| 1. |
- Bravo, L, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Tabiri, S, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Wang, Li-San, et al.
(author)
-
Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
-
In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
-
Journal article (peer-reviewed)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
- Toledo, Jon B, et al.
(author)
-
Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.
- 2015
-
In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138:Pt 9, s. 2701-15
-
Journal article (peer-reviewed)abstract
- In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
|
|
| 15. |
- Woodruff, J. B., et al.
(author)
-
The Centrosome Is a Selective Condensate that Nucleates Microtubules by Concentrating Tubulin
- 2017
-
In: Cell. - : Elsevier BV. - 0092-8674. ; 169:6, s. 1066-1077
-
Journal article (peer-reviewed)abstract
- Centrosomes are non-membrane-bound compartments that nucleate microtubule arrays. They consist of nanometer-scale centrioles surrounded by a micron-scale, dynamic assembly of protein called the pericentriolar material (PCM). To study how PCM forms a spherical compartment that nucleates microtubules, we reconstituted PCM-dependent microtubule nucleation in vitro using recombinant C. elegans proteins. We found that macromolecular crowding drives assembly of the key PCM scaffold protein SPD-5 into spherical condensates that morphologically and dynamically resemble in vivo PCM. These SPD-5 condensates recruited the microtubule polymerase ZYG-9 (XMAP215 homolog) and the microtubule-stabilizing protein TPXL-1 (TPX2 homolog). Together, these three proteins concentrated tubulin similar to 4-fold over background, which was sufficient to reconstitute nucleation of microtubule asters in vitro. Our results suggest that in vivo PCM is a selective phase that organizes microtubule arrays through localized concentration of tubulin by microtubule effector proteins.
|
|
| 16. |
|
|
| 17. |
- Bengtsson, B, et al.
(author)
-
Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial.
- 2007
-
In: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 114:2, s. 205-209
-
Journal article (peer-reviewed)abstract
- Purpose: To investigate whether increased fluctuation of intraocular pressure (IOP) is an independent factor for glaucoma progression. Design: A cohort of patients was followed up in a randomized clinical trial. Participants: Two hundred fifty-five glaucoma patients from the Early Manifest Glaucoma Trial (EMGT; 129 treated and 126 control patients). Methods: Study visits, conducted every 3 months, included ophthalmologic examinations, IOP measurements, and standard automated perimetry, with fundus photography every 6 months. Intraocular pressure values were included only until the time of progression in those eyes that showed such progression. Individual mean follow-up IOP and IOP fluctuation, calculated as the standard deviation of IOP at applicable visits, were the variables of main interest. Cox regression with time-dependent variables was used to evaluate the association between IOP fluctuation and time to progression, both with and without IOP mean in the models. These analyses also controlled for other significant variables. Main Outcome Measures: Glaucoma progression, as defined by a predetermined visual field criterion, worsening of the disk, assessed by an independent disc reading center, or both. Results: Median follow-up time was 8 years (range, 0.1-11.1 years). Sixty-eight percent of the patients progressed. When considering mean follow-up IOP and IOP fluctuation in the same time-dependent model, mean IOP was a significant risk factor for progression. The hazard ratio (HR) was 1.11 (95% confidence interval [CI], 1.06-1.17; P < 0.0001). Intraocular pressure fluctuation was not related to progression, with an HR of 1.00 (95% Cl, 0.81-1.24; P = 0.999). Conclusions: These results confirm our earlier finding that elevated IOP is a strong factor for glaucoma progression, with the HR increasing by 11% for every 1 mmHg of higher IOP. Intraocular pressure fluctuation was not an independent factor in our analyses, a finding that conflicts with some earlier reports. One explanation for the discrepancy is that our analyses did not include postprogression IOP values, which would be biased toward larger fluctuations because of more intensive treatment. In contrast, in this EMGT report, no changes in patient management occurred during the period analyzed.
|
|
| 18. |
- Crary, John F., et al.
(author)
-
Primary age-related tauopathy (PART) : a common pathology associated with human aging
- 2014
-
In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 128:6, s. 755-766
-
Journal article (peer-reviewed)abstract
- We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
|
|
| 19. |
- Desikan, Rahul S, et al.
(author)
-
Amyloid-β associated volume loss occurs only in the presence of phospho-tau.
- 2011
-
In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:4, s. 657-61
-
Journal article (peer-reviewed)abstract
- The relationship between neurodegeneration and the 2 hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 nondemented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal magnetic resonance (MR) imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy rate, cerebrospinal fluid (CSF) p-tau(181p) and CSF Aβ(1-42) . We found a significant relationship between elevated entorhinal cortex atrophy rate and decreased CSF Aβ(1-42) only with elevated CSF p-tau(181p) . Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tau in humans at risk for dementia.
|
|
| 20. |
|
|
| 21. |
- Desikan, Rahul S, et al.
(author)
-
The role of clusterin in amyloid-β-associated neurodegeneration.
- 2014
-
In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 71:2, s. 180-7
-
Journal article (peer-reviewed)abstract
- Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
|
|
| 22. |
|
|
| 23. |
- Kim, Minji, et al.
(author)
-
Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families
- 2007
-
In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 282:11, s. 7825-7832
-
Journal article (peer-reviewed)abstract
- Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid beta-peptide, the key component of Alzheimer disease (AD)-associated senile plaques. We have previously reported evidence for genetic linkage and association of AD on chromosome 10q23-24 in the region harboring the IDE gene. Here we have presented the first functional assessment of IDE in AD families showing the strongest evidence of the genetic linkage. We have examined the catalytic activity and expression of IDE in lymphoblast samples from 12 affected and unaffected members of three chromosome 10-linked AD pedigrees in the National Institute of Mental Health AD Genetics Initiative family sample. We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families. Further, we have shown the decrease in activity is not due to reduced IDE expression, suggesting the possible defects in IDE function in these AD families. In attempts to find potential mutations in the IDE gene in these families, we have found no coding region substitutions or alterations in splicing of the canonical exons and exon 15b of IDE. We have also found that total IDE mRNA levels are not significantly different in sporadic AD versus age-matched control brains. Collectively, our data suggest that the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression, further supporting a role for IDE in AD pathogenesis.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Mattsson, Niklas, 1979, et al.
(author)
-
CSF biomarker variability in the Alzheimer's Association quality control program
- 2013
-
In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 9:3, s. 251-261
-
Journal article (peer-reviewed)abstract
- Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
|
|
| 27. |
- Mattsson, Niklas, 1979, et al.
(author)
-
The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
-
In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
-
Journal article (peer-reviewed)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
|
|
| 28. |
- Nelson, Peter T., et al.
(author)
-
Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status : A Review of the Literature
- 2012
-
In: Journal of Neuropathology and Experimental Neurology. - 0022-3069 .- 1554-6578. ; 71:5, s. 362-381
-
Research review (peer-reviewed)abstract
- Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. beta-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of AA plaques and neurofibrillary tangles. Although AA plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
|
|
| 29. |
|
|
| 30. |
- Sundelöf, Johan, et al.
(author)
-
Serum cystatin C and the risk of Alzheimer disease in elderly men
- 2008
-
In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 71:14, s. 1072-1079
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.
|
|
| 31. |
- Woodruff, J. B., et al.
(author)
-
Regulated assembly of a supramolecular centrosome scaffold in vitro
- 2015
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 348:6236, s. 808-812
-
Journal article (peer-reviewed)abstract
- The centrosome organizes microtubule arrays within animal cells and comprises two centrioles surrounded by an amorphous protein mass called the pericentriolar material (PCM). Despite the importance of centrosomes as microtubule-organizing centers, the mechanism and regulation of PCM assembly are not well understood. In Caenorhabditis elegans, PCM assembly requires the coiled-coil protein SPD-5.We found that recombinant SPD-5 could polymerize to form micrometer-sized porous networks in vitro. Network assembly was accelerated by two conserved regulators that control PCM assembly in vivo, Polo-like kinase-1 and SPD-2/Cep192. Only the assembled SPD-5 networks, and not unassembled SPD-5 protein, functioned as a scaffold for other PCM proteins. Thus, PCM size and binding capacity emerge from the regulated polymerization of one coiled-coil protein to form a porous network.
|
|
