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1.  Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals 
Archives of Neurology  2012;69(2):223-229.
Background
Subjective cognitive impairment (SCI) as an early clinical manifestation in Alzheimer disease (AD) is a central and highly debated question.
Objective
To study the relationship between subjective cognition and the neuropathological hallmark of AD, amyloid-beta (Aβ) deposition, imaged with [11C]-Pittsburg compound B (PiB) - positron emission tomography (PET), in normal elderly individuals.
Design
Cross-sectional analysis.
Subjects
Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations and MRI and PET scanning.
Results
High PiB subjects showed significantly lower performance than low PiB subjects on an episodic memory measure, and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB groups did not differ on the accuracy of their cognitive self-reports compare to objective cognitive performance. General memory self-reports from the whole group were significantly correlated to regional PiB uptake in the right medial prefrontal cortex (PFC)/anterior cingulate cortex (ACC) and in the right precuneus/posterior cingulate cortex (PCC). Reduced confidence about memory abilities was associated with greater PiB in these brain regions. All results are independent of demographic variables and depressive affects.
Conclusions
Our findings suggest that a decrease of self-confidence about memory abilities in cognitively normal elderly subjects is related to the neuropathological hallmark of AD measured with PiB-PET imaging. The relevance of SCI in the early stages of the AD pathological process is addressed.
doi:10.1001/archneurol.2011.666
PMCID: PMC4004919  PMID: 22332189
Aged; Aged, 80 and over; Aging; physiology; Amyloid beta-Peptides; metabolism; Aniline Compounds; Biological Markers; Cerebral Cortex; radionuclide imaging; Cognition; physiology; Cognition Disorders; metabolism; psychology; radionuclide imaging; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; physiology; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prefrontal Cortex; radionuclide imaging; Radiopharmaceuticals; Reference Values; Thiazoles; subjective cognition; normal aging; Alzheimer's disease (AD); amyloid-beta (Aβ); [11C]-Pittsburgh compound B (PiB) - positron emission tomography (PET)
2.  Investigation of C9orf72 in 4 Neurodegenerative Disorders 
Archives of neurology  2012;69(12):1583-1590.
Objective
To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
Design
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Setting
Hospitals specializing in neurodegenerative disorders.
Subjects
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure
The expansion frequency.
Results
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
Conclusions
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
doi:10.1001/archneurol.2012.2016
PMCID: PMC4005900  PMID: 22964832
3.  Spreading Depolarization 
Archives of neurology  2010;68(1):31-36.
A neurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high mortality and morbidity rate. Gradual improvements have been made in the reduction of mortality rates associated with the disease during the last 30 years. However, delayed cerebral ischemia (DCI), the major delayed complication of SAH, remains a significant contributor to mortality and morbidity despite substantial research and clinical efforts. During the last several years, the predominant role of cerebral vasospasm, the long-accepted etiologic factor behind DCI, has been questioned. It is now becoming increasingly clear that the pathophysiology underlying DCI is multifactorial. Cortical spreading depression is emerging as a likely factor in this complex web of pathologic changes after SAH. Understanding its role after SAH and its relationship with the other pathologic processes such as vasospasm, microcirculatory dysfunction, and microemboli will be vital to the development of new therapeutic approaches to reduce DCI and improve the clinical outcome of the disease.
doi:10.1001/archneurol.2010.226
PMCID: PMC3998646  PMID: 20837823
4.  Age-Dependent Structural Connectivity Effects in Fragile X Premutation 
Archives of neurology  2012;69(4):482-489.
Objective
To examine the effects of premutation alleles on major brain fiber tracts in males.
Design
Cross-sectional study performed in 2007–2009.
Setting
Institutional practice.
Patients
Fifteen younger (18–45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X–associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level.
Main Outcome Measures
Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter.
Results
In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum.
Conclusions
The findings revealed widespread alterations in structural connectivity associated with fragile X–associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder.
Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.
doi:10.1001/archneurol.2011.2023
PMCID: PMC3979438  PMID: 22491193
5.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
Objective
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Design
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Setting
Six US academic medical centers.
Patients
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
Results
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Conclusions
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
6.  A purpose “driven” life: Is it potentially neuroprotective? 
Archives of neurology  2010;67(8):1010-1011.
doi:10.1001/archneurol.2010.170
PMCID: PMC3918477  PMID: 20697053
7.  Acute Severe Animal Model of Muscle-Specific Kinase Myasthenia: Combined Postsynaptic and Presynaptic Changes 
Archives of neurology  2011;69(4):453-460.
Objective
To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies, characterized by focal muscle weakness and wasting, and absence of acetylcholine receptor antibodies; also to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ.
Design/Methods
Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically and by repetitive stimulation of median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy.
Results
Animals immunized with 100ug of MuSK 60 develop severe progressive weakness, starting at day 16, with 100% mortality by day 27. The weakness is associated with high MuSK antibody titers, weight loss, axial muscle wasting and decrementing compound muscle action potentials. Light and electron microscopy demonstrate fragmented NMJs with varying degrees of postsynaptic muscle endplate destruction along with abnormal nerve terminals, lack of registration between endplates and nerve terminals, local axon sprouting and extrajunctional dispersion of cholinesterase activity.
Conclusions
These findings: 1) support the role of MuSK antibodies in the human disease; 2) demonstrate the role of MuSK, not only in the development of the NMJ, but also in the maintenance of the mature synapse; and 3) demonstrate involvement in this disease of both pre- and post-synaptic components of the NMJ.
doi:10.1001/archneurol.2011.2200
PMCID: PMC3915865  PMID: 22158720
8.  Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins 
Archives of neurology  2012;69(10):1303-1309.
Objective
To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS).
Design
Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy.
Patients
The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin.
Interventions
Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity.
Results
In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation.
Conclusions
High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.
doi:10.1001/archneurol.2012.465
PMCID: PMC3910505  PMID: 22801747
9.  Primary progressive aphasia and transient global amnesia 
Archives of neurology  2012;69(3):401-404.
Objective
To report three patients with history of transient global amnesia who developed primary progressive aphasia.
Patients
Three patients presenting to the Neurology clinic with language complaints
Setting
Tertiary care center
Results
We describe three patients with a history of transient global amnesia who were subsequently diagnosed with primary progressive aphasia. All patients had recurrent attacks of transient global amnesia. The diagnoses of primary progressive aphasia were supported by speech pathology evaluations, neuropsychometric testing and imaging findings. PET scans, for example, revealed left posterior frontal hypometabolism in one patient, predominately left temporal-parietal hypometabolism in another while single-photon emission computed tomography demonstrated decreased perfusion in the anterior left temporal and frontal lobe in the third.
Conclusions
There may be a relationship between recurrent transient global amnesia and the development of primary progressive aphasia.
doi:10.1001/archneurol.2011.1129
PMCID: PMC3904294  PMID: 22410450
10.  Multilevel Intramedullary Spinal Neurocysticercosis With Eosinophilic Meningitis 
Archives of neurology  2004;61(5):770-772.
Background
Cysticercal involvement of the spinal cord is a very rare form of neurocysticercosis. Intramedullary cysts are even less common.
Objective
To describe a novel presentation of multilevel intramedullary neurocysticercosis with eosinophilic meningitis.
Design
Case report.
Patient
A 35-year-old man with a history of cerebral neurocysticercosis who presented with both cauda equina and Brown-Sequard syndromes associated with cerebrospinal fluid findings of eosinophilic meningitis.
Results
Magnetic resonance imaging confirmed the multilevel intramedullary cord lesions. The patientwas treated medically with dexamethasone and albendazole and had a good recovery.
Conclusion
Intramedullary neurocysticercosis should be considered as a potentially treatable cause of multilevel spinal lesions with subacute meningitis.
doi:10.1001/archneur.61.5.770
PMCID: PMC3902854  PMID: 15148157
11.  Antibodies to Low Density Lipoprotein Receptor-Related Protein 4 in Seronegative Myasthenia Gravis 
Archives of neurology  2011;69(4):434-435.
doi:10.1001/archneurol.2011.2855
PMCID: PMC3903387  PMID: 22158717
12.  Disparate Diseases Due to Copycat Copy Number Variations 
Archives of neurology  2009;66(9):1158-1159.
doi:10.1001/archneurol.2009.197
PMCID: PMC3903580  PMID: 19752307
13.  MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions 
Archives of neurology  2012;69(12):1648-1651.
Objective
To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA).
Design
Case report.
Setting
University hospitals.
Patient
A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility.
Results
Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase–deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions.
Conclusions
In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions.
doi:10.1001/archneurol.2012.405
PMCID: PMC3894685  PMID: 22964873
14.  Spinal Muscular Atrophy 
Archives of neurology  2011;68(8):10.1001/archneurol.2011.74.
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.
doi:10.1001/archneurol.2011.74
PMCID: PMC3860273  PMID: 21482919
15.  “Unequivocally Abnormal” vs “Usual” Signs and Symptoms for Proficient Diagnosis of Diabetic Polyneuropathy 
Archives of neurology  2012;69(12):1609-1614.
Objective
To repeat the Clinical vs Neurophysiology (Cl vs N Phys) trial using “unequivocally abnormal” signs and symptoms (Trial 2) compared with the earlier trial (Trial 1), which used “usual” signs and symptoms.
Design
Standard and referenced nerve conduction abnormalities were used in both Trials 1 and 2 as the standard criterion indicative of diabetic sensorimotor poly-neuropathy. Physician proficiency (accuracy among evaluators) was compared between Trials 1 and 2.
Setting
Academic medical centers in Canada, Denmark, England, and the United States.
Participants
Thirteen expert neuromuscular physicians. One expert was replaced in Trial 2.
Results
The marked overreporting, especially of signs, in Trial 1 was avoided in Trial 2. Reproducibility of diagnosis between days 1 and 2 was significantly (P=.005) better in Trial 2. The correlation of the following clinical scores with composite nerve conduction measures spanning the range of normality and abnormality was improved in Trial 2: pinprick sensation (P = .03), decreased reflexes (P = .06), touch-pressure sensation (P=.06), and the sum of symptoms (P=.06).
Conclusions
The simple pretrial decision to use unequivocally abnormal signs and symptoms—taking age, sex, and physical variables into account—in making clinical judgments for the diagnosis of diabetic sensorimotor polyneuropathy (Trial 2) improves physician proficiency compared with use of usual elicitation of signs and symptoms (Trial 1); both compare to confirmed nerve conduction abnormality.
doi:10.1001/archneurol.2012.1481
PMCID: PMC3570730  PMID: 22986424
16.  Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer’s disease in the community 
Archives of neurology  2012;69(12):1621-1627.
Background
New onset Alzheimer’s disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on MRI, remains unclear.
Objective
To determine whether regional WMH and hippocampal volume predict incident AD in an epidemiological study.
Design
A longitudinal community-based epidemiological study of older adults from northern Manhattan.
Setting
The Washington Heights/Inwood Columbia Aging Project
Participants
Between 2005 and 2007, 717 non-demented participants received MRI scans. An average of 40.28 (SD=9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMH and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the two measurements.
Main outcome measures
Incident Alzheimer’s disease.
Results
White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (HR=1.194, p=0.031). Relative hippocampal volume did not predict incident dementia when considered alone (HR=0.419, p=0.768) or with the WMH measures included in the model (HR=0.302, p=0.701). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMH (HR=1.197, p=0.049).
Conclusion
The findings highlight the regional specificity of the association of WMH with AD. It is not clear whether parietal WMH solely represent a marker for cerebrovascular burden or point to distinct injury compared to other regions. Future work should elucidate pathogenic mechanisms linking WMH and AD pathology.
doi:10.1001/archneurol.2012.1527
PMCID: PMC3597387  PMID: 22945686
Alzheimer’s disease; MRI; cerebrovascular disease; hippocampus
17.  Observational Study of Spinal Muscular Atrophy Type 2 and 3 
Archives of neurology  2011;68(6):10.1001/archneurol.2010.373.
Objective
To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA.
Design
A comprehensive multicenter, longitudinal, observational study.
Setting
The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites.
Participants
Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated.
Intervention
We collected demographic and medical history information and determined the SMN2 copy number.
Main Outcome Measures
Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function.
Results
There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function.
Conclusions
Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.
doi:10.1001/archneurol.2010.373
PMCID: PMC3839315  PMID: 21320981
18.  A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes 
Archives of neurology  2010;67(2):10.1001/archneurol.2009.332.
Objective
To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children.
Design
Genotype-phenotype correlation.
Setting
Tertiary care universities.
Patients
Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure.
Interventions
Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene.
Main Outcome Measures
Definition of clinical variability.
Results
All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation.
Conclusions
The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.
doi:10.1001/archneurol.2009.332
PMCID: PMC3826985  PMID: 20142534
19.  Use of Anterior Temporal Lobectomy for Epilepsy in a Community-Based Population 
Archives of neurology  2012;69(11):1476-1481.
Objective
To assess the hypothesis that use of anterior temporal lobectomy (ATL) for temporal epilepsy has diminished over time.
Design
Population-based cohort study.
Setting
The Rochester Epidemiology Project based in Olmsted County, Minnesota.
Participants
Residents of Olmsted County.
Main Outcome Measures
Poisson regression was used to evaluate changes in ATL use over time by sex.
Results
Over a 17-year period, from 1993 to 2009, 847 ATLs were performed with the primary indication of epilepsy (average, 50 procedures/y). Of these, 26 occurred among Olmsted County residents. The use rates de clined significantly between 1993 and 2000 (8 years) and 2001 and 2009 (9 years) according to Poisson regression analysis, from 1.9 to 0.7 per 100 000 person-years (P=.01). The rate of ATL use among Olmsted County residents was 1.2 (95% CI, 0.9 to 2.4) per 100 000 person-years of follow-up over this 17-year period. The sex-specific rates were 1.6 (95% CI, 0.9 to 2.4) and 0.7 (95% CI, 0.2 to 1.3) per 100 000 person-years for females and males, respectively.
Conclusions
In this community-based cohort, the rate of ATL use was 1.2 per 100 000 person-years of follow-up. Use of this procedure has declined over time; the reasons for this are unknown but do not include referral pattern changes.
doi:10.1001/archneurol.2012.1200
PMCID: PMC3526693  PMID: 22911042
20.  Quantitative Pilomotor Axon-Reflex Test – A Novel Test of Pilomotor Function 
Archives of neurology  2012;69(11):1488-1492.
Objective
Cutaneous autonomic function can be quantified by the assessment of sudomotor and vasomotor responses. Although piloerector muscles are innervated by the sympathetic nervous system, there are, at present, no methods to quantify pilomotor function. This study aims to quantify piloerection using phenylephrine in humans.
Design
Pilot study.
Setting
Hospital based study.
Participants
Twenty-two healthy volunteers (18 males, 4 females) aged 24–48 years participated in several studies.
Interventions
Piloerection was stimulated by iontophoresis of 1% phenylephrine. Silicone impressions of piloerection were quantified by number and area. The direct and indirect response to phenylephrine iontophoresis was compared on both forearms, after pretreatment to topical and subcutaneous lidocaine and iontophoresis of normal saline.
Results
Iontophoresis of phenylephrine induced piloerection in both the direct and axon-reflex mediated regions with similar responses in both arms. Topical lidocaine blocked axon-reflex mediated piloerection post-iontophoresis (control 66.6±19.2 impressions vs. lidocaine 7.2±4.3 impressions; P<0.001). Subcutaneous lidocaine completely blocked piloerection. The area of axon-reflex mediated piloerection was also attenuated in the lidocaine treated region post-iontophoresis (46.2±16.1 cm2 vs. 7.2±3.9 cm2, P<0.0001). Piloerection was delayed in the axon-reflex region compared to the direct region. Normal saline did not cause piloerection.
Conclusions
Phenylephrine provokes piloerection directly and indirectly through an axon-reflex mediated response that is attenuated by lidocaine. Piloerection is not stimulated by iontophoresis of normal saline alone. The quantitative pilomotor axon-reflex test (QPART) may complement other measures of cutaneous autonomic nerve fiber function.
doi:10.1001/archneurol.2012.1092
PMCID: PMC3563419  PMID: 22868966
Pilomotor; Axon Reflex; Iontophoresis; Silicone Impression
21.  Amyloid-β Dynamics in Human Plasma 
Archives of neurology  2012;69(12):10.1001/archneurol.2012.18107.
Background
A marked decrease of Aβ42 in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's Disease (AD) has been well documented. However, contradictory results have been reported from studies on plasma Aβ levels as diagnostic markers for AD.
Objective
To investigate dynamic changes in human plasma Aβ levels, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with CSF Aβ levels.
Design, Settings, and Participants
This was a repeated plasma and CSF sampling study conducted at the Washington University School of Medicine in St. Louis. Older adults with amyloid deposition (Amyloid +), age-matched controls without amyloid deposition (Amyloid −), and younger normal controls (YNC) were enrolled for the study.
Main Outcome Measures
Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ levels were compared for correlation, linear increase, and circadian patterns.
Results
Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in YNC and Amyloid − groups, but not in the Amyloid + group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ levels.
Conclusions
Plasma Aβ, like CSF, demonstrates a circadian pattern which is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ levels were related on an hourly or individual basis.
doi:10.1001/archneurol.2012.18107
PMCID: PMC3808092  PMID: 23229043
22.  Association of Shorter Leukocyte Telomere Repeat Length with Dementia and Mortality 
Archives of neurology  2012;69(10):1332-1339.
Objective
Shortening of chromosomal telomeres is a consequence of cell division, and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. We have hypothesized that shorter telomere length, as measured in human blood samples, is associated with the development of Alzheimer disease, and with mortality.
Design/Setting
Using data from a multiethnic community-based study of aging and dementia, we studied 1,983 subjects over age 65 yr, who had available stored leukocyte DNA. Mean age-at-blood-draw was 78.3 ± 6.9 yr. Mean age of death was 86.0 ± 7.4 yr. Median follow-up for mortality was 9.3 yr; 190 (9.6%) developed incident dementia. We used real-time PCR to determine mean telomere length (TL) in a modified telomere-sequence to single-copy-gene-sequence ratio method.
Results
TL was inversely related to age, and shorter in men than women. Persons dying during follow-up had shorter TL compared to survivors (6,218±819 vs. 6,491±881 basepairs, p<0.0001) even after adjustment for age, sex, education, and APOE genotype. Individuals who developed dementia had significantly shorter TL (6,131±798 for prevalent cases, and 6,315±817 for incident cases) compared with those remaining dementia-free (6,431±864). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (p=0.05), but stratified analyses for sex showed that this association of age-at-onset of dementia with shorter TL was significant in women, but not in men.
Conclusions
Our findings suggest that shortened leukocyte TL is associated with risks of dementia and mortality, and may therefore be a marker of biological aging.
doi:10.1001/archneurol.2012.1541
PMCID: PMC3622729  PMID: 22825311
biological aging; Alzheimer's disease; apolipoprotein E; leukocyte; DNA
23.  Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies 
Archives of neurology  2011;69(4):527-529.
Objective
To report the safe and successful use of the carbonic anhydrase inhibitor acetazolamide for treatment of patients with episodic ataxia and periodic paralysis who had been denied treatment because of a history of severe allergic reactions to antibiotic sulfonamides.
Design
Case reports.
Setting
University of Rochester Medical Center, Rochester, New York.
Patients
A 61-year-old man with late-onset episodic ataxia, an 83-year-old woman with mutation-positive Andersen-Tawil syndrome, and a 21-year-old woman with mutation-positive episodic ataxia 2, all of whom had a history of severe skin rash with the use of sulfonamides for treatment of infection.
Results
The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.
Conclusions
These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.
doi:10.1001/archneurol.2011.2723
PMCID: PMC3785308  PMID: 22158718
24.  Plasma Amyloid β as a Predictor of Dementia and Cognitive Decline: A Systematic Review and Meta-analysis 
Archives of neurology  2012;69(7):824-831.
Context
Preclinical prediction of Alzheimer’s disease is important, critical to effective intervention. Plasma levels of amyloid β-peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods and sample size, making it difficult to readily interpret the overall data.
Objective
To conduct a systematic review and meta-analysis of relevant prospective studies in order to determine if plasma amyloid β levels may predict development of dementia, Alzheimer’s disease, and cognitive decline.
Data Sources
Prospective studies published between 1995 and 2011 indexed in the PubMed, EMBASE, and PsycInfo databases were searched.
Study Selection
Selected studies included those measuring at least one relevant plasma amyloid β species (Aβ40, Aβ42, Aβ42:Aβ40 ratio) and reporting an effect estimate for dementia, Alzheimer’s disease, or cognitive change.
Data Extraction
Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were utilized to generate summary risk ratios and 95% confidence intervals, comparing the bottom versus top quantile for each plasma measure.
Results
Thirteen studies with a total of 10,303 subjects met inclusion criteria for meta-analysis. Lower Aβ42:Aβ40 ratios were significantly associated with development of Alzheimer’s disease (summary RR=1.60, 95% CI=1.04,2.46; p=0.03) and dementia (RR=1.67 95% CI=1.02,2.75; p=0.04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants’ age, sex distribution, the study’s follow-up time, or year of publication. Plasma levels of Aβ40 and Aβ42 alone were not significantly associated with either outcome.
Conclusions
Overall, the literature indicates that plasma Aβ42:Aβ40 ratios predict development of Alzheimer’s disease and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid β levels as a preclinical biomarker.
doi:10.1001/archneurol.2011.1841
PMCID: PMC3772635  PMID: 22451159
25.  Ganglionic Acetylcholine Receptor Autoantibody 
Archives of neurology  2009;66(6):735-741.
Objective
To describe the clinical utility of the nicotinic ganglionic acetylcholine receptor (α3-AChR) autoantibody as a marker of neurological autoimmunity and cancer.
Design
Case-control study.
Setting
Mayo Clinic, Rochester, Minnesota.
Patients
A total of 15 000 patients seen at Mayo Clinic (2005–2007) and evaluated on a service basis for paraneoplastic neurological autoimmunity for whom clinical information was obtained retrospectively by medical record review as well as 457 neurologically asymptomatic patients or control subjects of whom 173 were healthy, 245 had lung cancer, and 39 had systemic lupus erythematosus or Sjögren syndrome.
Outcome Measures
Neurological, oncological, and serological associations of α3-AChR autoantibody seropositivity.
Results
Of 15 000 patients tested on a service basis, 1% were seropositive (median, 0.12 nmol/L; range, 0.03–18.8 nmol/L; normal, ≤0.02 nmol/L), 55% were male, and the median age was 65 years. Cancer was found (new or by history) in 24 of 78 patients evaluated for cancer while at Mayo Clinic (30%); 43% had adenocarcinoma (more patients had breast cancer than prostate, lung, and gastrointestinal cancers; each of the latter groups had about the same number of patients). Of 12 patients with high antibody values (≥1.00 nmol/L), 83% had pandysautonomia. Of 85 patients with medium antibody values (0.10–0.99 nmol/L), neurological presentations were more diverse and included peripheral neuropathies (36%), dysautonomia (20%, usually limited), and encephalopathy (13%). Of 58 patients with low antibody values (0.03–0.09 nmol/L), 54% had a nonautoimmune neurological disorder or no neurological disorder. Of 245 control patients with lung cancer, 7.8% were seropositive. Only 1 of 212 control patients without cancer (0.5%) was seropositive (P<.001).
Conclusion
The detection of α3-AChR autoantibody aids the diagnosis of neurological autoimmunity and cancer.
doi:10.1001/archneurol.2009.78
PMCID: PMC3764484  PMID: 19506133

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