p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial.

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989 .

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial.

We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aß38, Aß40, Aß42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aß42/Aß40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27.

Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer's disease.

Amyloid ß (Aß) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aß and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aß1-42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aß-), mild cognitively impaired (Aß-), preclinical AD (Aß+), and prodromal AD (Aß+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = -0.434; p < 0.001) and p-tau181P (r = -0.389; p < 0.001). When classified by Aß status, this correlation to t-tau was applicable only in Aß+ participants (n = 139; r = -0.451, p < 0.001) but not Aß- participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aß1-42 with tau (p = 0.006) affected RBANS, but not Aß1-42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aß dependent.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study.

BACKGROUND: ß-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aß1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. RESULTS: In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aß1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aß1-40 reductions, respectively. The trend of the reduction was similar across the Aß1-37, Aß1-38, and Aß1-42 fragments in both atabecestat dose groups, consistent with Aß1-40. CSF amyloid precursor protein fragment (sAPPß) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. CONCLUSIONS: JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aß1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. TRIAL REGISTRATION: ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.

Prevalence of preclinical Alzheimer disease: Comparison of current classification systems.

OBJECTIVE: To determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden. METHOD: The sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of ß-amyloid (Aß)42, Aß40, total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score >0 were excluded, leaving 259 cognitively unimpaired individuals. RESULTS: The prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T-/N- was 13.1%, A+/T-/N+ was 7.3%, A+/T+/N+ was 2.3%, A-/T-/N+ was 18.9%, and A-/T+/N+ was 4.6%. When the Dubois criteria were applied, the prevalence of asymptomatic at risk for AD was 36.7% and of preclinical AD was 9.7%. With the NIA-AA criteria, the prevalence of stage 1 was 13.1% and stage 2 was 9.7%. With the IWG-2 criteria, the prevalence of asymptomatic at risk for AD was 9.7%. The APOE ε4 allele was associated with several of the categories. Men more often had total tau pathology, A+/T-/N+, preclinical AD according to Dubois 2016, asymptomatic at risk for AD according to the IWG-2 criteria, and NIA-AA stage 2. CONCLUSION: The prevalence of pathologic AD markers was very common (46%) in a representative population sample of 70-year-olds. The clinical implications of these findings need to be scrutinized further in longitudinal studies.

Low Cerebrospinal Fluid Aß42 and Aß40 are Related to White Matter Lesions in Cognitively Normal Elderly.

BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aß42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aß interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aß markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aß42 and Aß40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aß42 and CSF Aß40 were associated with WMLs. CSF Aß42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aß42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aß and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aß42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aß deposition than cortical degeneration.

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study.

INTRODUCTION: The safety, pharmacokinetics, and effect on peripheral and central amyloid ß (Aß) of multiple doses of ponezumab, an anti-Aß monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. METHODS: Subjects were aged ≥50 years with Mini-Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. RESULTS: Ponezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aß increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. CONCLUSIONS: Both ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

Decreasing prevalence of dementia in 85-year olds examined 22 years apart: the influence of education and stroke.

Individuals aged 80 years and older constitute the fastest growing segment of the population worldwide, leading to an expected increase in dementia cases. Education level and treatment of vascular risk factors has increased during the last decades. We examined whether this has influenced the prevalence of dementia according to DSM-III-R using population-based samples of 85-year-olds (N = 1065) examined with identical methods 1986-87 and 2008-10. The prevalence of dementia was 29.8% in 1986-87 and 21.7% in 2008-10 (OR 0.66; 95%-CI: 0.50-0.86). The decline was mainly observed for vascular dementia. The proportion with more than basic education (25.2% and 57.7%), and the prevalence of stroke (20% and 30%) increased, but the odds ratio for dementia with stroke decreased from 4.3 to 1.8 (interaction stroke*birth cohort; p = 0.008). In a logistic regression, education (OR 0.70; 95%-CI 0.51-0.96), stroke (OR 3.78; 95%-CI 2.28-6.29), interaction stroke*birth cohort (OR 0.50; 95%-CI 0.26-0.97), but not birth cohort (OR 0.98; 95%-CI 0.68-1.41), were related to prevalence of dementia. Thus, the decline in dementia prevalence was mainly explained by higher education and lower odds for dementia with stroke in later born birth cohorts. The findings may be related to an increased cognitive reserve and better treatment of stroke in later-born cohorts.

A Longitudinal Study of the Mini-Mental State Examination in Late Nonagenarians and Its Relationship with Dementia, Mortality, and Education.

OBJECTIVES: To examine level of and change in cognitive status using the Mini-Mental State Examination (MMSE) in relation to dementia, mortality, education, and sex in late nonagenarians. DESIGN: Three-year longitudinal study with examinations at ages 97, 99, and 100. SETTING: Trained psychiatric research nurses examined participants at their place of living. PARTICIPANTS: A representative population-based sample of 97-year-old Swedes (N = 591; 107 men, 484 women) living in Gothenburg, Sweden. MEASUREMENTS: A Swedish version of the MMSE was used to measure cognitive status. Geriatric psychiatrists diagnosed dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Mixed models were fitted to the data to model the longitudinal relationship between MMSE score and explanatory variables. RESULTS: Individuals with dementia between age 97 and 100 had lower mean MMSE scores than those without dementia. Those who died during the 3-year follow-up had lower MMSE scores than those who survived. MMSE scores at baseline did not differ between those without dementia and those who developed dementia during the 3-year follow-up. Participants with more education had higher MMSE scores, but there was no association between education and linear change. CONCLUSION: MMSE score is associated with dementia and subsequent mortality even in very old individuals, although the preclinical phase of dementia may be short in older age. Level of education is positively associated with MMSE score but not rate of decline in individuals approaching age 100.

DSM-IV and DSM-5 Prevalence of Social Anxiety Disorder in a Population Sample of Older People.

OBJECTIVES: To examine the prevalence of social anxiety disorders (SAD) with (DSM-IV) and without (DSM-5) the person's own assessment that the fear was unreasonable, in a population sample of older adults. Further, to determine whether clinical and sociodemographic correlates of SAD differ depending on the criteria applied. DESIGN: Cross-sectional. SETTING: General population in Gothenburg, Sweden. PARTICIPANTS: A random population-based sample of 75- and 85-year olds (N = 1200) without dementia. MEASUREMENTS: Psychiatric research nurses carried out a semi-structured psychiatric examination including the Comprehensive Psychopathological Rating Scale. DSM-IV SAD was diagnosed with the Mini International Neuropsychiatric Interview. SAD was diagnosed according to DSM-IV and DSM-5 criteria. The 6-month duration criterion in DSM-5 was not applied because of lack of information. Other assessments included the Global Assessment of Functioning (GAF), the Brief Scale for Anxiety (BSA), and the Montgomery Åsberg Depression Rating Scale (MADRS). RESULTS: The 1-month prevalence of SAD was 2.5% (N = 30) when the unreasonable fear criterion was defined in accordance with DSM-IV and 5.1% (N = 61) when the DSM-5 criterion was applied. Clinical correlates (GAF, MADRS, and BSA) were worse in SAD cases identified by either procedure compared with all others, and ratings for those reporting unreasonable fear suggested greater (albeit nonsignificant) overall psychopathology. CONCLUSIONS: Shifting the judgment of how reasonable the fear was, from the individual to the clinician, doubled the prevalence of SAD. This indicates that the DSM-5 version might increase prevalence rates of SAD in the general population. Further studies strictly applying all DSM-5 criteria are needed in order to confirm these findings.

Calcium supplementation and risk of dementia in women with cerebrovascular disease.

OBJECTIVE: To determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up. METHODS: This was a longitudinal population-based study. The sample was derived from the Prospective Population Study of Women and H70 Birth Cohort Study in Gothenburg, Sweden, and included 700 dementia-free women aged 70-92 years. At baseline in 2000-2001, and at follow-up in 2005-2006, the women underwent comprehensive neuropsychiatric and somatic examinations. A CT scan was performed in 447 participants at baseline. Information on the use and dosage of calcium supplements was collected. Dementia was diagnosed according to DSM-III-R criteria. RESULTS: Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.01-4.37, p = 0.046) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40, 95% CI 1.54-12.61, p = 0.006) than women not given supplementation (n = 602). In stratified analyses, calcium supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77, 95% CI 1.36-33.75, p = 0.020) or presence of white matter lesions (OR 2.99, 95% CI 1.28-6.96, p = 0.011), but not in groups without these conditions. CONCLUSIONS: Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease. Because our sample was relatively small and the study was observational, these findings need to be confirmed.

European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

INTRODUCTION: In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. METHODS AND ANALYSIS: All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78. ETHICS AND DISSEMINATION: All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. TRIAL REGISTRATION NUMBER: EUDRACT 2012-002764-27; Pre-results.

Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases.

AIM: Brain clusterin is known to be associated with the amyloid-ß deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases. METHODS: Post-mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL. RESULTS: Immunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non-phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid-ß in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL. CONCLUSIONS: Our results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states.

Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years.

BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aß42, T-tau, P-tau181, and CSF: serum albumin ratio. METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aß42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aß42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aß metabolism.