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26.  Effects of Growth Hormone–Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults 
Archives of neurology  2012;69(11):1420-1429.
Growth hormone–releasing hormone (GHRH), growth hormone, and insulinlike growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI).
To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI.
Randomized, double-blind, placebo-controlled trial.
Clinical Research Center, University of Washington School of Medicine in Seattle.
A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study.
Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout (week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition.
Main Outcome Measures
Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference, Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test, and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample.
The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults. The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory (P=.08). Treatment with GHRH increased insulinlike growth factor 1 levels by 117% (P<.001), which remained within the physiological range, and reduced percent body fat by 7.4% (P<.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35% in adults with MCI (P<.001) but not in healthy adults. Adverse events were mild and were reported by 68% of GHRH-treated adults and 36% of those who received placebo.
Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.”
Trial Registration Identifier: NCT00257712
PMCID: PMC3764914  PMID: 22869065
27.  Frontotemporal dementia in a Brazilian Caucasian kindred with the C9orf72 mutation 
Archives of neurology  2012;69(9):1149-1153.
Describe the clinical features of a Brazilian C9orf72 frontotemporal dementia – amyotrophic lateral sclerosis (FTD-ALS) kindred, and compare them to other reported C9orf72 families and FTD-ALS causing mutations.
Report of a kindred.
Dementia center at an University hospital.
One kindred encompassing 3 generations.
The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed PCR and Southern blot. The observed phenotypes were behavioral variant FTD and ALS with dementia, with significant variability in age of onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations and more posterior atrophy on neuroimaging than is typical for FTD were seen.
bvFTD due to C9orf72 expansions displays some phenotypic heterogeneity, and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede by many years the diagnosis of dementia and may be a distinguishing feature of this mutation.
PMCID: PMC3625641  PMID: 22964910
28.  Cellular Immune Suppression in Paraneoplastic Neurologic Syndromes Targeting Intracellular Antigens 
Archives of neurology  2012;69(9):1132-1140.
Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited.
To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted.
Retrospective single-center case series of patients with PND treated with tacrolimus.
The Rockefeller University Hospital, a research hospital in New York, New York.
Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 auto-antibodies were enrolled. Patients were referred from Memorial Sloan-Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events.
Patients were treated with tacrolimus, 0.15–0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone tapered off during 1 to 4 weeks.
Main Outcome Measures
The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described.
Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus.
A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study.
PMCID: PMC3721351  PMID: 22566506
29.  Diabetes, glucose control and 9 year cognitive decline among non-demented older adults 
Archives of neurology  2012;69(9):1170-1175.
While several studies report an association between prevalent diabetes mellitus (DM) and cognitive impairment, less is known about incident DM in late life and cognitive decline. Glycemic control among elders with DM may also be associated with cognitive function, but findings are inconsistent.
To determine if prevalent and incident DM increases risk of cognitive decline, and if, among elders with DM, poor glucose control is related to worse cognitive performance.
Prospective cohort study.
Health Aging and Body Composition Study at two community clinics.
A total of 3,069 elders (mean age 74.2 years; 42% black; 52% female).
Main Outcome Measures
Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. DM status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c (HbA1c) was measured at year 1 (baseline), 4, 6, and 10 from fasting whole blood.
At baseline 717 (23.4%) participants had prevalent DM and 2352 (76.6%) were without diabetes, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs. 90.9; DSST: 32.5 vs 36.3, respectively; |t|=6.09, p=0.001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: −6.0 vs. −4.5 point decline; |t|=2.66, p=0.008; DSST: −7.9 vs. −5.7, point decline; |t|=3.69, p=0.001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other two groups but were not statistically different from the group without diabetes. Multivariate adjustment for demographics and medical co-morbidities produced similar results. Among participants with prevalent DM, HbA1c level was associated with lower average mean cognitive scores (3MS p for overall=0.003; DSST p for overall=0.04), even after multivariate adjustment.
Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests severity of DM may contribute to accelerated cognitive aging.
PMCID: PMC3752423  PMID: 22710333
30.  Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease 
Archives of neurology  2012;69(10):1255-1258.
Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.
PMCID: PMC3747667  PMID: 22801784
31.  Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition 
Archives of neurology  2012;69(5):623-629.
To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Cross-sectional clinical study.
Berkeley, California.
Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures
Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P <.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Individuals with greater early- and middle-life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
PMCID: PMC3747737  PMID: 22271235
32.  Effects of Age and Sex on Aquaporin-4 Autoimmunity 
Archives of neurology  2012;69(8):1039-1043.
To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56 464 patient samples.
Observational analysis.
Mayo Clinic Neuroimmunology Laboratory.
Between October 1, 2005, and January 4, 2011, 56 464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive.
Main Outcome Measure
Seropositivity for AQP4-IgG.
Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P<.001). More females than males were tested (37 662 vs 16 810, respectively; P<.001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P<.001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female: male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P<.001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P<.001). The proportion of AQP4-IgG–seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years.
Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.
PMCID: PMC3746965  PMID: 22507888
33.  Varicella-Zoster Virus Expression in the Cerebral Arteries of Diabetic Subjects 
Archives of neurology  2012;69(1):142-144.
Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox), after which VZV becomes latent in ganglionic neurons along the entire neuraxis. A decline in cell-mediated immunity to VZV in elderly and immunocompromised individuals results in zoster (shingles). Within the first year after herpes zoster, there is a 30% increased risk of stroke.1–2 Approximately one-third of patients with VZV vasculopathy do not have zoster rash and diabetic patients are at greater risk for both zoster3 and stroke; therefore, we examined the cerebral arteries of 4 diabetic subjects for the presence of VZV DNA and antigen.
PMCID: PMC3743235  PMID: 22232360
34.  Comparison of Cerebrospinal Fluid Levels of Tau and Aß1-42 in Alzheimer’s disease and Frontotemporal Degeneration Using Two Analytical Platforms 
Archives of neurology  2012;69(8):1018-1025.
To utilize values of cerebrospinal fluid (CSF) tau and ß-amyloid obtained from two different analytical immunoassays to differentiate Alzheimer’s disease (AD) from frontotemporal lobar degeneration (FTLD).
CSF values of total tau (t-tau) and ß-amyloid (Aß1-42) obtained using the INNOTEST® ELISA were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3™ (xMAP Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross-validated in another series of autopsy-confirmed samples using transformed ELISA values to assess sensitivity and specificity for differentiating AD from FTLD.
Tertiary memory disorders clinics and neuropathological and biomarker core centers.
75 samples from patients with CSF data obtained from both assays were used for transformation of ELISA values. 40 autopsy-confirmed cases (30 AD, 10 FTLD) were used to establish diagnostic cutoff values, and then cross-validated in a second sample set of 21 autopsy-confirmed cases (11 AD, 10 FTLD) with transformed ELISA values.
Main outcome measure
Diagnostic accuracy using transformed biomarker values.
Data obtained from both assays were highly correlated. The t-tau:Aß1-42 ratio had the highest correlation between measures (r=0.928, p<0.001) and high reliability of transformation (ICC=0.89). A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively.
Values from two analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.
PMCID: PMC3528180  PMID: 22490326
Archives of neurology  2012;69(8):969-977.
Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models have resulted in advances in diagnosis. Likewise translational research has allowed application of increasing basic scientific knowledge regarding neurodegeneration, to the rational development of new investigational therapies based on current understanding of disease pathogenesis. This review discusses application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that more assist in the diagnosis of neurodegenerative dementias, especially Alzheimer’s disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led towards new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empiric trial of established drugs, but rather upon trial of drugs shown through culture and animal models to interfere with known elements of the pathogenetic cascade of Alzheimer disease.
PMCID: PMC3644591  PMID: 22473767
36.  Autoimmune autonomic ganglionopathy treated with long-term rituximab in a patient with lymphoma 
Archives of neurology  2010;68(3):372-375.
To report on response to therapy in a patient with Autoimmune Autonomic Ganglionopathy, with a high titer of an autoantibody directed against the alpha-3 subunit of the nicotinic ganglionic acetylcholine receptor (nAChR).
Case Report
University based referral center for Autonomic Dysfunction.
Patient with prior indolent B cell lymphoma who presented with symptomatic orthostatic hypotension and autonomic failure and was found to have a high titer of nAChR antibody.
Plasma exchange and rituximab (both initial 4 week cycle and maintenance therapy).
Outcome Measures
Autonomic ganglionic antibody titer; Autonomic assessments including orthostatic hypotension, plasma norepinephrine, and quantitative sweat testing.
Rituximab followed by plasma exchange significantly decreased the nAChR antibody titer for a short time, and then the titers increased. The titers suppressed to almost undetectable levels once regular maintenance therapy with rituximab was initiated. Reduction of nAChR antibody titer resulted in less orthostatic hypotension, increased upright plasma norepinephrine, improvement in some sweat function and improvement in symptoms.
Long-term rituximab therapy suppressed autoantibody production to undetectable levels over the course of two years, and resulted in sustained clinical improvement in this patient with debilitating Autoimmune Autonomic Ganglionopathy. Further data is needed before rituximab can be recommended as routine therapy for this disorder.
PMCID: PMC3725638  PMID: 21059985
Autoimmune autonomic ganglionopathy; Pure autonomic failure; Rituximab; Plasma exchange
37.  Dementia Resulting From Traumatic Brain Injury 
Archives of neurology  2012;69(10):1245-1251.
Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era. It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries. One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life. The best data indicate that moderate and severe TBIs increase risk of dementia between 2-and 4-fold. It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias. However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features. The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome. It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity. Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia. Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed.
PMCID: PMC3716376  PMID: 22776913
38.  Mechanisms Underlying Recovery of Motor Function After Stroke 
Archives of neurology  2004;61(12):1844-1848.
Stroke is the leading cause of long-term disability worldwide and a condition for which there is no universally accepted treatment. The development of new effective therapeutic strategies relies on a better understanding of the mechanisms underlying recovery of function. Noninvasive techniques to study brain function, including functional magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation, electroencephalography, and magnetoencephalography, led to recent studies that identified some of these operating mechanisms, resulting in the formulation of novel approaches to motor rehabilitation.
PMCID: PMC3713312  PMID: 15596603
39.  Neuropathy in Human and Mice with PMP22 null 
Archives of neurology  2011;68(6):814-821.
Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP). However, the biological functions of PMP22 in humans are largely unexplored due to the absence of patients with PMP22 null mutations.
Design, Setting and Participants
We have evaluated a 7-year-old boy with PMP22 null. Findings were compared with those from nerves of Pmp22 null mice.
Motor and sensory deficits in the proband were non-length dependent. Weakness was found in cranial muscles, but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and DRG during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells that were more significant in motor nerve fibers than in sensory nerve fibers.
Taken together, these data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with absence of PMP22.
PMCID: PMC3711535  PMID: 21670407
40.  Stroke-Related Translational Research 
Archives of neurology  2011;68(9):1110-1123.
Stroke-related translational research is multifaceted. Herein, we highlight genome-wide association studies and genetic studies of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1 mutations, and cerebral cavernous malformations; advances in molecular biology and biomarkers; newer brain imaging research; and recovery from stroke emphasizing cell-based and other rehabilitative modalities.
PMCID: PMC3691989  PMID: 21555605
41.  Management of Thrombolysis-Associated Symptomatic Intracerebral Hemorrhage 
Archives of neurology  2010;67(8):965-969.
Symptomatic intracerebral hemorrhage (sICH) is the most devastating complication of thrombolytic therapy for acute stroke. It is not clear whether patients with sICH continue to bleed after diagnosis, nor has the most appropriate treatment been determined.
We performed a retrospective analysis of our prospectively collected Get With the Guidelines–Stroke database between April 1, 2003, and December 31, 2007. Radiologic images and all procoagulant agents used were reviewed. Multivariable logistic regression was performed to identify factors associated with in-hospital mortality.
Of 2362 patients with acute ischemic stroke during the study period, sICH occurred in 19 of the 311 patients (6.1%) who received intravenous tissue plasminogen activator and 2 of the 72 (2.8%) who received intra-arterial thrombolysis. In-hospital mortality was significantly higher in patients with sICH than in those without (15 of 20 [75.0]% vs 56 of 332 [16.9%], P<.001). Eleven of 20 patients (55.0%) received therapy for co-agulopathy: 7 received fresh frozen plasma; 5, cryoprecipitate; 4, phytonadione (vitamin K1); 3, platelets; and 1, aminocaproic acid. Independent predictors of inhospital mortality included sICH (odds ratio, 32.6; 95% confidence interval, 8.8–120.2), increasing National Institutes of Health Stroke Scale score (1.2; 1.1–1.2), older age (1.3; 1.0–1.7), and intra-arterial thrombolysis (2.9; 1.4–6.0). Treatment for coagulopathy was not associated with outcome. Continued bleeding (>33% increase in intracerebral hemorrhage volume) occurred in 4 of 10 patients with follow-up scans available (40.0%).
In many patients with sICH after thrombolysis, coagulopathy goes untreated. Our finding of continued bleeding after diagnosis in 40.0% of patients suggests a powerful opportunity for intervention. A multicenter registry to analyze management of thrombolysis-associated intracerebral hemorrhage and outcomes is warranted.
PMCID: PMC3690951  PMID: 20697046
42.  Emerging Role of Epigenetics in Stroke 
Archives of neurology  2010;67(11):1316-1322.
Epigenetic mechanisms refer to the complex and interrelated molecular processes that dynamically modulate gene expression and function within every cell in the body. These regulatory systems represent the long-sought-after molecular interfaces that mediate gene × environment interactions. Changes in the epigenome throughout life are responsible not only for controlling normal development, adult homeostasis, and aging but also for mediating responses to injury. Emerging evidence implicates a spectrum of epigenetic processes in the pathophysiology of stroke. In this review, we describe conventional epigenetic mechanisms (including DNA methylation, histone code modifications, nucleosome remodeling, and higher-order chromatin formation) and highlight the emerging roles each of these processes play in the pathobiology of stroke. We suggest that understanding these mechanisms may be important for discovering more sensitive and specific biomarkers for risk, onset, and progression of stroke. In addition, we highlight epigenetic approaches for stroke therapy, including the inhibition of DNA methyltransferase and histone deacetylase enzyme activities. These therapeutic approaches are still in their infancy, but preliminary results suggest that contemporary agents targeting these pathways can regulate the deployment of stress responses that modulate neural cell viability and promote brain repair and functional reorganization. Indeed, these agents even appear to orchestrate sophisticated cognitive functions, including learning and memory.
PMCID: PMC3685873  PMID: 21060009
43.  Biomarkers Associated With the Apolipoprotein E Genotype and Alzheimer Disease 
Archives of neurology  2012;69(10):1310-1317.
A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment.
To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer’s Disease Neuroimaging Initiative cohort.
Cohort study.
The Biomarkers Consortium Alzheimer’s Disease Plasma Proteomics Project.
Plasma samples at baseline and at 1 year were analyzed from 396 (345 at 1 year) patients with mild cognitive impairment, 112 (97 at 1 year) patients with AD, and 58 (54 at 1 year) healthy control subjects.
Main Outcome Measures
Multivariate and univariate statistical analyses were used to examine differences across diagnostic groups and relative to the apolipoprotein E (ApoE) genotype.
Increased levels of eotaxin 3, pancreatic polypeptide, and N-terminal protein B–type brain natriuretic peptide were observed in patients, confirming similar changes reported in cerebrospinal fluid samples of patients with AD and MCI. Increases in tenascin C levels and decreases in IgM and ApoE levels were also observed. All participants with Apo ε3/ε4 or ε4/ε4 alleles showed a distinct biochemical profile characterized by low C-reactive protein and ApoE levels and by high Cortisol, interleukin 13, apolipoprotein B, and gamma interferon levels. The use of plasma biomarkers improved specificity in differentiating patients with AD from controls, and ApoE plasma levels were lowest in patients whose mild cognitive impairment had progressed to dementia.
Plasma biomarker results confirm cerebrospinal fluid studies reporting increased levels of pancreatic polypeptide and N-terminal protein B–type brain natriuretic peptide in patients with AD and mild cognitive impairment. Incorporation of plasma biomarkers yielded high sensitivity with improved specificity, supporting their usefulness as a screening tool. The ApoE genotype was associated with a unique biochemical profile irrespective of diagnosis, highlighting the importance of genotype on blood protein profiles.
PMCID: PMC3683865  PMID: 22801723
44.  Rett Syndrome: Exploring the Autism Link 
Archives of neurology  2011;68(8):985-989.
The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome (FXS) or Down syndrome (DS), suggests the possibility of common neurobiological mechanisms whose elucidation could advance fundamentally their understanding. This review explores the commonalities and differences of autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in MECP2, the gene responsible for 95% of individuals with RTT. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important testbeds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances.
PMCID: PMC3674963  PMID: 21825235
45.  Loss of Myelin-Associated Glycoprotein in Kearns-Sayre Syndrome 
Archives of neurology  2012;69(4):490-499.
To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations.
Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real-time and long-range polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions.
Department of Clinical Pathology, Columbia University Medical Center, and Newcastle Brain Tissue Resource.
Seventeen patients with mitochondrial disorders and 7 controls were studied from August 1, 2009, to August 1, 2010.
Main Outcome Measure
Regions of myelin-associated glycoprotein (MAG) loss.
Myelin-associated glycoprotein loss in Kearns-Sayre syndrome was associated with oligodendrocyte loss and nuclear translocation of apoptosis-inducing factor, whereas inflammation, neuronal loss, and axonal injury were minimal. In a Kearns-Sayre syndrome MAG loss region, high levels of mtDNA deletions together with cytochrome- c oxidase–deficient cells and loss of mitochondrial respiratory chain subunits (more prominent in the white than gray matter and glia than axons) confirmed the pathogenicity of mtDNA deletions.
Primary mitochondrial respiratory chain defects affecting the white matter, and unrelated to inflammation, are associated with MAG loss and central nervous system demyelination.
PMCID: PMC3672633  PMID: 22491194
46.  The Emerging Role of Epigenetics in Stroke 
Archives of neurology  2011;68(3):294-302.
The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain.
PMCID: PMC3671373  PMID: 21403016
47.  Cerebral Amyloid Deposition and Serotoninergic Innervation in Parkinson Disease 
Archives of neurology  2012;69(12):1628-1631.
Prior studies suggest that serotoninergic neurotransmission reduces β-amyloid (Aβ) production.
To determine whether serotoninergic system degeneration in Parkinson disease promotes Aβ deposition, using in vivo positron emission tomographic probes of serotonin system integrity and Aβ deposition.
Design, Setting, and Patients
Cross-sectional study of 13 subjects with Parkinson disease from the movement disorders clinics at the University of Michigan Health System and Veterans Affairs Ann Arbor Healthcare System, with positron emission tomography using the serotonin transporter ligand carbon 11 ([11C])–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and the Aβ ligand [11C]Pittsburgh compound B.
Inverse correlations were found between DASB and Pittsburgh compound B distribution volume ratios in the neocortex (ρ=−0.577; P=.04) and striatum (ρ=−0.780; P=.002).
Serotoninergic system degeneration in Parkinson disease may promote the development of cerebral amyloidopathy.
PMCID: PMC3671396  PMID: 22964894
48.  Translational Research in Neurology and Neuroscience 2010 
Archives of neurology  2010;67(11):1307-1315.
Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration–approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.
PMCID: PMC3670826  PMID: 20625066
49.  Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia 
Archives of neurology  2012;69(6):700-708.
To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a Workgroup sponsored by the National Institute on Aging and the Alzheimer’s Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.
Retrospective review of ratings of functional impairment across diagnostic categories. Participants: The functional ratings of individuals (N = 17,535) with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer’s Disease Centers and submitted to the National Alzheimer’s Coordinating Center were assessed in accordance with the definition of “functional independence” allowed by the revised criteria.
Pairwise demographic differences between the 3 diagnostic groups were tested using t-tests for continuous variables and chi-square for categorical variables.
Almost all (99.8%) of individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these AD dementia individuals also meet the revised “functional independence” criterion for MCI as measured by the Functional Assessment Questionnaire.
The categorical distinction between MCI and milder stages of Alzheimer dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that “MCI due to AD” represents the earliest symptomatic stage of AD.
PMCID: PMC3423496  PMID: 22312163
Dementia Diagnosis; Alzheimer disease; MCI
50.  Plasma Signaling Proteins in Persons at Genetic Risk for Alzheimer Disease 
Archives of neurology  2012;69(6):757-764.
To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels.
Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays.
A tertiary referral dementia research center.
Thirty-three persons from families harboring PSEN1 or APP mutations, aged 19 to 59 years.
Main Outcome Measures
Protein levels were compared between FAD mutation carriers (MCs) and non-carriers (NCs) and among APOE genotype groups, using multiple linear regression models.
Twenty-one participants were FAD MCs and 12 were NCs. Six had the APOE ε2/3, 6 had the ε3/4, and 21 had the ε3/3 genotype. Levels of 17 proteins differed among APOE genotype groups, and there were significant interactions between age and APOE genotype for 12 proteins. Plasma levels of apolipoprotein E and superoxide dismutase 1 were highest in the ε2 carriers, lowest in ε4 carriers, and intermediate in the ε3 carriers. Levels of multiple interleukins showed the opposite pattern and, among the ε4 carriers, demonstrated significant negative correlations with age. Although there were no significant differences between FAD MCs and NCs, there were interactions between mutation status and APOE genotype for 13 proteins.
We found different patterns of inflammatory markers in young and middle-aged persons among APOE genotype groups. The APOE ε4 carriers had the lowest levels of apolipoprotein E. Young ε4 carriers have increased inflammatory markers that diminish with age. We demonstrated altered inflammatory responses in young and middle adulthood in ε4 carriers that may relate to AD risk later in life.
PMCID: PMC3668092  PMID: 22689192

Results 26-50 (276)