trained examiners, including the Montreal Cognitive Assessment, the Symbol Digit Modalities Test, the Beck Depression Inventory-II, the Overactive Bladder Questionnaire Short Form symptom bother, the 10-Meter Walk Test, the Boon iNPH gait scale, the Lawton Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) questionnaire, the iNPH grading scale, and the modified Rankin Scale. RESULTS: Overall, 517 individuals were enrolled. Age ranged from 18.1 to 90.7 years, with patients in the transition group (32.7 ± 10.0 years) being the youngest and those in the suspected iNPH group (76.5 ± 5.2 years) being the oldest. The proportion of patients in each group was as follows: 16.6% transition, 26.5% unrecognized congenital, 18.2% acquired, and 38.7% suspected iNPH. Excluding the 86 patients in the transition group, who all had received treatment, 79.4% of adults in the remaining 3 groups had not been treated at the time of enrollment. Patients in the suspected iNPH group had the poorest performance in cognitive evaluations, and those in the unrecognized congenital group had the best performance. The same pattern was seen in the Lawton ADL/IADL scores. Gait velocity was lowest in patients in the suspected iNPH group. Categories that had the most comorbidities (suspected iNPH) or etiologies of hydrocephalus that directly cause neurological injury (transition, acquired) had greater degrees of impairment compared to unrecognized congenital, which had the fewest comorbidities or etiologies associated with neurological injury. CONCLUSIONS: The clinical spectrum of hydrocephalus in adults comprises more than iNPH or acquired hydrocephalus. Only 39% of patients had suspected iNPH, whereas 43% had childhood onset (i.e., those in the transition and unrecognized congenital groups). The severity of symptoms and impairment was worsened when the etiology of the hydrocephalus or complications of treatment caused additional neurological injury or when multiple comorbidities were present. However, more than half of patients in the transition, unrecognized congenital, and acquired hydrocephalus groups had minimal or no impairment. Excluding the transition group, nearly 80% of patients in the AHCRN registry were untreated at the time of enrollment. A future goal for the AHCRN is to determine whether patients with unrecognized congenital and acquired hydrocephalus need treatment and which patients in the suspected iNPH cohort actually have possible hydrocephalus and should undergo further diagnostic testing. Future prospective research is needed in the diagnosis, treatment, outcomes, quality of life, and macroeconomics of all categories of adult hydrocephalus.

Natural human antibodies to amyloid beta peptide.

Properties of human, natural anti-Abeta antibodies and commercially available intravenous immunoglobulin (IVIg) have been examined in light of the beneficial effects of passive immunotherapy with IVIg for patients with mild to moderate Alzheimer's disease (AD). Anti-Abeta antibodies in IVIg recognize conformation-specific epitopes as well as linear epitopes from different regions of the Abeta peptide. Anti-Abeta antibodies in circulation, especially those with high avidity, are often masked by ligands and the avidity of these antibodies increases upon dissociation of the bound ligands from the antibodies. Such natural anti-Abeta antibodies have the capacity to prevent Abeta oligomer-induced neurotoxicity in N2A neuroblastoma cells. This neuro-protective effect may reflect the therapeutic potential of the natural anti-Abeta antibodies found in IVIg for the treatment of patients with AD.

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience.

PURPOSE: To describe how investigators in a multisite randomized clinical trial addressed scientific and ethical issues involved in creating risk models based on genetic testing for African American participants. METHODS: The following informed our decision whether to stratify risk assessment by ethnicity: evaluation of epidemiological data, appraisal of benefits and risks of incorporating ethnicity into calculations, and feasibility of creating ethnicity-specific risk curves. Once the decision was made, risk curves were created based on data from a large, diverse study of first-degree relatives of patients with Alzheimer disease. RESULTS: Review of epidemiological data suggested notable differences in risk between African Americans and whites and that Apolipoprotein E genotype predicts risk in both groups. Discussions about the benefits and risks of stratified risk assessments reached consensus that estimates based on data from whites should not preclude enrolling African Americans, but population-specific risk curves should be created if feasible. Risk models specific to ethnicity, gender, and Apolipoprotein E genotype were subsequently developed for the randomized clinical trial that oversampled African Americans. CONCLUSION: The Risk Evaluation and Education for Alzheimer Disease study provides an instructive example of a process to develop risk assessment protocols that are sensitive to the implications of genetic testing for multiple ethnic groups with differing levels of risk.

Features of gait most responsive to tap test in normal pressure hydrocephalus.

OBJECTIVE: To identify components of gait associated with a positive tap test (TT) in patients with idiopathic normal pressure hydrocephalus (iNPH). PATIENTS AND METHODS: Thirty-three patients with iNPH underwent clinical evaluation pre- and post-TT and were classified as responders (Rs) or non-responders (NRs). Elements of gait were assessed with a formal standardized Gait Scale and compared between groups. RESULTS: Analysis of pre/post-TT group differences revealed an interaction for Total Gait Score and Walking Score, with improvements in responders only. Total Gait Scores improved by 29% in the Rs and 4.85% in the NRs. Rs showed significant post-TT improvements on a timed 10m walk, turning, and balance. Tandem walking, turning, truck balance and start stop hesitation showed trends toward improvement. CONCLUSIONS: The classic features of gait often used in determining diagnosis of NPH (wide based stride, reduced foot-floor clearance, and small steps) were not helpful in identifying responders to the TT. Walking speed, steps for turning, and tendency towards falling were most likely to improve post-TT. These straightforward measures can readily be adapted into clinical practice to assist in determination of shunt candidacy.

Disease-modifying approaches to Alzheimer's disease: challenges and opportunities-Lessons from donepezil therapy.

The era of disease modification as a therapeutic option for Alzheimer's disease (AD) is upon us. With dozens of novel drugs in development, there is more need than ever to develop biomarkers that distinguish normal aging from AD and AD from other dementias, track changes over time as disease progresses, and respond to interventions. Future trials will need to weight biomarker outcomes equal to cognitive outcomes especially when the biomarkers are linked to specific mechanisms, such as changes to beta amyloid (Abeta) deposition or brain volume. Since the advent of donepezil as a treatment for AD, new mechanisms of action of this molecule have been discovered. In this perspective, we review trial design and discuss the use of biomarkers by using lessons learned from previous trials conducted with cholinergic therapy.

Cerebrospinal fluid Aß42, t-tau, and p-tau levels in the differential diagnosis of idiopathic normal-pressure hydrocephalus: a systematic review and meta-analysis.

OBJECTIVES: The purpose of this systematic review and meta-analysis was to evaluate the performance of cerebrospinal fluid (CSF) beta amyloid 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) as potential diagnostic biomarkers for idiopathic normal-pressure hydrocephalus (iNPH) and to assess their utility indistinguishing patients with iNPH from those with Alzheimer disease (AD) and healthy normal controls. METHODS: Studies were identified by searching PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical Database, VIP Chinese database, and Chinese Bio-medicine Database (CBM) before August 2016. The standardized mean difference (SMD) and 95% confidence interval (CI), comparing CSF Aß42, t-tau, and p-tau levels between iNPH, AD and healthy controls, were calculated using random-effects models. Subgroup analyses were created according to ethnicity (Caucasian or Asian) and CSF type (lumbar or ventricular), and the publication bias was estimated using Egger's test and the Begg's test. RESULTS: A total of 10 studies including 413 patients with iNPH, 186 patients with AD and 147 healthy controls were included in this systematic review and meta-analysis. The concentrations of CSF t-tau, and p-tau were significantly lower in iNPH patients compared to AD (SMD = -1.26, 95% CI -1.95 to -0.57, P = 0.0004; SMD = -1.54, 95% CI -2.34 to -0.74, P = 0.0002, respectively) and lower than healthy controls (SMD = -0.80, 95% CI -1.50 to -0.09, P = 0.03; SMD = -1.12, 95% CI -1.38 to -0.86, P < 0.00001, respectively). Patients with iNPH had significantly lower Aß42 levels compared with controls (SMD = -1.14, 95% CI -1.74 to -0.55, P = 0.0002), and slightly higher Aß42 levels compared with AD patients (SMD = 0.32, 95% CI 0.00-0.63, P = 0.05). Subgroup analyses showed that the outcomes may have been influenced by ethnicity and CSF source. Compared to AD, overall sensitivity in differentiating iNPH was 0.813 (95% CI 0.636-0.928) for Aß42, 0.828 (95% CI 0.732-0.900) for t-tau, 0.943 (95% CI 0.871-0.981) for p-tau. Relative to AD, overall specificity in differentiating iNPH was 0.506 (95% CI 0.393-0.619) for Aß42, 0.842 (95% CI 0.756-0.907) for t-tau, 0.851 (95% CI 0.767-0.914) for p-tau. CONCLUSION: The results of our meta-analysis suggest that iNPH may be associated with significantly reduced levels of CSF Aß42, t-tau and p-tau compared to the healthy normal state. Compared to AD, both t-tau and p-tau were significantly decreased in iNPH, but CSF Aß42 was slightly increased. Prospective studies are needed to further assess the clinical utility of these and other CSF biomarkers in assisting in the diagnosis of iNPH and differentiating it from AD and other neurodegenerative disorders.

A phase 3 trial of IV immunoglobulin for Alzheimer disease.

OBJECTIVE: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. RESULTS: No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aß42 (but not Aß40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. CONCLUSIONS: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo. CLINICALTRIALSGOV IDENTIFIER: NCT00818662. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Development and testing of a new outcome measure of relationship between patients with Alzheimer's disease and their partners.

In mild Alzheimer's disease (AD), loss of relationship with the patient is a significant consequence for the partner (relative) and may be amenable to improvement with effective intervention. To evaluate relationship dynamics, the authors developed and tested content and discriminative validity of the self-administered Partner-Patient Questionnaire for Shared Activities among 100 partners of patients with mild to moderate Alzheimer's disease. Principal component analysis confirmed that interference in 17 activities derived from the literature and partner-specified activities comprised a relationship factor; internal consistency was very high. Time spent caregiving, caregiver esteem, lack of family support, and impact on partner health and activities were significant predictors of the Partner-Patient Questionnaire for Shared Activities, but the patient's cognitive and mood states were not. The Partner-Patient Questionnaire for Shared Activities warrants additional psychometric testing as a measure of Alzheimer's disease outcome.

Effective anti-Alzheimer Aß therapy involves depletion of specific Aß oligomer subtypes.

BACKGROUND: Recent studies have implicated specific assembly subtypes of ß-amyloid (Aß) peptide, specifically soluble oligomers (soAß) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aß assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aß assemblies including soAß. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aß antibodies to the clinical bioactivity of IVIg has been lacking. METHODS: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aß conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAß levels using standard anti-soAß antibodies. RESULTS: We provide evidence that NU4-type soAß (NU4-soAß) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aß plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAß and A11-soAß but not OC-type fibrillar Aß oligomers. CONCLUSIONS: We propose that targeting of specific soAß assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aß antibody drugs.

Alzheimer's disease cerebrospinal fluid biomarker discovery: a proteomics approach.

There is significant interest in the identification of effective biomarkers for Alzheimer's disease. Such biomarkers could aid in the clinical diagnosis of the disease and may be useful in assessing the efficacy of various treatment strategies. The search for biomarkers often includes the analysis of changes in cerebrospinal fluid protein expression that correlate with disease. These changes can be measured using a variety of technologies for protein expression profiling. Although there is great promise in the application of these methods to biomarker discovery based on some preliminary observations, there are significant issues in the capabilities of most of these technologies that have limited their effective application. The most recent literature involving proteomic discovery of new cerebrospinal fluid biomarkers for Alzheimer's disease is reviewed.