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1.  Mitochondrial encephalomyopathies—Fifty years on 
Neurology  2013;81(3):281-291.
doi:10.1212/WNL.0b013e31829bfe89
PMCID: PMC3959764  PMID: 23858410
2.  Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease 
Neurology  2008;70(16 0 2):1456-1460.
Objective
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.
Methods
We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
Results
The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30 –79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.
Conclusions
The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.
doi:10.1212/01.wnl.0000304044.22253.03
PMCID: PMC3906630  PMID: 18337586
3.  Associations of job demands and intelligence with cognitive performance among men in late life 
Neurology  2007;70(19 0 2):10.1212/01.wnl.0000295506.58497.7e.
Objective
To examine the association of job characteristics and intelligence to cognitive status in members of the National Academy of Sciences–National Research Council Twins Registry of World War II veterans.
Methods
Participants (n = 1,036) included individuals with an assessment of intelligence based on Armed Services testing in early adulthood. In late adulthood, these individuals completed the modified Telephone Interview for Cognitive Status (TICS-m) and occupational history as part of an epidemiologic study of aging and dementia. Occupational history was coded to produce a matrix of job characteristics. Based on factor analysis, job characteristics were interpreted as reflecting general intellectual demands (GI), human interaction and communication (HC), physical activity (PA), and visual attention (VA).
Results
Based on regression analysis of TICS-m score covarying for age, intelligence, and years of education, higher levels of GI and HC were independently associated with higher TICS-m performance, whereas higher PA was independently associated with lower performance. There was an interaction of GI and intelligence, indicating that individuals at the lower range of intellectual aptitude in early adulthood derived greater cognitive benefit from intellectually demanding work.
Conclusions
Intellectually demanding work was associated with greater benefit to cognitive performance in later life independent of related factors like education and intelligence. The fact that individuals with lower intellectual aptitude demonstrated a stronger positive association between work and higher cognitive performance during retirement suggests that behavior may enhance intellectual reserve, perhaps even years after peak intellectual activity.
doi:10.1212/01.wnl.0000295506.58497.7e
PMCID: PMC3873817  PMID: 18077796
4.  High-frequency oscillations mirror disease activity in patients with epilepsy 
Neurology  2009;72(11):979-986.
Objective
High-frequency oscillations (HFOs) can be recorded in epileptic patients with clinical intracranial EEG. HFOs have been associated with seizure genesis because they occur in the seizure focus and during seizure onset. HFOs are also found interictally, partly co-occurring with epileptic spikes. We studied how HFOs are influenced by antiepileptic medication and seizure occurrence, to improve understanding of the pathophysiology and clinical meaning of HFOs.
Methods
Intracerebral depth EEG was partly sampled at 2,000 Hz in 42 patients with intractable focal epilepsy. Patients with five or more usable nights of recording were selected. A sample of slow-wave sleep from each night was analyzed, and HFOs (ripples: 80–250 Hz, fast ripples: 250–500 Hz) and spikes were identified on all artifact-free channels. The HFOs and spikes were compared before and after seizures with stable medication dose and during medication reduction with no intervening seizures.
Results
Twelve patients with five to eight nights were included. After seizures, there was an increase in spikes, whereas HFO rates remained the same. Medication reduction was followed by an increase in HFO rates and mean duration.
Conclusions
Contrary to spikes, high-frequency oscillations (HFOs) do not increase after seizures, but do so after medication reduction, similarly to seizures. This implies that spikes and HFOs have different pathophysiologic mechanisms and that HFOs are more tightly linked to seizures than spikes. HFOs seem to play an important role in seizure genesis and can be a useful clinical marker for disease activity.
doi:10.1212/01.wnl.0000344402.20334.81
PMCID: PMC3797085  PMID: 19289737 CAMSID: cams3470
5.  Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD 
Neurology  2006;67(12):2192-2198.
Objective
To analyze the extent and spatial distribution of white matter hyperintensities (WMH) in brain regions from cognitively normal older individuals (CN) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD).
Methods
We studied 26 mild AD, 28 MCI, and 33 CN. MRI analysis included quantification of WMH volume, nonlinear mapping onto a common anatomic image, and spatial localization of each WMH voxel to create an anatomically precise frequency distribution map. Areas of greatest frequency of WMH from the WMH composite map were used to identify 10 anatomic regions involving periventricular areas and the corpus callosum (CC) for group comparisons.
Results
Total WMH volumes were associated with age, extent of concurrent vascular risk factors, and diagnosis. After correcting for age, total WMH volumes remained significantly associated with diagnosis and extent of vascular risk. Regional WMH analyses revealed significant differences in WMH across regions that also differed significantly according to diagnosis. In post-hoc analyses, significant differences were seen between CN and AD in posterior periventricular regions and the splenium of the CC. MCI subjects had intermediate values at all regions. Repeated measures analysis including vascular risk factors in the model found a significant relationship between periventricular WMH and vascular risk that differed by region, but regional differences according to diagnosis remained significant and there was no interaction between diagnosis and vascular risk.
Conclusions
Differences in white matter hyperintensities (WMH) associated with increasing cognitive impairment appear related to both extent and spatial location. Multiple regression analysis of regional WMH, vascular risk factors, and diagnosis suggest that these spatial differences may result from the additive effects of vascular and degenerative injury. Posterior periventricular and corpus callosum extension of WMH associated with mild cognitive impairment and Alzheimer disease indicate involvement of strategic white matter bundles that may contribute to the cognitive deficits seen with these syndromes.
doi:10.1212/01.wnl.0000249119.95747.1f
PMCID: PMC3776588  PMID: 17190943
6.  When two are worse than one 
Neurology  2006;67(8):1326-1327.
doi:10.1212/01.wnl.0000244911.16867.11
PMCID: PMC3768276  PMID: 17060553
7.  Thickening in the somatosensory cortex of patients with migraine 
Neurology  2007;69(21):1990-1995.
Objective
To examine morphologic changes in the somatosensory cortex (SSC) of patients with migraine.
Methods
Cortical thickness of the SSC of patients with migraine was measured in vivo and compared with age- and sex-matched healthy subjects. The cohort was composed of 24 patients with migraine, subdivided into 12 patients who had migraine with aura, 12 patients who had migraine without aura, and 12 controls. Group and individual analyses were performed in the SSC and shown as average maps of significant changes in cortical thickness.
Results
Migraineurs had on average thicker SSCs than the control group. The most significant thickness changes were noticed in the caudal SSC, where the trigeminal area, including head and face, is somatotopically represented.
Conclusions
Our findings indicate the presence of interictal structural changes in the somatosensory cortex (SSC) of migraineurs. The SSC plays a crucial role in the noxious and nonnoxious somatosensory processing. Thickening in the SSC is in line with diffusional abnormalities observed in the subcortical trigeminal somatosensory pathway of the same migraine cohort in a previous study. Repetitive migraine attacks may lead to, or be the result of, neuroplastic changes in cortical and subcortical structures of the trigeminal somatosensory system.
doi:10.1212/01.wnl.0000291618.32247.2d
PMCID: PMC3757544  PMID: 18025393
8.  INTERICTAL SCALP FAST OSCILLATIONS AS A MARKER OF THE SEIZURE ONSET ZONE 
Neurology  2012;78(3):224-225.
doi:10.1212/01.wnl.0000410956.29629.4d
PMCID: PMC3754949  PMID: 22249499 CAMSID: cams3338
9.  Statin use and Parkinson’s disease in Denmark 
Neurology  2008;70(16 0 2):1418-1422.
Objective
To investigate whether statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use is associated with risk of Parkinson’s disease (PD) in Denmark.
Methods
We identified 1,931 patients with a first time diagnosis of PD reported in hospital or outpatient clinic records between 2001– 2006. We density matched to these patients 9,651 population controls by birth year and sex relying on the Danish population register. For every participant, we identified pharmacy records of statin and anti-Parkinson drug prescriptions since 1995 and prior to index date from a prescription medication use database for all Danish residents. Whenever applicable, the index dates for cases and their corresponding controls were advanced to the date of first recorded prescription for anti-Parkinson drugs. In our primary analyses, we excluded all statin prescriptions 2-years before PD diagnosis.
Results
In unconditional logistic regression analyses adjusting for matching factors and co-morbidities, we observed none to slightly inverse associations between PD diagnosis and statin prescription drug use. Inverse associations with statin use were only observed for short-term (≤1 yrs) statin users (2-year lag OR 0.57; 95% CI 0.36 to 0.89); and suggested at higher intensity statin use (2-year lag OR 0.69; 95% CI 0.45–1.04). No associations were seen among longer-term users and no difference by sex, age, or type of statins used (lipophilic/hydrophilic).
Conclusion
We found little evidence for a neuroprotective role of statins in PD except for short-term or high intensity users. Yet, further investigations into the contributions of intensity, duration, and lag periods of statin use may still be warranted.
doi:10.1212/01.wnl.0000286942.14552.51
PMCID: PMC3690297  PMID: 18184918
10.  A Longitudinal Study of Drivers with Alzheimer Disease 
Neurology  2008;70(14):1171-1178.
Objective
The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia.
Methods
We studied 128 older drivers, including 84 with early Alzheimer’s disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurological, visual and physical function over three years. Self-reports of driving accidents and traffic violations were supplemented by reports from family informants and state records. Within two weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized road test.
Results
At baseline, AD subjects had experienced more accidents and performed more poorly on the road test, compared to controls. Over time, both groups declined in driving performance on the road test, with AD subjects declining more than controls. Survival analysis indicated that while the majority of subjects with AD passed the examination at baseline, greater severity of dementia, increased age, and lower education were associated with higher rates of failure and marginal performance.
Conclusions
This study confirms previous reports of potentially hazardous driving in persons with early AD, but also indicates that some individuals with very mild dementia can continue to drive safely for extended periods of time. Regular followup assessments, however, are warranted in those individuals.
doi:10.1212/01.wnl.0000294469.27156.30
PMCID: PMC3664938  PMID: 18216302
11.  [No title available] 
PMCID: PMC3643891  PMID: 21321355
12.  Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease 
Neurology  2007;69(12):1270-1277.
Objective
To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study.
Methods
We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category.
Results
13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO ≤ 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P.
Conclusions
This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.
doi:10.1212/01.wnl.0000276989.17578.02
PMCID: PMC3624967  PMID: 17875915
13.  Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations 
Neurology  2007;70(7):521-527.
Background
Mutations in the LRRK2 gene are an important cause of familial and nonfamilia parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations.
Objective
To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases.
Methods
We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated.
Results
Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia.
Conclusion
The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.
doi:10.1212/01.WNL.0000280574.17166.26
PMCID: PMC3619720  PMID: 17914064
14.  OCCIPITAL LEVELS OF GABA ARE RELATED TO SEVERE HEADACHES IN MIGRAINE 
Neurology  2008;70(22):2078-2080.
doi:10.1212/01.wnl.0000313376.07248.28
PMCID: PMC3600581  PMID: 18505983
15.  Lamotrigine in pregnancy 
Neurology  2007;70(22 Pt 2):2130-2136.
Objective
To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity.
Methods
A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency.
Results
Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52).
Conclusions
These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.
doi:10.1212/01.wnl.0000289511.20864.2a
PMCID: PMC3589527  PMID: 18046009
16.  Clinicopathologic differences among patients with behavioral variant frontotemporal dementia 
Neurology  2007;69(11):1113-1121.
Objective
To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy.
Methods
This study reviewed all patients entered as clinical bvFTD in the National Alzheimer’s Coordinating Center’s database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups.
Results
The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems.
Conclusion
During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD.
doi:10.1212/01.wnl.0000267701.58488.69
PMCID: PMC3545400  PMID: 17522386
17.  Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease 
Neurology  2004;63(8):1376-1384.
Background
Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity.
Objective
To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases.
Methods
Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted.
Results
The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and α-internexin.
Conclusion
NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.
PMCID: PMC3516854  PMID: 15505152
18.  The NIH registry on use of the Wingspan stent for symptomatic 70–99% intracranial arterial stenosis 
Neurology  2008;70(17):1518-1524.
Background
The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that patients with symptomatic 70% to 99% intracranial arterial stenosis are at particularly high risk of ipsilateral stroke on medical therapy: 18% at 1 year (95% CI = 3% to 24%). The Wingspan intracranial stent is another therapeutic option but there are limited data on the technical success of stenting and outcome of patients with 70% to 99% stenosis treated with a Wingspan stent.
Methods
Sixteen medical centers enrolled consecutive patients treated with a Wingspan stent in this registry between November 2005 and October 2006. Data on stenting indication, severity of stenosis, technical success (stent placement across the target lesion with <50% residual stenosis), follow-up angiography, and outcome were collected.
Results
A total of 129 patients with symptomatic 70% to 99% intracranial stenosis were enrolled. The technical success rate was 96.7%. The mean pre and post-stent stenoses were 82% and 20%. The frequency of any stroke, intracerebral hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 14.0% at 6 months (95% CI = 8.7% to 22.1%). The frequency of ≥50% restenosis on follow-up angiography was 13/52 (25%).
Conclusion
The use of a Wingspan stent in patients with severe intracranial stenosis is relatively safe with high rate of technical success with moderately high rate of restenosis. Comparison of the event rates in high-risk patients in Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) vs this registry do not rule out either that stenting could be associated with a substantial relative risk reduction (e.g., 50%) or has no advantage compared with medical therapy. A randomized trial comparing stenting with medical therapy is needed.
doi:10.1212/01.wnl.0000306308.08229.a3
PMCID: PMC3506389  PMID: 18235078
19.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI 
Neurology  2006;67(5):834-842.
Objective
To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI).
Methods
Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis.
Results
The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level.
Conclusions
Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.
doi:10.1212/01.wnl.0000234032.77541.a2
PMCID: PMC3488276  PMID: 16966547
20.  Disease burden in HIV-associated cognitive impairment 
Neurology  2004;63(12):2293-2297.
Objective
To study whole-brain MR measures derived from diffusion tensor imaging and magnetization transfer imaging (MTI) for the in vivo assessment of cumulative neuropathologic changes in HIV and to evaluate the quantitative imaging strategies with respect to cognitive status measures including the severity of dementia and the degree of impairment in specific cognitive domains including attention, memory, constructional abilities, and motor speed.
Methods
Quantitative whole-brain measurements, including fractional anisotropy (FA), apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR), were derived from histograms and compared in HIV and control participants. Relationships between the MR and cognitive status measures were examined.
Results
Whole-brain FA and MTR were reduced in patients with HIV and correlated with dementia severity. Whole-brain MTR and ADC were correlated with psychomotor deficits. Evaluation of relationships between the studied MR measures indicated a correlation between ADC and MTR; FA was not correlated with either ADC or MTR.
Conclusions
Findings from this investigation support the use of quantitative whole-brain MR measures for evaluation of disease burden in HIV. Reductions in whole-brain fractional anisotropy and magnetization transfer ratio (MTR) distinguished HIV and control subjects, and these measures were associated with dementia severity. Relationships were identified between whole-brain MTR and apparent diffusion coefficient and psychomotor deficits. Combining these quantitative strategies in neuroimaging examinations may provide more comprehensive information concerning ongoing changes in the brains of HIV patients.
PMCID: PMC3462070  PMID: 15623689
21.  Associations of vegetable and fruit consumption with age-related cognitive change 
Neurology  2006;67(8):1370-1376.
Objective
To examine the association between rates of cognitive change and dietary consumption of fruits and vegetables among older persons.
Methods
The authors conducted a prospective cohort study of 3,718 participants, aged 65 years and older of the Chicago Health and Aging Project. Participants completed a food frequency questionnaire and were administered at least two of three cognitive assessments at baseline, 3-year, and 6-year follow-ups. Cognitive function was measured using the average z-score of four tests: the East Boston Tests of immediate memory and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test.
Results
The mean cognitive score at baseline for the analyzed cohort was 0.18 (range: −3.5 to 1.6), and the overall mean change in score per year was a decline of 0.04 standardized units. In mixed effects models adjusted for age, sex, race, and education, compared with the rate of cognitive decline among persons in the lowest quintile of vegetable intake (median of 0.9 servings/day), the rate for persons in the fourth quintile (median, 2.8 servings/day) was slower by 0.019 standardized units per year (p = 0.01), a 40% decrease, and by 0.018 standardized units per year (p = 0.02) for the fifth quintile (median, 4.1 servings/day), or a 38% decrease in rates. The association remained significant (p for linear trend = 0.02) with further control of cardiovascular-related conditions and risk factors. Fruit consumption was not associated with cognitive change.
Conclusion
High vegetable but not fruit consumption may be associated with slower rate of cognitive decline with older age.
doi:10.1212/01.wnl.0000240224.38978.d8
PMCID: PMC3393520  PMID: 17060562
22.  Determinants of vascular dementia in the Cardiovascular Health Cognition Study 
Neurology  2005;64(9):1548-1552.
Objective
The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.
Methods
Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria.
Results
Approximately 44% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.
Conclusions
Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.
doi:10.1212/01.WNL.0000160115.55756.DE
PMCID: PMC3378359  PMID: 15883315
23.  Neuropsychological function in nondemented carriers of presenilin-1 mutations 
Neurology  2005;65(4):552-558.
Background
Prospective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD).
Objective
To investigate these observations by the study of persons at risk for autosomal dominant forms of AD.
Methods
Neuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE ε4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs.
Results
MCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE ε4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores.
Conclusions
This study is consistent with findings in sporadic Alzheimer disease of early problems with memory, visuospatial function, and particularly with executive function in PS1 mutation carriers. Depression, gender, and presence of an APOE ε4 allele did not demonstrate large influences on neuropsychological performance.
doi:10.1212/01.wnl.0000172919.50001.d6
PMCID: PMC3373251  PMID: 16116115
24.  MRI predictors of cognitive outcome in early multiple sclerosis 
Neurology  2011;76(13):1161-1167.
Objective
To determine MRI predictors for cognitive outcome in early relapsing remitting multiple sclerosis (MS) patients.
Methods
Inception Cohort. Forty-four patients recently diagnosed with clinically definite MS, were followed-up with clinical and cognitive evaluations at 1, 2, 5 and 7 years and underwent brain magnetic resonance imaging (MRI) including magnetization transfer (MT) imaging at baseline and two years. Cognitive evaluation was also performed in 56 matched healthy subjects at baseline. Cognitive testing included the Brief Repeatable Battery (BRB). Imaging parameters included lesion load, brain parenchyma fraction, ventricular fraction (VF), mean MT ratio (MTR) of lesion and normal appearing brain tissue (NABT) masks.
Results
At baseline, patients presented deficits of memory, attention and information processing speed (IPS). Over 2 years all MR parameters deteriorated significantly. Over 7 years, EDSS deteriorated significantly. Fifty percent of patients deteriorated on memory cognitive domain and 22.7% of patients on IPS domain. Seven-year change of memory scores was significantly associated with baseline diffuse brain damage (NABT MTR). IPS z score change over 7 years was correlated with baseline global atrophy (BPF), baseline diffuse brain damage and central brain atrophy (VF) change over 2 years.
Conclusion
The main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis.
doi:10.1212/WNL.0b013e318212a8be
PMCID: PMC3312081  PMID: 21444901
Adult; Biological Markers; Cognition; physiology; Cognition Disorders; etiology; pathology; physiopathology; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; methods; Male; Middle Aged; Multiple Sclerosis; complications; pathology; physiopathology; Neuropsychological Tests; Predictive Value of Tests; Regression Analysis; Multiple sclerosis; Brain atrophy; Ventricular fraction; Cognition; Magnetic resonance imaging.
25.  Measles virus–specific plasma cells are prominent in subacute sclerosing panencephalitis CSF 
Neurology  2007;68(21):1815-1819.
Objective
To demonstrate the specificity of expanded CD138+ plasma cell clones recovered from the CSF of a patient with subacute sclerosing panencephalitis (SSPE) for measles virus (MV).
Methods
IgG variable region sequences of single-antibody-secreting CD138+ cells sorted from SSPE CSF were amplified by single-cell PCR and analyzed. Human IgG1 recombinant antibodies (rAbs) were produced from four expanded CD138+ clones and assayed for immunoreactivity against MV proteins.
Results
Clonal expansion was a prominent feature of the SSPE plasma cell repertoire, and each of the four rAbs assayed was specific for either the MV fusion or the MV nucleocapsid protein.
Conclusions
Expanded plasma cell clones in the CSF of patients with subacute sclerosing panencephalitis produce disease-relevant antibodies. Recombinant antibodies derived from CSF B cells could provide a tool to identify target antigens in idiopathic inflammatory disorders.
doi:10.1212/01.wnl.0000262036.56594.7c
PMCID: PMC3278989  PMID: 17515543

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