In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in ... more In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(p<0.001) and non-carriers (p<0.001); higher Aβ38:40 inAPPversusPSEN1(p<0.001) and non-carriers (p<0.001), whil...
A laboratory simulation of lumbar puncture observed the possible effect on CSF Aβ concentration o... more A laboratory simulation of lumbar puncture observed the possible effect on CSF Aβ concentration of using a manometer. Pooled human CSF samples were divided in two, one half passed through a manometer into a collection tube, the other transferred directly to a collection tube. CSF was analysed for Aβ38, Aβ40, and Aβ42 using an electrochemiluminescence immunoassay. Use of a manometer decreased Aβ42 concentration by 4.3% (± 2.4SE), Aβ40 concentration by 4.4% (± 1.7SE), and Aβ38 by 5.6% (± 1.5SE), relative to CSF not exposed to a manometer. The ratios of Aβ42:40, Aβ42:38 and Aβ40:38 were not affected by manometer treatment. Factors which artificially lower CSF Aβ concentrations are of relevance to clinical diagnosis for AD and study design.
In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in... more In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-ca...
In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides... more In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in pathogenesis, however less is known about the behaviour of these mutations invivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a pathogenic mutation or were symptomatic. We tested for differences in plasma amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age-and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p<0.001) and noncarriers (p<0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p<0.001) and non-carriers (p<0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p<0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental AAO. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein and carriers provide insights into disease pathophysiology, which can inform therapy development.
One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bin... more One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ); and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials.
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor pro... more Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the develop...
To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically simil... more To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features. ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database. A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly...
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progr... more Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carr...
After publication of this work [1], we noted that the names of two authors Kailash Bhatia and Hen... more After publication of this work [1], we noted that the names of two authors Kailash Bhatia and Henrik Zetterberg had been misspelled. The names have now been corrected above.
Reversible frontotemporal brain sagging syndrome A 71-year-old man presented with 6 years of forg... more Reversible frontotemporal brain sagging syndrome A 71-year-old man presented with 6 years of forgetfulness, behavioral change, intrusive "growling" vocalizations, orthostatic headaches, and a cough. MRI brain was consistent with frontotemporal brain sagging syndrome (figure, A). He subsequently fell, hitting his chest on a chair, with immediate resolution of his cough, cognitive improvement, and corresponding radiologic desagging (figure, B; video on the Neurology ® Web site at Neurology.org). Frontotemporal brain sagging syndrome may be caused by intracranial hypotension secondary to CSF leakage along nerve root sleeves and is a potentially treatable frontotemporal dementia mimic. 1 In this case, the fall may have caused a contusion injury and given him an auto-blood patch.
Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to supp... more Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid b 1-42 (Ab1-42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. Methods: Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for .24 hours. Ab1-42, total tau (ttau), and phosphorylated tau (p-tau) levels measured using standard enzyme-linked immunosorbent assay techniques were compared between transfer methods. Results: There were no significant differences in Ab1-42, t-tau, or p-tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. Discussion: When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined.
Voxel-Based Morphometry (Ashburner and Friston, 2000) is a commonly used tool for studying patter... more Voxel-Based Morphometry (Ashburner and Friston, 2000) is a commonly used tool for studying patterns of brain change in development or disease and neuroanatomical correlates of subject characteristics. In performing a VBM study, many methodological options are available; if the study is to be easily interpretable and repeatable, the processing steps and decisions must be clearly described. Similarly, unusual methods and parameter choices should be justified in order to aid readers in judging the importance of such options or in comparing the work with other studies. This editorial suggests core principles that should be followed and information that should be included when reporting a VBM study, in order to make it transparent, replicable and useful.
Background Secondary progressive multiple sclerosis, for which no satisfactory treatment presentl... more Background Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profi le, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. Methods We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. Findings 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was signifi cantly lower in patients in the simvastatin group (0•288% per year [SD 0•521]) than in those in the placebo group (0•584% per year [0•498]). The adjusted diff erence in atrophy rate between groups was −0•254% per year (95% CI −0•422 to −0•087; p=0•003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no diff erences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). Interpretation High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing.
Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised b... more Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins. In this study we test whether the HECTD2 susceptibility allele seen in prion disease is also implicated in LOAD. Methods: DNA from 320 individuals with Alzheimer's disease and 601 controls were genotyped for a HECTD2 intronic tagging SNP, rs12249854 (A/T). Groups were further analysed following stratification by APOE genotype. Results: The rs12249854 minor allele (A) frequency was higher (5.8%) in the Alzheimer's disease group as compared to the controls (3.9%), however, this was not statistically significant (P = 0.0668). No significant difference was seen in minor allele frequency in the presence or absence of the APOE ε4 allele. Conclusion: The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD.
Background: Total intracranial volume (TIV) measurement commonly is used to correct for variation... more Background: Total intracranial volume (TIV) measurement commonly is used to correct for variations in premorbid brain size in imaging studies of cerebral structures in Alzheimer disease (AD). This assumes no intrinsic difference in TIV between patients and control subjects and that TIV measurements are unaffected by cerebral atrophy. However, an autopsy study has suggested that a larger premorbid brain may protect against AD onset. A recent computed tomographic study lent support to this by finding a correlation between intracranial size and age at onset of AD in women. Objective: To investigate the relationship between TIV and sporadic and familial AD.
The Neuroimaging Work Group of the Alzheimer's Association was convened to address the clinical a... more The Neuroimaging Work Group of the Alzheimer's Association was convened to address the clinical application of brain imaging for the detection and diagnosis of cognitive impairment leading to dementia. The intent of this document is to (1) review current evidence in support of brain imaging in the detection and diagnosis of dementia, (2) suggest guidelines for the use of imaging in the clinical assessment of dementia, and (3) stimulate further systematic multisite research to validate the use of these methods in the early diagnosis and treatment of AD.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in ... more In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(p<0.001) and non-carriers (p<0.001); higher Aβ38:40 inAPPversusPSEN1(p<0.001) and non-carriers (p<0.001), whil...
A laboratory simulation of lumbar puncture observed the possible effect on CSF Aβ concentration o... more A laboratory simulation of lumbar puncture observed the possible effect on CSF Aβ concentration of using a manometer. Pooled human CSF samples were divided in two, one half passed through a manometer into a collection tube, the other transferred directly to a collection tube. CSF was analysed for Aβ38, Aβ40, and Aβ42 using an electrochemiluminescence immunoassay. Use of a manometer decreased Aβ42 concentration by 4.3% (± 2.4SE), Aβ40 concentration by 4.4% (± 1.7SE), and Aβ38 by 5.6% (± 1.5SE), relative to CSF not exposed to a manometer. The ratios of Aβ42:40, Aβ42:38 and Aβ40:38 were not affected by manometer treatment. Factors which artificially lower CSF Aβ concentrations are of relevance to clinical diagnosis for AD and study design.
In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in... more In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-ca...
In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides... more In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in pathogenesis, however less is known about the behaviour of these mutations invivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a pathogenic mutation or were symptomatic. We tested for differences in plasma amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age-and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p<0.001) and noncarriers (p<0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p<0.001) and non-carriers (p<0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p<0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental AAO. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein and carriers provide insights into disease pathophysiology, which can inform therapy development.
One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bin... more One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ); and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials.
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor pro... more Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the develop...
To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically simil... more To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features. ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database. A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly...
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progr... more Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carr...
After publication of this work [1], we noted that the names of two authors Kailash Bhatia and Hen... more After publication of this work [1], we noted that the names of two authors Kailash Bhatia and Henrik Zetterberg had been misspelled. The names have now been corrected above.
Reversible frontotemporal brain sagging syndrome A 71-year-old man presented with 6 years of forg... more Reversible frontotemporal brain sagging syndrome A 71-year-old man presented with 6 years of forgetfulness, behavioral change, intrusive "growling" vocalizations, orthostatic headaches, and a cough. MRI brain was consistent with frontotemporal brain sagging syndrome (figure, A). He subsequently fell, hitting his chest on a chair, with immediate resolution of his cough, cognitive improvement, and corresponding radiologic desagging (figure, B; video on the Neurology ® Web site at Neurology.org). Frontotemporal brain sagging syndrome may be caused by intracranial hypotension secondary to CSF leakage along nerve root sleeves and is a potentially treatable frontotemporal dementia mimic. 1 In this case, the fall may have caused a contusion injury and given him an auto-blood patch.
Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to supp... more Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid b 1-42 (Ab1-42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. Methods: Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for .24 hours. Ab1-42, total tau (ttau), and phosphorylated tau (p-tau) levels measured using standard enzyme-linked immunosorbent assay techniques were compared between transfer methods. Results: There were no significant differences in Ab1-42, t-tau, or p-tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. Discussion: When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined.
Voxel-Based Morphometry (Ashburner and Friston, 2000) is a commonly used tool for studying patter... more Voxel-Based Morphometry (Ashburner and Friston, 2000) is a commonly used tool for studying patterns of brain change in development or disease and neuroanatomical correlates of subject characteristics. In performing a VBM study, many methodological options are available; if the study is to be easily interpretable and repeatable, the processing steps and decisions must be clearly described. Similarly, unusual methods and parameter choices should be justified in order to aid readers in judging the importance of such options or in comparing the work with other studies. This editorial suggests core principles that should be followed and information that should be included when reporting a VBM study, in order to make it transparent, replicable and useful.
Background Secondary progressive multiple sclerosis, for which no satisfactory treatment presentl... more Background Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profi le, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. Methods We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. Findings 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was signifi cantly lower in patients in the simvastatin group (0•288% per year [SD 0•521]) than in those in the placebo group (0•584% per year [0•498]). The adjusted diff erence in atrophy rate between groups was −0•254% per year (95% CI −0•422 to −0•087; p=0•003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no diff erences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). Interpretation High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing.
Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised b... more Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins. In this study we test whether the HECTD2 susceptibility allele seen in prion disease is also implicated in LOAD. Methods: DNA from 320 individuals with Alzheimer's disease and 601 controls were genotyped for a HECTD2 intronic tagging SNP, rs12249854 (A/T). Groups were further analysed following stratification by APOE genotype. Results: The rs12249854 minor allele (A) frequency was higher (5.8%) in the Alzheimer's disease group as compared to the controls (3.9%), however, this was not statistically significant (P = 0.0668). No significant difference was seen in minor allele frequency in the presence or absence of the APOE ε4 allele. Conclusion: The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD.
Background: Total intracranial volume (TIV) measurement commonly is used to correct for variation... more Background: Total intracranial volume (TIV) measurement commonly is used to correct for variations in premorbid brain size in imaging studies of cerebral structures in Alzheimer disease (AD). This assumes no intrinsic difference in TIV between patients and control subjects and that TIV measurements are unaffected by cerebral atrophy. However, an autopsy study has suggested that a larger premorbid brain may protect against AD onset. A recent computed tomographic study lent support to this by finding a correlation between intracranial size and age at onset of AD in women. Objective: To investigate the relationship between TIV and sporadic and familial AD.
The Neuroimaging Work Group of the Alzheimer's Association was convened to address the clinical a... more The Neuroimaging Work Group of the Alzheimer's Association was convened to address the clinical application of brain imaging for the detection and diagnosis of cognitive impairment leading to dementia. The intent of this document is to (1) review current evidence in support of brain imaging in the detection and diagnosis of dementia, (2) suggest guidelines for the use of imaging in the clinical assessment of dementia, and (3) stimulate further systematic multisite research to validate the use of these methods in the early diagnosis and treatment of AD.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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