Abhay Moghekar

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers 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.

Longitudinal Changes in Cerebral Blood Flow in the Older Hypertensive Brain

Background and Purpose— Changes in patterns of regional cerebral blood flow (rCBF) were assessed over a period of 6 years in 14 treated hypertensive participants (HTNs) and 14 age-matched healthy older participants (healthy controls [HCs]) in the Baltimore Longitudinal Study of Aging. Methods— Resting-state PET scans collected at years 1, 3, 5, and 7 were used to determine differences in longitudinal patterns of rCBF change in HTNs relative to HCs. Pulse pressure, arterial pressure, systolic/diastolic blood pressure, and hypertension duration were also correlated with patterns of rCBF change in the HTN group. Results— Relative to HCs, the HTN group shows greater rCBF decreases in prefrontal, anterior cingulate, and occipital areas over time, suggesting that these regions are more susceptible to hypertension-related dysfunction with advancing age. The HTN group also fails to show preservation of function over time in motor regions and in the temporal cortex and hippocampus as observed in HC. Although pulse pressure, mean arterial pressure, and systolic and diastolic pressure all correlate similarly with longitudinal rCBF changes, increased duration of hypertension is associated with decreased rCBF in prefrontal and anterior cingulate areas of functional vulnerability observed in the HTN group. Conclusions— These results show that hypertension significantly affects resting brain function in older individuals and suggest that duration of hypertension contributes significantly to the patterns of change over time.

EFFECT OF A CLINICAL STROKE ON THE RISK OF DEMENTIA IN A PROSPECTIVE COHORT

Objective: To examine the risk and determinants of dementia following a clinically overt stroke in a prospectively followed cohort of elderly subjects. Methods: We examined the effect of a clinically detectable stroke on the risk of dementia using prospective data from 335 subjects in the Baltimore Longitudinal Study of Aging, all of whom were cognitively and neurologically normal at entry into the study (mean age at entry 75.1 ± 4.2 years). Results: Clinically overt strokes are common in our cohort (cumulative risk by age 90, 15.4%; 95% CI: 10 to 22%) and confer an increased risk of dementia compared to subjects without stroke (odds ratio [OR] 5.55; 95% CI: 2.76 to 11.4). The majority of patients who became demented after a stroke had evidence of mild cognitive impairment preceding the stroke (14 of 19). Moreover, a clinically symptomatic stroke was a major risk factor for the conversion of mild cognitive impairment to dementia (OR 12.4; 95% CI: 1.5 to 99). When cognitive impairment did not precede the stroke, there was no increase in the risk of subsequent dementia. Pathologic data indicate that both vascular and Alzheimer pathology leads to the prestroke impairment. Conclusion: Dementia after stroke may be determined by cognitive impairments that exist prior to the stroke.

Visual and neurological outcomes following endovascular stenting for pseudotumor cerebri associated with transverse sinus stenosis

Background: Pseudotumor cerebri (PTC) is characterized by raised intracranial pressure (ICP) without an identifiable mass, evidence of hydrocephalus, or abnormal cerebrospinal fluid content. In the past, most cases of PTC appeared to have no identifiable etiology, and thus, they were classified as “idiopathic intracranial hypertension” (IIH). Recently, however, a subset of patients with presumed IIH has been found to have evidence of cerebral dural sinus stenoses, particularly involving one or both transverse sinuses (TS). The belief that the stenoses are the cause, rather than an effect of the increased ICP, has led investigators to recommend stenting of the stenosed sinus for the treatment of the condition. We describe detailed visual and neurological outcomes after stenting for PTC associated with hemodynamically significant dural sinus stenosis. Methods: All patients with PTC had initial neurological, neuro-ophthalmological, and imaging assessments. Regardless of the findings, all were treated with medical therapy. If medical therapy failed and TS stenosis was detected on contrast-enhanced magnetic resonance or computed tomographic venography, catheter cerebral angiography with venous manometry was performed. If a mean pressure gradient (MPG) of 4 mm Hg or greater was present, unilateral transverse sinus stenting was performed. Results: Twelve patients with PTC and TS stenosis associated with an MPG of >4 mm Hg who failed medical therapy were identified. TS stenting significantly decreased the pressure gradient in all cases. Unilateral stenting was sufficient to reduce pressure gradients even when the stenosis was bilateral. At a mean follow-up of 16 months (range, 9–36 months), tinnitus had improved in all patients, and 10 of 12 patients had improvement in visual function. Seven patients had significant improvement in headaches. Conclusion: In this small series of patients with PTC associated with TS stenosis, endovascular stent placement was generally effective in treating visual dysfunction and tinnitus, although not headaches. The optimum gradient and vascular characteristics amenable for selection of patients for stenting needs further research.

Obesity and headache: part I--a systematic review of the epidemiology of obesity and headache.

Individually, both obesity and headache are conditions associated with a substantial personal and societal impact. Recent data support that obesity is comorbid with headache in general and migraine specifically, as well as with certain secondary headache conditions such as idiopathic intracranial hypertension. In the current manuscript, we first briefly review the epidemiology of obesity and common primary and secondary headache disorders individually. This is followed by a systematic review of the general population data evaluating the association between obesity and headache in general, and then obesity and migraine and tension‐type headache disorders. Finally, we briefly discuss the data on the association between obesity and a common secondary headache disorder that is associated with obesity, idiopathic intracranial hypertension. Taken together, these data suggest that it is important for clinicians and patients to be aware of the headache/migraine‐obesity association, given that it is potentially modifiable. Hypotheses for mechanisms of the obesity‐migraine association and treatment considerations for overweight and obese headache sufferers are discussed in the companion manuscript, as part II of this topic.

CSF biomarker changes precede symptom onset of mild cognitive impairment

Objective: This study evaluated longitudinal CSF biomarker measures collected when participants were cognitively normal to determine the magnitude and time course of biomarker changes before the onset of clinical symptoms in subjects with mild cognitive impairment (MCI). Methods: Longitudinal CSF collection and cognitive assessments were performed on a cohort of 265 participants who were cognitively normal at their baseline assessment and subsequently developed MCI or dementia. CSF β-amyloid 1–42 (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) were determined longitudinally. Consensus diagnoses were completed annually. Cox regression analyses were performed, with baseline CSF values and time-dependent rate of change in CSF values as covariates (adjusted by baseline age, race, and education), in relation to time to onset of mild cognitive symptoms. Results: The mean time from baseline to onset of mild cognitive symptoms was 5.41 years. Increased risk of progressing from normal cognition to onset of clinical symptoms was associated with baseline values of Aβ1–42, p-tau, and the ratios of p-tau/Aβ1–42 and t-tau/Aβ1–42 (p < 0.002). Additionally, the rate of change in the ratios of t-tau/Aβ1–42 (p < 0.004) and p-tau/Aβ1–42 (p < 0.02) was greater among participants who were subsequently diagnosed with MCI. Conclusions: Baseline differences in CSF values were predictive of clinical symptoms that were a harbinger of a diagnosis of MCI more than 5 years before symptom onset, and continue to show longitudinal changes as cognitive symptoms develop, demonstrating that baseline and longitudinal changes in CSF biomarkers are evident during the preclinical phase of Alzheimer disease.

Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease

The aging-suppressor gene klotho encodes a single-pass transmembrane protein that is predominantly secreted by the choroid plexus of the brain and in the kidney. Klotho-deficient mice develop multiple aging phenotypes, including impaired cognition. Klotho concentrations have not been described in the CSF of humans. We measured klotho in the CSF of 20 older adults with Alzheimers disease and in 20 older and 20 younger adults with normal cognition. In 10 adults, aged 38-87 years, CSF klotho measurements were made at baseline and every 6h up to 18-30 h later. Mean (95% confidence interval [C.I.]) CSF klotho in men versus women were 899 (814, 983) and 716 (632, 801) pg/mL, respectively (P=0.002). Mean (95% C.I.) CSF klotho in older adults with and without Alzheimers disease were 664 (603, 725) and 776 (705, 828) pg/mL, respectively (P=0.02), adjusting for sex. Mean (95% C.I.) klotho in older versus younger adults were 766 (658, 874) and 992 (884, 1100) pg/mL, respectively (P=0.005), adjusting for sex. In the longitudinal study of CSF klotho, no significant circadian fluctuations were found in CSF klotho levels. This study suggests that CSF klotho concentrations are lower in females compared with males, in Alzheimers disease, and in older versus younger adults.

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

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 Alzheimers 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 Alzheimers 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.

Brief screening tests for the diagnosis of dementia : Comparison with the mini-mental state exam

Dementia is a common and under-diagnosed problem among the elderly. An accurate screening test would greatly aid the ability of physicians to evaluate dementia and memory problems in clinical practice. We sought to determine whether simple and brief psychometric tests perform similarly to the Mini-Mental State Examination (MMSE) in screening for dementia. Using a retrospective analysis, a series of standard, brief, psychometric tests were compared with each other and to the MMSE as screening tests for very mild dementia, using DSM-III-R criterion as the gold standard. Two independent cohorts from the Baltimore Longitudinal Study of Aging and the Washington University Alzheimers Disease Research Center were evaluated. We found that two brief and simple-to-administer tests appear to offer similar degrees of sensitivity and specificity to the MMSE. These are the recall of a five-item name and address, “John Brown 42 Market Street Chicago” and the one-minute verbal fluency for animals. Combining these two tests further improves sensitivity and specificity, surpassing the MMSE, to detect dementia in individuals with memory complaints.

AMPA Receptor-Dependent Clustering of Synaptic NMDA Receptors Is Mediated by Stargazin and NR2A/B in Spinal Neurons and Hippocampal Interneurons

Under standard conditions, cultured ventral spinal neurons cluster AMPA- but not NMDA-type glutamate receptors at excitatory synapses on their dendritic shafts in spite of abundant expression of the ubiquitous NMDA receptor subunit NR1. We demonstrate here that the NMDA receptor subunits NR2A and NR2B are not routinely expressed in cultured spinal neurons and that transfection with NR2A or NR2B reconstitutes the synaptic targeting of NMDA receptors and confers on exogenous application of the immediate early gene product Narp the ability to cluster both AMPA and NMDA receptors. The use of dominant-negative mutants of GluR2 further showed that the synaptic targeting of NMDA receptors is dependent on the presence of synaptic AMPA receptors and that synaptic AMPA and NMDA receptors are linked by Stargazin and a MAGUK protein. This system of AMPA receptor-dependent synaptic NMDA receptor localization was preserved in hippocampal interneurons but reversed in hippocampal pyramidal neurons.