Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

Introduction Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer’s progression assessment strategies. Methods We examined the temporal order of changes in plasma amyloid-β ratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ42, p-tau231/Aβ42) relative to 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. Results PiB groups exhibited different rates of longitudinal change in Aβ42/Aβ40 (β = 5.41 × 10-4, SE = 1.95 × 10-4, p = 0.0073). Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). Greatest relative decline in Aβ42/Aβ40 (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). Discussion Plasma Aβ42/Aβ40 may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time

Cognitive impairment in chronic migraine compared to pseudotumor cerebri

Introduction. We aimed to define the prevalence of objective cognitive impairment in a group of chronic migraineurs, and to define how migraineurs with cognitive impairment differed from those without impairment, and in doing so to compare cognitive impairment in chronic migraine to another chronic headache-related disorder already associated with cognitive impairment (i.e. pseudotumor cerebri syndrome). Objectives. Cognitive impairment in migraine, especially chronic migraine, has been too little studied. Only a few studies have been done, demonstrating that cognitive impairment exists in chronic migraineurs. It is not known how this compares to other headache-related conditions. Material and methods. We administered a cognitive battery consisting of the National Adult Reading Test, Mini-Mental Status Examination, Digit Span, Boston Naming Test, Rey Auditory Verbal Learning Test, Trail Making Test, Controlled Oral Word Association, and Category Fluency. Cognitive impairment was defined as mild single-domain with one test score, and mild multi- -domain with two scores more than two standard deviations below the mean for age-, gender-, and education-adjusted norms. The data from this study was compared to our previously published population of patients with pseudotumor cerebri syndrome. Results. One hundred prospectively recruited patients with chronic migraine were enrolled. Fifty-seven patients had normal cognitive profiles. Forty-three patients demonstrated mild cognitive impairment, and more than half (n = 24) showed impairment in multiple cognitive domains. Migraineurs with multi-domain impairment had higher pain intensity, shorter duration of disease, were taking narcotics, had more impaired vision-related mental health scores, and worse social health scores. We found an association between objective cognitive impairment and subjective perception of impairment only when controlling for pain. We found no associations with depression and topiramate use. The mean composite cognitive Z score was no different in chronic migraineurs and patients with pseudotumor cerebri. Conclusions and clinical implications. Most chronic migraineurs have normal cognitive profiles, but a large proportion of them do experience mild cognitive impairment, especially in multiple domains. The impairment seen in migraine is similar to that in pseudotumor cerebri syndrome, which has already been associated with mild cognitive impairment. Cognitively impaired migraineurs are different from non-impaired/less impaired migraineurs in several ways, which may be an important factor in influencing their migraine treatment

Phosphotyrosine profiling of human cerebrospinal fluid

Additional file 3: Figure S1. A relative abundance of the tyrosine phosphorylated peptides in the CSF samples

Spontaneous Intracranial Hypotension after Vestibular Schwannoma Resection Due to an Unexpected Pathology: Tarlov Cysts

While infrequent, cerebrospinal fluid (CSF) leaks are known to occur after surgical resection of vestibular schwannomas. Early signs of CSF leak often include headache and altered mental status. If untreated, life-threatening complications can occur, including brainstem herniation and meningitis. The appropriate surgical treatment for a CSF leak requires accurate localization of the source. While the most likely location of a CSF leak after lateral skull base surgery is through the aerated portions of the temporal bone, we present a unique case of a man with a prolonged CSF leak after an acoustic tumor removal who was ultimately found to have an occult spinal perineural (Tarlov) cyst as the source. Accurate localization was ultimately achieved with CT myelogram after empirically obliterating his mastoid failed to restore intracranial CSF volume. Tarlov cysts are the most common cause of idiopathic intracranial hypotension, and this case highlights the importance of considering this entity in the differential diagnosis of postoperative CSF leaks

Identifying Changepoints in Biomarkers During the Preclinical Phase of Alzheimer’s Disease

Objective: Several models have been proposed for the evolution of Alzheimer’s disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD.Methods: We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset.Results: All nine measures had significant changepoints, all of which preceded symptom onset, however, the timing of these changepoints varied considerably. A single measure, CSF t-tau, had an early changepoint (34 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF Abeta and phosphorylated tau) and all cognitive tests had changepoints 10–15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a 6-year time difference between the right and left side (respectively nine and 3 years prior to symptom onset).Conclusion: These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

In a large multicentre study, Toledo et al. examine core Alzheimer's disease CSF biomarkers in 1233 cognitively normal subjects aged 40-85 years. Alzheimer disease-like changes in Aβ1-42 are seen as early as middle age, while APOE genotype strongly modifies age-related effects on both Aβ1-42 and phosphorylated/total ta

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 (Aβ42), 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 Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -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: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 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 Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (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