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BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aß-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aß-amyloid (32 Aß-amyloid-and 45 Aß-amyloid+), as well as concordance between CSF biomarker levels and PET Aß-amyloid imaging. METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. RESULTS: Across all three platforms, the T-tau/Aß42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aß42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aß-amyloid-and Aß-amyloid+ groups were strongest for the Aß42/Aß40 and T-tau/Aß42 ratios (p < 0.0001); however, comparison of predictive models for PET Aß-amyloid showed no difference between Aß42 alone and the T-tau/Aß42 ratio. CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aß-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

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OBJECTIVE: Improving and minimizing challenging behaviors seen in psychiatric conditions, including behavioral and psychological symptoms of dementia are important in the care of people with these conditions. Yet there is a lack of systematic evaluation of these as a part of routine clinical care. The Neuropsychiatric Inventory is a validated and reliable tool for rating the severity and disruptiveness of challenging behaviors. We report on the evaluation of a Web-based symptom assessment manager (SAM), designed to address the limitation of previous tools using some of the Neuropsychiatric Inventory functions, to monitor behaviors by staff caring for people with dementia and other psychiatric conditions in inpatient and residential care settings. METHODS: The SAM was piloted in an 8-bed inpatient neuropsychiatry unit over 5 months. Eleven nurses and 4 clinicians were trained in usage of SAM. Primary outcomes were usage of SAM and perceived usability, utility, and acceptance of SAM. Secondary outcomes were the frequencies of documented behavior. Usage data were analyzed using chi-square and logistic regression analyses. RESULTS: The SAM was used for all admitted patients regardless of diagnosis, with a usage rate of 64% for nurses regularly employed in the unit. Staff provided positive feedback regarding the utility of SAM. CONCLUSIONS: The SAM appeared to offer individualized behavior assessment by providing a quick, structured, and standardized platform for assessing behavior in a real-world setting. Further research would involve trialing SAM with more staff in alternative settings such as in home or residential care settings.

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Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.

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INTRODUCTION: Changes in cerebrospinal fluid (CSF) tau and amyloid ß (Aß)42 accompany development of Alzheimer's brain pathology. Robust tau and Aß42 immunoassays were developed to establish a tau/Aß42 cutoff distinguishing mild-to-moderate Alzheimer's disease (AD) subjects from healthy elderly control (HC) subjects. METHODS: A CSF tau/Aß42 cutoff criteria was chosen, which distinguished the groups and maximized concordance with amyloid PET. Performance was assessed using an independent validation cohort. RESULTS: A tau/Aß42 = 0.215 cutoff provided 94.8% sensitivity and 77.7% specificity. Concordance with PET visual reads was estimated at 86.9% in a ∼50% PET positive population. In the validation cohort, the cutoff demonstrated 78.4% sensitivity and 84.9% specificity to distinguish the AD and HC populations. DISCUSSION: A tau/Aß42 cutoff with acceptable sensitivity and specificity distinguished HC from mild-to-moderate AD subjects and maximized concordance to brain amyloidosis. The defined cutoff demonstrated that CSF analysis may be useful as a surrogate to imaging assessment of AD pathology.

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INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. METHODS: Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. RESULTS: For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Aß42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Aß42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. CONCLUSIONS: Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers.

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IMPORTANCE: This study assesses factors associated with the most common adverse event following lumbar puncture. OBJECTIVE: To identify factors associated with the risk, onset, and persistence of post-dural puncture headache (PDPH). DESIGN, SETTING, AND PARTICIPANTS: We performed univariate and multivariable analyses of 338 lumbar punctures in the Dominantly Inherited Alzheimer Network observational study using linear mixed models, adjusting for participant-level and family-level random effects. MAIN OUTCOMES AND MEASURES: We directly evaluated associations of 3 post-lumbar puncture outcomes (immediate postprocedural headache, PDPH at 24-hour follow-up, and PDPH receiving a therapeutic blood patch) with participant age and sex, positioning, collection method, needle size, needle insertion site, and cerebrospinal fluid (CSF) volume collected. RESULTS: The incidence of adverse events included 73 immediate postprocedural headaches (21.6%), 59 PDPHs at 24-hour follow-up (17.5%), and 15 PDPHs receiving a therapeutic blood patch (4.4%). Greater volume of CSF collected was associated with increased risk of immediate postprocedural headache, largely owing to a nonlinear increase in risk on collection of volumes above 30 mL (odds ratio, 3.73 for >30 mL and 0.98 for <17 mL). In contrast, collection of higher volumes showed a protective effect in decreasing rates of PDPH at 24-hour follow-up and rates of PDPH receiving a therapeutic blood patch (odds ratio, 0.35 per 10 mL). Although differences in needle size did not reach statistical significance, no participant in the 24G needle group received a therapeutic blood patch compared to 8 of 253 for the larger 22G needles. CONCLUSIONS AND RELEVANCE: Factors that acutely lower CSF pressure (eg, seated positioning or extracting very high volumes of CSF) may be associated with transient post-lumbar puncture headache, without increasing rates of persistent PDPH or therapeutic blood patch. Collection of up to 30 mL of CSF appears to be well tolerated and safe.

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Concussion-related cognitive impairments are typically evaluated with repeated neuropsychological assessments where post-injury performances are compared with pre-injury baseline data (baseline method). Many cases of concussions, however, are evaluated in the absence of baseline data by comparing post-injury performances with normative data (normative method). This study aimed to compare the sensitivity and specificity of these two methods using the CogSport/Axon test battery. Normative data and reliable change indices were computed from a non-injured athlete sample (n = 235). Test-retest data from non-injured (n = 260) and recently concussed (n = 29) athlete samples were then used to compare the two methods. The baseline method was found to be more sensitive than the normative method, and both methods had high specificity and overall correct classification rates. This suggests that while the normative method identifies most cases of recent concussions, the baseline method remains a more precise approach to assessing concussion-related cognitive impairments.

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OBJECTIVES: Concussion is common in contact sports such as boxing. Diagnosis of concussion depends on symptom report or recognition of clinical features, and true incidence may be underestimated. Persistent morbidity is a possible risk of repeated or unrecognised concussion. This study aimed to evaluate pre and postbout cognitive performance in motivated amateur boxers in order to detect objective evidence of unrecognised cognitive impairment suggestive of concussive injury. METHODS: The study employed a prospective and observational design. Participants were amateur boxers who won at least one bout in a single elimination competition. Optimal preparticipation performance using a computerised cognitive assessment tool (CCAT, Axon Sports) and no significant deterioration in cognitive performance within 24 h postbout were required to compete. All boxers were screened for clinical evidence of concussion by a ringside physician. RESULTS: Of approximately 200 competing boxers, 96 were eligible having won at least one of the total 160 bouts. Mean age was 21.3 (SD 1.9) years (range 18.5-29.7). Of these, 17 (10.6%) failed their first postbout CCAT, with 12 (71%) passing a repeat test. Of the five remaining boxers, there were two boxers (1.3% of bouts) not suspected of a concussion after their bouts, who showed evolving slowing in cognitive performance typical of a concussion. CONCLUSIONS: Cognitive impairment, as detected by subtle deterioration in reaction time measures, can occur in amateur boxers postbout that is not recognised at ringside. Although the vast majority of bouts were conducted safely, unrecognised injury may occur and be detectable using objective computerised cognitive assessment.

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BACKGROUND: Progressive intraindividual decline in memory and cognition is characteristic of dementia and may be useful in detecting very early Alzheimer's disease pathology. METHODS: This study evaluated the slopes of cognitive performance over a 12-month period in 263 healthy, community-dwelling, adult volunteers aged ≥50 years. Participants completed a brief computerized battery of cognitive tests (CogState) at baseline and during 3-, 6-, 9-, and 12-month follow-up assessments. Linear mixed models were used to estimate age-adjusted mean slopes and 95% confidence intervals of change for each of the cognitive measures. RESULTS: By defining age-adjusted mean slopes, and 95% confidence intervals for a measure of episodic memory, individuals with greater than expected decline (equal to or lower than the fifth percentile level of decline) were identified. From these, four individuals completed a full medical, neurologic, and neuropsychological evaluation, with none of them fulfilling criteria for mild cognitive impairment, but three (75%) having positive amyloid-positron emission tomographic scans. CONCLUSIONS: Intraindividual decline in cognitive performance can be detected in otherwise healthy, community-dwelling, older persons, and this may deserve further study as a potential indicator of early Alzheimer's disease pathology.

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Intra-individual decline in memory and cognition is characteristic of prodromal Alzheimer's disease (AD) and may allow detection of very early AD pathology. Episodic memory task scores on a brief computerized cognitive battery (CogState) were prospectively evaluated at baseline, and 3-, 6-, 9-, 12-, and 24-months post-baseline. Linear mixed models were conducted to compute age-adjusted slopes. Subjects with slopes declining ≥90th percentile ("memory decliners") and age- and gender-matched subjects without such decline ("non-decliners") were studied with clinical, neuropsychological, and neuroimaging evaluations. Of 195 who completed 24-month evaluation (age 51 to 80 years), 15 memory decliners (mean age 62.7 years, SD 7.6) were identified, and matched with 33 non-decliners (mean age 63.3 years, SD 8.2). Amyloid-PET imaging was qualitatively abnormal with excess cortical amyloid accumulation in 7 memory decliners (46.7%) and 4 (12.1%) non-decliners (odds ratio 6.34), and quantitatively abnormal with standardized uptake value ratios >1.4 in 5 memory decliners (33.3%) and 2 (6.1%) non-decliners (odds ratio 8.3). One of the memory decliners and none of the non-decliners fulfilled criteria for mild cognitive impairment, but the groups did not differ with respect to subjective memory impairment, neuropsychological evidence of episodic memory impairment, or MRI imaging abnormalities. Intra-individual decline in episodic memory can be detected using a brief computerized cognitive performance test optimized to detect change in community-dwelling non-demented older persons and appears predictive of the presence of cerebral amyloid in about half of these persons. This approach may help detect early prodromal AD pathology in wider-scale community screening programs.

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There are many situations in which cognitive tests need to be administered on more than two occasions and at very brief test-retest intervals to detect change in group performance. However, previous literature has not specifically addressed these important issues. The main aim of the current study was to examine these two factors by using a computerized cognitive battery designed specifically for the repeated assessment of cognition (i.e., CogState) in healthy young adult individuals. A further aim of the study was to examine how many times the battery needed to be completed before performance, as measured by the battery, stabilized. Forty-five adults (age range: 18-40 years) completed the battery four times at 10-minute test-retest intervals, and a fifth time at an interval of one week. The results illustrated that when brief test-retest intervals were used (i.e., 10 minutes), performance stabilized after the second assessment, as significant practice effects were generally observed between the first and the second assessments. Practice effects were also observed on some of the tasks at a one-week test-retest interval. Due to these findings, 55 adults (age range: 18-40 years) completed the battery twice at 10-minute test-retest intervals (i.e., to eliminate the initial practice effect), and a third time at an interval of one month. No practice effects were observed. The implications of the results are discussed in terms of methods that can be adopted in order to minimize practice effects when this particular cognitive battery is used.

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Previous studies that have quantified fatigue-related cognitive impairment as blood alcohol concentration (BAC) equivalents have been limited by two issues: the effect of practice on tests of cognition and, more importantly, the statistic used to quantify change in cognitive performance. The current study addressed these issues by adopting an ABACA design, which allowed for the adequate control of practice effects, and by using effect size metrics, which enabled direct comparisons to be made in performance impairments as a result of fatigue (i.e. sustained wakefulness of 24 h) and alcohol (i.e. BAC of 0.05%). Cognitive performance under the fatigue and alcohol conditions required the use of the CogState battery. It was demonstrated that fatigue caused greater impairment than alcohol on the speed of continuous attention and memory and learning, and on the accuracy of complex matching. Alcohol was more detrimental than fatigue only on the accuracy of memory and learning. Performances on the remaining tasks were the same for both the fatigue and alcohol conditions. These differences and similarities in performance impairment are discussed emphasizing the deleterious cognitive effects of relatively short periods of sustained wakefulness.

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Performance on many cognitive and neuropsychological tests may be improved by prior exposure to testing stimuli and procedures. These beneficial practice effects can have a significant impact on test performance when conventional neuropsychological tests are administered at test-retest intervals of weeks, months or years. Many recent investigations have sought to determine changes in cognitive function over periods of minutes or hours (e.g., before and after anesthesia) using computerized tests. However, the effects of practice at such brief test-retest intervals has not been reported. The current study sought to determine the magnitude of practice effects in a group of 113 individuals assessed with an automated cognitive test battery on 4 occasions in 1 day. Practice effects were evident both between and within assessments, and also within individual tests. However, these effects occurred mostly between the 1st and 2nd administration of the test battery, with smaller, nonsignificant improvements observed between the 2nd, 3rd, and 4th administrations. On the basis of these results, methodological and statistical strategies that may aid in the differentiation of practice effects from drug-induced cognitive changes are proposed.

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BACKGROUND: The clinical diagnosis of subcortical cerebral infarction is inaccurate for lesion location and pathogenesis. Clinically suspected small perforating artery occlusions may be embolic infarcts, with important implications for investigation and treatment. New MRI techniques may allow more accurate determination of the stroke mechanism soon after admission. METHODS: In a prospective series of 106 patients evaluated with acute diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) within 24 hours of stroke, we enrolled 19 with a lacunar syndrome. On the basis of the topography, DWI and PWI findings, and outcome T2 MRI, we determined whether the mechanism of infarction was single perforating vessel occlusion or large artery embolism. RESULTS: Thirteen patients had pure motor stroke, 2 had ataxic hemiparesis, and 4 had sensorimotor stroke. Six patients had lacunes on MRI, none with PWI lesions. Four patients had subcortical and distal cortical infarcts on DWI. Nine had solitary restricted striatocapsular infarcts. Seven of these 9 had PWI studies, 5 with PWI lesions. The presence of a PWI lesion reliably differentiated striatocapsular from lacunar infarction for solitary small subcortical infarcts (P=0.03). CONCLUSION: DWI and PWI altered the final diagnosis of infarct pathogenesis from small perforating artery occlusion to large artery embolism in 13 of 19 patients presenting with lacunar syndromes. Lacunes cannot be reliably diagnosed on clinical grounds.

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Controversy exists whether acute hyperglycemia is causally associated with worse stroke outcome or simply reflects a more severe stroke. In reversible ischemia models, hyperglycemia is associated with lactic acidosis and conversion of penumbral tissue to infarction. However, the relationship between hyperglycemia, lactic acidosis, and stroke outcome has not been explored in humans. Sixty-three acute stroke patients were prospectively evaluated with serial diffusion-weighted and perfusion-weighted magnetic resonance imaging and acute blood glucose measurements. Patients with hypoperfused at-risk tissue were identified by acute perfusion-diffusion lesion mismatch. As a substudy, acute and subacute magnetic resonance spectroscopy was performed in the 33 most recent patients to assess the relationship between acute blood glucose and lactate production in the ischemic region. In 40 of 63 patients with acute perfusion-diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome. These correlations were independent of baseline stroke severity, lesion size, and diabetic status. Furthermore, higher acute blood glucose in patients with perfusion-diffusion mismatch was associated with greater acute-subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. In contrast, acute blood glucose levels in nonmismatch patients did not independently correlate with outcome measures, nor was there any acute-subacute increase in lactate in this group. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at-risk tissue into infarction, which may adversely affect stroke outcome. These findings support the need for randomized controlled trials of aggressive glycemic control in acute stroke.

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Currently, cognitive decline after coronary surgery is said to be significant if the individual's postoperative test score is at least 1 standard deviation (SD) worse than their preoperative score. This "1-SD" technique fails to account for factors that may confound interpretation of serially acquired cognitive test scores, including regression to the mean, measurement error caused by poor test-retest reliability, and practice effects. We review the many alternative and potentially superior statistical techniques that have been described in the neuropsychologic and psychiatric literature for differentiating "true" changes in cognitive test score from changes caused by these factors.

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Diffusion- and perfusion-weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub-6-hour stroke patients using serial diffusion- and perfusion-weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub-6-hour ischemic stroke patients studied serially with diffusion- and perfusion-weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion-weighted imaging-diffusion-weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion-weighted imaging-diffusion-weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs -25% in controls). Despite similar baseline diffusion-weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm(3) vs 56cm(3) in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of > or = 7 points. The natural evolution of acute perfusion-weighted imaging-diffusion-weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion- and perfusion-weighted imaging in selecting and monitoring patients for thrombolytic therapy.

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