Mortality in patients with behavioural and psychological symptoms of dementia: a registry-based study.

OBJECTIVES: Behavioural and psychological symptoms of dementia (BPSD) are common in patients with dementia. In the elderly population, comorbidities frequently coexist with dementia and mortality in dementia is high. The aim of this study was to investigate the impact of BPSD on mortality in severe dementia. METHODS: This study of 11,448 individuals was based on linked information from the Swedish BPSD registry, the National Patient Register and the Cause of Death register. BPSD was assessed with the Neuropsychiatric Inventory (NPI). Cox proportional hazards regressions were performed for survival analysis. To study different degrees of BPSD, data was categorized into groups: no (NPI, 0 points), mild (NPI, 1-3 points on ≥1 item), moderate (NPI, 4-8 points on ≥1 item) and severe (NPI, 9-12 points on ≥1 item) BPSD based on the highest score on any of the BPSD assessed (NPI items). RESULTS: The presence of moderate or severe BPSD was associated with a stepwise increased risk of mortality (hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.08-1.60 and HR 1.74; 95% CI 1.44-2.12, respectively) compared with individuals with no BPSD. In addition, there was an association between total NPI score and mortality (HR 1.01; 95% CI 1.007-1.010). The results remained significant after multivariable adjustment for age, sex, dementia diagnosis, medication, previous myocardial infarction, hip fracture and stroke. CONCLUSIONS: The results show a stepwise increase in mortality risk with increased BPSD, highlighting the importance of adequate management of BPSD to reduce mortality in dementia.

Validation of a European Cross-Cultural Neuropsychological Test Battery (CNTB) for evaluation of dementia.

BACKGROUND: The aims of this study were to establish the diagnostic accuracy of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for dementia in different ethnic populations in Western Europe, to examine its ability to differentiate cognitive impairment profiles for dementia subtypes, and to assess the impact of demographic variables on diagnostic properties. METHODS: The study was a Western European cross-sectional multi-center study. A total of 66 patients with dementia and 118 cognitively intact participants were included across six memory clinics; 93 had ethnic minority background and 91 had ethnic majority background. Tests in the CNTB cover global cognitive function, memory, language, executive functions, and visuospatial functions. RESULTS: Significant differences with moderate to large effect sizes were present between patients with dementia and control participants on all CNTB measures. Area under the curves (AUC) ranged from .62 to .99 with a mean AUC across all measures of .83. Comparison of ethnic minority and majority groups generally revealed higher sensitivity in the minority group but no significant difference in the mean AUC's across all measures (.84 vs78, P = .42). Comparison of impairment profiles for patients with Alzheimer's disease (AD) and non-AD dementia revealed that AD patients were significantly more impaired on the memory domain, whereas patients with non-AD dementia were more impaired on the executive functions domain. CONCLUSIONS: The CNTB was found to have promising cross-cultural diagnostic properties for evaluation of dementia in the targeted minority and majority populations and could represent a valid cross-cultural alternative to other well-established neuropsychological test batteries when assessing patients from these populations.

Validation of a brief Multicultural Cognitive Examination (MCE) for evaluation of dementia.

BACKGROUND: The aims of this study were to present the psychometric properties of a newly designed cognitive screening instrument, the Multicultural Cognitive Examination (MCE), and to compare it with the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural population. METHODS: The study was a Western European cross-sectional multicenter study. The MCE consists of four components evaluating separate cognitive functions and was constructed by adding measures of memory, verbal fluency, and visuospatial function to the RUDAS to create a scale with 0 to 100 points. RESULTS: A total of 66 patients with dementia and 123 cognitively intact participants were included across six memory clinics; 96 had minority ethnic background, and 93 had majority ethnic background. Moderate to large differences were present between patients with dementia and control participants on all MCE components. The MCE significantly improved diagnostic accuracy compared with using the RUDAS alone, with area under the curves of .918, .984, and .991 for the RUDAS, MCE composite, and demographically corrected composite scores, respectively. Diagnostic accuracy of the MCE did not significantly differ between minority and majority ethnic groups. Across MCE subcomponents, patients with Alzheimer's disease (AD) dementia performed significantly poorer on the memory component compared with those with non-AD dementia. CONCLUSIONS: The MCE is a brief cross-cultural cognitive screening instrument that expands evaluation of the cognitive functions covered by the RUDAS, does not require any specialized training, and may be useful for classification of mild dementia or dementia subtypes.

Validation of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample across five Western European countries: diagnostic accuracy and normative data.

ABSTRACTBackground:With increasing cultural diversity and growing elderly immigrant populations in Western European countries, the availability of brief cognitive screening instruments adequate for assessment of dementia in people from diverse backgrounds becomes increasingly important. The aim of the present study was to investigate diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample and to calculate normative data as a basis for demographic adjustment of RUDAS scores. METHODS: The study was a prospective international cross-sectional multi-center study. Receiver operating characteristic curve analysis was used to examine diagnostic accuracy. Regression analysis was used to assess the impact of demographic variables. RESULTS: Data was collected from 341 cognitively intact participants and 80 people with dementia with a wide age- and educational range. Of the 421 included participants, 239 (57%) had immigrant background. The RUDAS had high diagnostic accuracy with an area under the curve (AUC) of 0.93. The optimal cut-off score was <25 (sensitivity 0.80, specificity 0.90). Regression analysis revealed that RUDAS scores were mainly affected by education and were unrelated to data collection site and immigrant status. Education-adjusted normative data was calculated as a basis for education adjustment of RUDAS scores. Applying education-adjusted RUDAS scores slightly but significantly improved diagnostic accuracy with an AUC of 0.95. CONCLUSION: We found the RUDAS to have excellent diagnostic properties in our multicultural sample. However, we suggest that RUDAS scores should be adjusted for education to increase diagnostic accuracy and that the choice of cut-off score should be considered based on the clinical context and expected base rate of dementia.

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Psychosocial behaviour management programme for home-dwelling people with dementia: A cluster-randomized controlled trial.

Little is known about the effectiveness of a psychosocial behaviour management programme on home-dwelling people with dementia. We developed a Behaviour Analytics & Support Enhancement (BASE) programme for care managers and professional caregivers of home care services in Japan. We investigated the effects of BASE on challenging behaviour of home-dwelling people with dementia. METHODS: A cluster-randomized controlled trial was conducted with home care providers from 3 different districts in Tokyo. Each provider recruited persons with dementia aged 65 years or older to receive home care in the BASE programme in August 2016. An online monitoring and assessment system was introduced to the intervention group for repeated measures of challenging behaviour with a total score of the Neuropsychiatric Inventory. Care professionals in both the intervention and control groups evaluated challenging behaviour of persons with dementia at baseline (September 2016) and follow-up (February 2017). RESULTS: A majority of persons with dementia had Alzheimer disease (59.3%). One-hundred and forty-one persons with dementia were included in the intervention group and 142 in the control group. Multilevel modelling revealed a significant reduction in challenging behaviour in the intervention group after 6 months (mean score, 18.3 to 11.2) compared with that of the control group (11.6 to 10.8; P < .05). CONCLUSION: The implementation of the BASE programme resulted in a reduction of challenging behaviour of home-dwelling people with dementia. Future research should examine the long-term effects of behaviour management programmes on behaviour, nursing home placement, and hospital admission of home-dwelling people with dementia.

Dementia behaviour management programme at home: impact of a palliative care approach on care managers and professional caregivers of home care services.

OBJECTIVES: Care managers and professional caregivers of home care services are sometimes unaware of the psychosocial approaches to the challenging behaviour of dementia. Therefore, we developed a Behaviour Analytics & Support Enhancement (BASE) programme. We investigated the effects of the programme on the attitudes towards dementia care among professionals. METHOD: Forty-six participants in Japan received training in August 2016. The ongoing monitoring and assessment system was introduced to the participants for repeated measures of challenging behaviour. A 1-day follow-up meeting for debriefing was also performed after two months. A baseline and follow-up questionnaire survey was administered to the participating caregivers using a Japanese version of the Approaches to Dementia Questionnaire (ADQ) and the Zarit Burden Interview (ZBI). RESULTS: A significant improvement was observed in the total ADQ score among the participating caregivers from baseline to follow-up assessment. There was no significant difference between the baseline and follow-up assessment in the ZBI scores. In the follow-up meeting, several participants reported challenges and suggested solutions in facilitating a discussion on an action plan among professionals from various organizations. CONCLUSION: The implementation of the programme resulted in enhanced attitudes towards dementia care among the participants without an increased burden of care. Future studies should examine the programme's effectiveness on the challenging behaviour of persons with dementia.

Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a ß3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aß peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aß peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aß peptide production.

Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aß42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aß42 near GLIS1 on 1p32.3 (ß = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (ß = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: ß = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: ß = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aß-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aß42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Longitudinal and postural changes of blood pressure predict dementia: the Malmö Preventive Project.

The role of blood pressure (BP) changes in dementia is debatable. We aimed to analyse how resting and postural BP changes relate to incident dementia over a long-term follow-up. In the prospective population-based Malmö Preventive Project, 18,240 study participants (mean age: 45 ± 7 years, 63% male) were examined between 1974 and 1992 with resting and standing BP measurement, and re-examined between 2002 and 2006 at mean age of 68 ± 6 years with resting BP. A total of 428 participants (2.3%) were diagnosed with dementia through Dec 31, 2009. The association of resting and postural BP changes with risk of dementia was studied using multivariable-adjusted Cox regression models controlling for traditional risk factors. Diastolic BP (DBP) decrease on standing indicated higher risk of dementia [Hazard ratio (HR) per 10 mmHg: 1.22; 95% confidence interval (CI) 1.01-1.44, p = 0.036], which was mainly driven by increased risk in normotensive individuals. Higher systolic (SBP) and diastolic BP at re-examination was associated with lower risk of dementia (HR per 10 mmHg: 0.94; 95% CI 0.89-0.99, p = 0.011; and 0.87; 0.78-0.96, p = 0.006, respectively). Extreme decrease in SBP/DBP between baseline and re-examination (4th quartile; -7 ± 12/-15 ± 7 mmHg, respectively) indicated higher risk of dementia (HR 1.46; 95% CI 1.11-1.93, p = 0.008, and 1.54; 95% CI 1.14-2.08, p = 0.005; respectively) compared with reference group characterised by pronounced BP increase over the same period (1st quartile; +44 ± 13/+15 ± 7 mmHg). Diastolic BP decrease on standing in the middle age, decline in BP between middle-and advanced age, and lower BP in advanced age are independent risk factors of developing dementia.

Reference measurement procedure for CSF amyloid beta (Aß)1-42 and the CSF Aß1-42 /Aß1-40 ratio - a cross-validation study against amyloid PET.

A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aß) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aß1-42 in CSF. The CSF Aß1-42 /Aß1-40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aß production. Our aim was to cross-validate the reference measurement procedure as well as the Aß1-42 /Aß1-40 and Aß1-42 /Aß1-38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aß fibrils as measured by amyloid (18 F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and 18 F-flutemetamol PET. Comparing CSF Aß1-42 concentrations with 18 F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aß1-42 /Aß1-40 or Aß1-42 /Aß1-38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aß1-42 /Aß1-40 and Aß1-42 /Aß1-38 ratios using the described MS method are strongly associated with cortical Aß fibrils measured by 18 F-flutemetamol PET.

Cholinesterase inhibitors do not alter the length of stay in nursing homes among patients with Alzheimer's disease: a prospective, observational study of factors affecting survival time from admission to death.

BACKGROUND: The survival time in nursing homes (NHs) in Alzheimer's disease (AD) might be affected by sociodemographic/clinical characteristics, rate of disease progression, and use of specific medications and community-based services. Whether different aspects of cholinesterase inhibitor (ChEI) therapy modify time spent in NHs is unclear. Therefore, we examined the relationship between these potential predictors and survival time in NHs. METHODS: This prospective, multicenter study of ChEI treatment in clinical practice included 220 deceased patients clinically diagnosed with mild-to-moderate AD who were admitted to NHs during the study. Cognitive and activities of daily living (ADL) performance, ChEI dose, and amount of services used/week were evaluated every 6 months over 3 years. Dates of nursing-home placement (NHP) and death were recorded. Variables that determined survival time in NHs were analyzed using general linear models. RESULTS: The mean survival time in NHs was 4.06 years (men, 2.78 years; women, 4.53 years; P < 0.001). The multivariate model showed that a shorter stay in NHs was associated with the interaction term male living with a family member, use of antihypertensive/cardiac therapy or anxiolytics/sedatives/hypnotics, and worse basic ADL at NHP, but not with age or cognitive and instrumental ADL capacities. CONCLUSIONS: Increased community-based care did not reduce the survival time in NHs among individuals with AD. Men living with family spent significantly less time in NHs compared with the corresponding women, which suggests that the situation of female spouses of AD patients may need attention and possibly support. There was no indication that different aspects of ChEI therapy, e.g., drug type, dose, or duration, alter survival time in NHs.

Reliability, validity and clinical correlates of the Quality of Life in Alzheimer's disease (QoL-AD) scale in medical inpatients.

BACKGROUND: There is a lack of standardisation in quality of life (QoL) measurements to be used in older multimorbid patients. An ideal QoL measurement should be reliable, valid, subjective, multidimensional, feasible and generic. We hypothesised that the QoL-AD (Quality of Life in Alzheimer's Disease) scale could have these properties. Our aim was to determine the psychometric properties and clinical correlations of QoL-AD in a population of elderly, multimorbid medical inpatients. METHODS: QoL-AD was performed in 200 medical inpatients, and available caregivers. Reliability was determined using cronbach's alpha and corrected item-total correlations. The agreement between patient and proxy ratings were examined using intra-class correlations (ICC). Correlations between QoL-AD and demographic data, comorbidity, cognitive tests, ADL (activities of daily living) and depression were examined. To characterise the underlying constructs of QoL-AD, an exploratory factor analysis was performed. RESULTS: In total, 199 patients fulfilled the QoL-AD rating, with 139 proxy ratings. Cronbach's alpha (95 % CI) was 0.74 (0.68-0.79) for patients and 0.86 (0.83-0.90) for proxies. Patient-proxy ICC (95 % CI) was 0.31 (0.16-0.46). Lower QoL was correlated to depression, cognitive impairment, ADL impairment and solitary living, but not with comorbidity. The factor analysis gave a three-factor solution, with factors representing phsyical, social and psychological well-being. CONCLUSION: The QoL-AD scale showed some promising properties but more research is needed before it can be recommended in this setting. If replicated, the finding that cognitive impairment, depression and ADL impairment were more associated with lower QoL than somatic comorbidity could have clinical implications for further studies aiming to improve QoL in this population.

Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study.

INTRODUCTION: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations. METHODS: We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. RESULTS: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. DISCUSSIONS: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.

An integrated workflow for multiplex CSF proteomics and peptidomics-identification of candidate cerebrospinal fluid biomarkers of Alzheimer's disease.

Many disease processes in the brain are reflected in the protein composition of the cerebrospinal fluid (CSF). In addition to proteins, CSF also contains a large number of endogenous peptides whose potential as disease biomarkers largely remains to be explored. We have developed a novel workflow in which multiplex isobaric labeling is used for simultaneous quantification of endogenous CSF peptides and proteins by liquid chromatography coupled with mass spectrometry. After the labeling of CSF samples, endogenous peptides are separated from proteins by ultrafiltration. The proteins retained on the filters are trypsinized, and the tryptic peptides are collected separately. We evaluated this technique in a comparative pilot study of CSF peptide and protein profiles in eight patients with Alzheimer's disease (AD) and eight nondemented controls. We identified several differences between the AD and control group among endogenous peptides derived from proteins known to be associated with AD, including neurosecretory protein VGF (ratios AD/controls 0.45-0.81), integral membrane protein 2B (ratios AD/controls 0.72-0.84), and metallothionein-3 (ratios AD/controls 0.51-0.61). Analysis of tryptic peptides identified several proteins that were altered in the AD group, some of which have previously been reported as changed in AD, for example, VGF (ratio AD/controls 0.70).

Longitudinal Associations between Survival in Alzheimer's Disease and Cholinesterase Inhibitor Use, Progression, and Community-Based Services.

BACKGROUND/AIMS: Factors including rate of disease progression, different aspects of cholinesterase inhibitor (ChEI) treatment, and use of community-based services might affect the longitudinal outcome of Alzheimer's disease (AD). Whether these factors alter life expectancy in AD is unclear. We therefore examined the association between long-term ChEI therapy and survival. METHODS: The present study included 1,021 patients with a clinical diagnosis of AD and a Mini-Mental State Examination score of 10-26 at baseline from a 3-year, prospective, multicenter study of ChEI therapy in clinical practice. The relationship of potential predictors with mortality was analyzed using Cox regression models. RESULTS: After up to 16 years of follow-up, 841 (82%) of the participants had died. In the Alzheimer's Disease Assessment Scale-cognitive subscale, a mean decline of ≥ 4 points/year or ≥ 2 points/year on the Physical Self-Maintenance Scale was a risk factor for an earlier death. In the multivariate models, longer survival was associated with higher ChEI dose and longer duration of treatment. Users of community-based services at baseline exhibited a 1-year shorter mean life expectancy than nonusers. CONCLUSION: A longer survival time can be anticipated for AD patients with slower deterioration who receive and tolerate higher ChEI doses and a longer duration of treatment.

Medial temporal lobe atrophy is underreported and may have important clinical correlates in medical inpatients.

BACKGROUND: The diagnostic workup in dementia includes brain imaging with reading focussed on signs of cerebrovascular and neurodegenerative disease. We hypothesised that these findings may be underreported in hospital patients, where imaging is often performed to rule out obvious pathology such as haemorrhage. In this study, we review cranial computed tomography (CT) in medical inpatients for white matter changes and atrophy. Our aim was to determine the clinical relevance of such findings and to what extent they were underreported. METHODS: Records from 200 inpatients aged over 60 years, who had been subjected to MMSE (mini-mental state examination) and CDT (clock-drawing test), were reviewed for cranial CT. Transverse and coronal slices were reassessed using visual rating scales regarding white matter changes (WMC), global cortical atrophy (GCA) and medial temporal lobe atrophy (MTA). Findings were compared with the original radiology reports and cognitive test results. RESULTS: Cranial CT had been performed in 94 of 200(47 %) patients. Of these, 58(62 %) had abnormal WMC, 35(37 %) abnormal GCA and 34(36 %) abnormal MTA. All three findings had associations with cognitive test results. Abnormal MTA was associated with lower results on the overall score on MMSE and on orientation, memory and language items. All three measurements were underreported in the original radiology reports; none of the 34 patients with abnormal MTA had been reported originally. CONCLUSIONS: Signs of neurodegenerative disease, especially MTA, were highly underreported in cranial CT scans performed in medical inpatients. At the same time, MTA seemed to hold the most important clinical correlates. Our results suggest that MTA should be reported more regularly in this setting.

Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease.

INTRODUCTION: Synaptic dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and directly related to cognitive impairment. Consequently, synaptic biomarkers may be valuable tools for both early diagnosis and disease stage. Neurogranin (Ng) is a postsynaptic protein involved in memory consolidation. METHODS: We developed three monoclonal anti-Ng antibodies. Mass spectrometry and a novel enzyme-linked immunosorbent assay were used to analyze cerebrospinal fluid (CSF) Ng in three independent clinical cohorts including patients with AD dementia (n = 100 in total), mild cognitive impairment patients (MCI), (n = 40) and controls (n = 80 in total). RESULTS: We show in three independent clinical cohorts a marked increase in CSF Ng levels in AD dementia (P < .001 in all studies). In addition, high CSF Ng levels at the MCI stage predicted progression to dementia due to AD with a hazard ratio of 12.8 (95% confidence interval 1.6-103.0, P = .02). In amyloid-positive MCI patients, high CSF Ng correlated with a more rapid change in cognition during clinical follow-up (P = .03). DISCUSSION: These results suggest that CSF Ng is a novel AD biomarker that may be used to monitor synaptic degeneration, and correlates with the rate of cognitive decline in prodromal AD.

CSF biomarkers for the differential diagnosis of Alzheimer's disease: A large-scale international multicenter study.

INTRODUCTION: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aß1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. METHODS: A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. RESULTS: CSF Aß1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90). DISCUSSION: CSF Aß1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.

Assessment of peptide chemical modifications on the development of an accurate and precise multiplex selected reaction monitoring assay for apolipoprotein e isoforms.

Apolipoprotein E (ApoE) is a polymorphic protein that plays a major role in lipid metabolism in the central nervous system and periphery. It has three common allelic isoforms, ApoE2, ApoE3, and ApoE4, that differ in only one or two amino acids. ApoE isoforms have been associated with the occurrence and progression of several pathological conditions, such as coronary atherosclerosis and Alzheimer's disease. The aim of this study was to develop a mass spectrometry (MS)-based assay for absolute quantification of ApoE isoforms in cerebrospinal fluid and plasma samples using isotope-labeled peptides. The assay included five tryptic peptides: CLAVYQAGAR (ApoE2), LGADMEDVCGR (ApoE2 and 3), LAVYQAGAR (ApoE3 and 4), LGADMEDVR (ApoE4), and LGPLVEQGR (total ApoE). Both cerebrospinal fluid and plasma samples were assayed to validate the method. The digestion yield and the extension of chemical modifications in selected amino acid residues (methionine oxidation, glutamine deamidation, and cyclization of N-terminus carbamidomethylcysteine) were also studied. The ApoE phenotype was successfully assigned to all samples analyzed in a blinded manner. The method showed good linearity (R(2) > 0.99) and reproducibility (within laboratory imprecision <13%). The comparison of the MS-based assay with an ELISA for total ApoE concentration showed a moderate correlation (R(2) = 0.59). This MS-based assay can serve as an important tool in clinical studies aiming to elucidate the association between ApoE genotype, total ApoE, and ApoE isoform concentrations in various disorders related to ApoE polymorphisms.