Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

The Current of Consciousness: Neural Correlates and Clinical Aspects.

PURPOSE OF REVIEW: In this review, we summarize the current understanding of consciousness including its neuroanatomic basis. We discuss major theories of consciousness, physical exam-based and electroencephalographic metrics used to stratify levels of consciousness, and tools used to shed light on the neural correlates of the conscious experience. Lastly, we review an expanded category of 'disorders of consciousness,' which includes disorders that impact either the level or experience of consciousness. RECENT FINDINGS: Recent studies have revealed many of the requisite EEG, ERP, and fMRI signals to predict aspects of the conscious experience. Neurological disorders that disrupt the reticular activating system can affect the level of consciousness, whereas cortical disorders from seizures and migraines to strokes and dementia may disrupt phenomenal consciousness. The recently introduced memory theory of consciousness provides a new explanation of phenomenal consciousness that may explain better than prior theories both experimental studies and the neurologist's clinical experience. Although the complete neurobiological basis of consciousness remains a mystery, recent advances have improved our understanding of the physiology underlying level of consciousness and phenomenal consciousness.

Impact of amyloid PET in the clinical care of veterans in a tertiary memory disorders clinic.

Introduction: We aimed to characterize the clinical impact of amyloid PET (APET) in a veteran population with cognitive decline by comparing differences in management between those who did and did not have an APET. Methods: This was a retrospective observational study. Poisson regressions and logistic regression were used for comparisons. Results: Out of 565 veterans, 197 underwent APET; positivity rate was 36.55%. Having an APET was associated with longer follow-up, and increased diagnostic variability; it was not associated with number of additional studies, cholinesterase inhibitors prescription, or referrals to research. A positive APET was associated with less diagnostic variability, fewer additional tests, greater cholinesterase inhibitor prescriptions, and more research referrals. Discussion: In a medically complex, real-world population, APET yielded lower positivity rates and was not associated with classical clinical utility variables when comparing patients with and without an APET. APET may be used more to "rule out" rather than to confirm Alzheimer's disease. Highlights: Amyloid PET was associated with longer follow-up, and higher diagnostic variability.No association was seen with cholinesterase inhibitors prescription, or referrals to research.In complex patients, expected amyloid PET positivity rates are lower than previously described.Amyloid PETs were used to "rule out" AD than to confirm the diagnosis of AD.

Amyloid PET ordering practices in a memory disorders clinic.

Introduction: This study assessed the ordering of amyloid positron emission tomography (PET) scans in a Veterans Affairs (VA) memory disorders clinic as part of routine clinical care, with possible implications for the extent to which ordering may occur outside of the VA in the future if covered by insurance. Methods: Clinical features predictive of ordering amyloid PET scans were retrospectively assessed; the percentage of patients who met appropriate use criteria were evaluated. Results: Among 565 veterans, 34.9% of received an amyloid PET scan and 98.0% of these were consistent with appropriate use criteria. Patients with a PET were younger and more likely to have an initial diagnosis of Alzheimer's disease (AD). Of patients without an amyloid PET scan ordered, 64.4% would have met appropriate use criteria for amyloid PET. Discussion: The majority of scans ordered were consistent with appropriate use criteria and more patients were eligible than received a scan. The current study's findings that approximately one-third of patients in a memory disorders clinic received an amyloid PET scan has implications for memory disorders clinics inside and outside of the US Veterans Health Administration.

Distinguishing Between Genuine and Feigned Dementia Using Event-related Potentials.

BACKGROUND: Individuals with probable Alzheimer disease (AD) may perform below cutoffs on traditional, memory-based performance validity tests. Previous studies have found success using event-related potentials (ERPs) to detect feigned neurocognitive impairment in younger populations. OBJECTIVE: To evaluate the utility of an auditory oddball task in conjunction with the P3b peak amplitude to distinguish probable AD from simulated dementia. METHOD: Twenty individuals with probable AD and 20 older healthy controls (HC) underwent an ERP auditory oddball protocol and the Test of Memory Malingering (TOMM). The HC were asked to perform honestly for one condition and to simulate dementia for the other. The individuals with probable AD were asked to perform honestly. The P3b peak amplitude and button press accuracy were collected from each participant and were analyzed to determine their effectiveness in detecting performance validity. RESULTS: The P3b peak amplitude remained stable regardless of behavioral condition in the HC group. When combined with the TOMM Trial 2 score, the P3b peak amplitude further improved the ability to correctly differentiate individuals with probable AD from HC simulating dementia with 100% sensitivity and 90% specificity. CONCLUSION: The P3b peak amplitude was found to be an effective physiologic measure of cognitive impairment in individuals with probable AD compared with HC simulating dementia. When combined with the TOMM Trial 2 score, the P3b peak amplitude served as a promising performance validity measure for differentiating individuals with probable AD from HC simulating dementia.

Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

A comparison between tau and amyloid-ß cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease.

BACKGROUND: Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer's disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD. METHODS: In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aß1-40, Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau181 and p-tau231). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE. RESULTS: Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aß1-42 compared to the control group. The high CTE group had higher levels of p-tau231 and lower levels of Aß1-42 compared to Intermediate/High AD group. CONCLUSIONS: Importantly, p-tau231 and Aß1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau231 is a promising potentially sensitive biomarker of CTE, and CSF Aß1-42 needs further investigation in CTE.

Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E ɛ4 Carriers.

OBJECTIVE: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer's disease (AD) risk only in apoliprotein E4 genotype (APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E (APOE) genotype on cognition and AD biomarkers. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-ß peptide (Aß42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes. RESULTS: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [ß (95%CI): -0.52 ( -1.01, -0.12)] and 12-month follow-up [ß (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (ß = +11.21, SE = 3.37, p < 0.001) and p-Tau (ß = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up. CONCLUSIONS: CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.

Head Injury Exposure in Veterans Presenting to Memory Disorders Clinic: An Observational Study of Clinical Characteristics and Relationship of Event-Related Potentials and Imaging Markers.

Objective: Traumatic brain injury (TBI) and repetitive head impacts (RHI) related to blasts or contact sports are commonly reported among military service members. However, the clinical implications of remote TBI and RHI in veterans remains a challenge when evaluating older veterans at risk of neurodegenerative conditions including Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). This study aimed to test the hypothesis that veterans in a memory disorders clinic with remote head injury would be more likely to have neurodegenerative clinical diagnoses, increased rates of amyloid PET positivity, higher prevalence of cavum septum pellucidi/vergae, and alterations in event-related potential (ERP) middle latency auditory evoked potentials (MLAEPs) and long latency ERP responses compared to those without head injuries. Methods: Older veterans aged 50-100 were recruited from a memory disorders clinic at VA Boston Healthcare system with a history of head injury (n = 72) and without head injury history (n = 52). Patients were classified as reporting prior head injury including TBI and/or RHI exposure based on self-report and chart review. Participants underwent MRI to determine presence/absence of cavum and an ERP auditory oddball protocol. Results: The head injury group was equally likely to have a positive amyloid PET compared to the non-head injury group. Additionally, the head injury group were less likely to have a diagnosis of a neurodegenerative condition than those without head injury. P200 target amplitude and MLAEP amplitudes for standard and target tones were decreased in the head injury group compared to the non-head injury group while P3b amplitude did not differ. Conclusions: Veterans with reported remote head injury evaluated in a memory disorders clinic were not more likely to have a neurodegenerative diagnosis or imaging markers of neurodegeneration than those without head injury. Decreased P200 target and MLAEP target and standard tone amplitudes in the head injury group may be relevant as potential diagnostic markers of remote head injury.

The Effectiveness of Item-Specific Encoding and Conservative Responding to Reduce False Memories in Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease Dementia.

OBJECTIVE: Patients with mild Alzheimer's disease dementia are more susceptible to false memories than healthy older adults. Evidence that these patients can use cognitive strategies to reduce false memory is inconsistent. METHOD: In the present study, we examined the effectiveness of conservative responding and item-specific deep encoding strategies, alone and in combination, to reduce false memory in a categorized word list paradigm among participants with mild Alzheimer's disease dementia (AD), amnestic single-domain mild cognitive impairment (MCI), and healthy age-matched older controls (OCs). A battery of clinical neuropsychological measures was also administered. RESULTS: Although use of conservative responding alone tended to reduce performance in the MCI and OC groups, both deep encoding alone and deep encoding combined with conservative strategies led to improved discrimination for both gist memory and item-specific recollection for these two groups. In the AD group, only gist memory benefited from the use of strategies, boosted equally by deep encoding alone and deep encoding combined with conservative strategies; item-specific recollection was not improved. No correlation between the use of these strategies and performance on neuropsychological measures was found. CONCLUSIONS: These results suggest that further evaluation of these strategies is warranted as they have the potential to reduce related and unrelated memory errors and increase both gist memory and item-specific recollection in healthy older adults and individuals with amnestic MCI. Patients with AD were less able to benefit from such strategies, yet were still able to use them to reduce unrelated memory errors and increase gist memory.

False Memories: The Other Side of Forgetting.

OBJECTIVE: To measure caregivers' and clinicians' perception of false memories in the lives of patients with memory loss due to Alzheimer's disease (AD) and mild cognitive impairment (MCI) using a novel false memories questionnaire. Our hypotheses were that false memories are occurring as often as forgetting according to clinicians and family members. METHOD: This prospective, questionnaire-based study consisting of 20 false memory questions paired with 20 forgetting questions had two forms: one for clinicians and the other for family members of older subjects. In total, 226 clinicians and 150 family members of 49 patients with AD, 44 patients with MCI, and 57 healthy older controls (OCs) completed the questionnaire. RESULTS: False memories occurred nearly as often as forgetting according to clinicians and family members of patients with MCI and AD. Family members of OCs and patients with MCI reported fewer false memories compared to those of the AD group. As Mini-Mental State Examination scores decreased, the mean score increased for both forgetting and false memories. Among clinicians, correlations were observed between the dementia severity of patients seen with both forgetting and false memories questionnaire scores as well as with the impact of forgetting and false memories on daily life. CONCLUSION: Patients with AD experience false memories almost as frequently as they do forgetting. Given how common false memories are in AD patients, additional work is needed to understand the clinical implications of these false memories on patients' daily lives. The novel false memories questionnaire developed may be a valuable tool.

Chronic Traumatic Encephalopathy.

PURPOSE OF REVIEW: This article provides a discussion on the current state of knowledge of chronic traumatic encephalopathy (CTE), with an emphasis on clinical features and emerging biomarkers of the condition. RECENT FINDINGS: The results of several large brain bank case series among subjects with a history of contact sports or repetitive head trauma have indicated that a high frequency of CTE may exist in this population. However, the true prevalence of CTE among individuals with a history of head trauma remains unknown, given that individuals who experienced cognitive, behavioral, and mood symptoms during life are more likely to have their brains donated for autopsy at death and epidemiologic studies of the condition are lacking. Neuropathologic consensus criteria have been published. Research-based clinical criteria have been proposed and are beginning to be applied, but the definitive diagnosis of CTE in a living patient remains impossible without effective biomarkers for the condition, which is an active area of study. SUMMARY: The field of CTE research is rapidly growing and parallels many of the advances seen for other neurodegenerative conditions, such as Alzheimer disease decades ago.

Lifetime exposure to ultraviolet radiation and the risk of multiple sclerosis in the US radiologic technologists cohort study.

BACKGROUND: Low exposure to ultraviolet radiation (UVR) from sunlight may be a risk factor for developing multiple sclerosis (MS). Possible pathways may be related to effects on immune system function or vitamin D insufficiency, as UVR plays a role in the production of the active form of vitamin D in the body. OBJECTIVE: This study examined whether lower levels of residential UVR exposure from sunlight were associated with increased MS risk in a cohort of radiologic technologists. METHODS: Participants in the third and fourth surveys of the US Radiologic Technologists (USRT) Cohort Study eligible (N = 39,801) for analysis provided complete residential histories and reported MS diagnoses. MS-specialized neurologists conducted medical record reviews and confirmed 148 cases. Residential locations throughout life were matched to satellite data from NASA's Total Ozone Mapping Spectrometer (TOMS) project to estimate UVR dose. RESULTS: Findings indicate that MS risk increased as average lifetime levels of UVR exposures in winter decreased. The effects were consistent across age groups <40 years. There was little indication that low exposures during summer or at older ages were related to MS risk. CONCLUSION: Our findings are consistent with the hypothesis that UVR exposure reduces MS risk and may ultimately suggest prevention strategies.

Late Positive Component Event-related Potential Amplitude Predicts Long-term Classroom-based Learning.

It is difficult to predict whether newly learned information will be retrievable in the future. A biomarker of long-lasting learning, capable of predicting an individual's future ability to retrieve a particular memory, could positively influence teaching and educational methods. ERPs were investigated as a potential biomarker of long-lasting learning. Prior ERP studies have supported a dual-process model of recognition memory that categorizes recollection and familiarity as distinct memorial processes with distinct ERP correlates. The late positive component is thought to underlie conscious recollection and the frontal N400 signal is thought to reflect familiarity [Yonelinas, A. P. Components of episodic memory: The contribution of recollection and familiarity. Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 356, 1363-1374, 2001]. Here we show that the magnitude of the late positive component, soon after initial learning, is predictive of subsequent recollection of anatomical terms among medical students 6 months later.

Psychosis in Spinocerebellar Ataxias: a Case Series and Study of Tyrosine Hydroxylase in Substantia Nigra.

Spinocerebellar ataxias are a genetically heterogeneous group of degenerative diseases typically characterized by progressive ataxia and to various degrees, neuropathy, amyotrophy, and ocular abnormalities. There is increasing evidence for non-motor manifestations associated with cerebellar syndromes including cognitive and psychiatric features. We studied a retrospective clinical case series of eight subjects with spinocerebellar ataxias (SCAs) 2, 3, 7, and 17, all displaying features of psychosis, and also measured tyrosine hydroxylase (TH) staining of the substantia nigra (SN) at autopsy, among four of the subjects. We hypothesized that increased dopamine production in the SN may underlie the pathophysiology of psychosis in SCAs, given evidence of increased dopamine production in the SN in schizophrenia, as measured by TH staining. We analyzed differences in TH staining between the SCA psychosis cohort (n = 4), a heterogeneous ataxic cohort without psychosis (n = 22), and non-diseased age- and sex-matched control group (n = 12). SCA subjects with psychosis did not differ significantly in TH staining versus ataxic cases without psychosis. There was, however, increased TH staining in the ataxic cohort with and without psychosis (n = 26), compared to non-diseased controls (n = 12). Psychotic features were similar across subjects, with the presence of delusions, paranoia, and auditory hallucinations. Our findings are preliminary because of small numbers of subjects and variable neuropathology; however, they suggest that psychosis is a clinical feature of SCAs and may be under-recognized. While the underlying pathophysiology remains to be fully established, it may be related to extra-cerebellar pathology, including a possible propensity for increased dopamine activity in the SN.

Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin.

We investigated the overlap shared between the immunoglobulin (Ig) proteome of the cerebrospinal fluid (CSF) and the B cell Ig-transcriptome of CSF and the central nervous system (CNS) tissue of three patients with multiple sclerosis. We determined the IgG-proteomes of CSF by mass spectrometry, and compared them to the IgG-transcriptomes from CSF and brain lesions, which were analyzed by cDNA cloning. Characteristic peptides that were identified in the CSF-proteome could also be detected in the transcriptomes of both, brain lesions and CSF, providing evidence for a strong overlap of the IgG repertoires in brain lesions and in the CSF.

In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain.

BACKGROUND: In vivo proton magnetic resonance spectroscopy (1H-MRS) studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection. RESULTS: Changes in the N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), creatine (Cr) and glutamine/glutamate (Glx) resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi). At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions. CONCLUSION: These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus.