PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (35)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
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.  Autoimmune autonomic ganglionopathy with reversible cognitive impairment 
Archives of Neurology  2011;69(4):461-466.
Background
Autoimmune autonomic ganglionopathy (AAG) is a rare disorder of antibody mediated impaired transmission across the autonomic ganglia resulting in severe autonomic failure. Some patients with AAG report cognitive impairment of unclear etiology despite treatment of autonomic symptoms.
Objectives
To investigate the relationship between orthostatic hypotension, antibody titers and cognitive impairment in patients with AAG.
Design
Prospective cohort.
Setting
Academic medical center.
Participants
Three patients with AAG underwent neuropsychological testing before and after cycles of plasma exchange in both the seated and standing position to determine the effects of orthostatic hypotension and antibody titers on cognition.
Main Outcome Measures
Patient responses to neuropsychological tests were measured by percent change from baseline in the seated and standing positions pre- and post-plasma exchange to determine the effects of orthostatic hypotension and antibody titers on cognition.
Results
Orthostatic hypotension and elevated antibody titer were associated independently with neuropsychological impairment (P<0.05), particularly in domains of executive function, sustained attention, and working memory. Cognitive dysfunction improved, even in the seated normotensive position, after plasmapheresis and consequent reduction in antibody levels.
Conclusion
The data presented in this study demonstrate reversible cognitive impairment is independently associated with both orthostatic hypotension and elevated nicotinic acetylcholine receptor autoantibodies thereby expanding the clinical spectrum of autonomic ganglionopathy and, in so doing, providing an additional treatable cause of cognitive impairment.
doi:10.1001/archneurol.2011.2372
PMCID: PMC3359761  PMID: 22158721
Autoimmune autonomic ganglionopathy; autonomic failure, orthostatic hypotension, cognitive impairment
3.  A prospective study of statin use and risk of Parkinson disease 
Archives of Neurology  2012;69(3):380-384.
Objective
Statins have been found to have potent anti-inflammatory and immunomodulating effects, which led to the hypothesis that statins could be neuroprotective agents. However, the beneficial effects of statins could be offset by their unfavorable effects on lowering plasma coenzyme Q10 and urate. We therefore prospectively examined whether use of statins was associated with altered risk of PD.
Design, setting, and participants
A prospective study including 38,191 men and 90,874 women participating in two ongoing US cohorts, the Health Professional Follow-up and the Nurses’ Health Study. Information on regular cholesterol lowering drug use (2+ times/week) was collected in 1994 in both cohorts via questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were computed using Cox proportional hazards models adjusting for age, smoking, caffeine intake, duration of hypercholesterolemia, and other covariates.
Main outcome
Incident PD.
Results
During 12 years of follow-up (1994-2006), we documented 644 incident PD cases (338 women and 306 men). The risk of PD was lower among current statin users (adjusted pooled RR=0.74; 95% CI: 0.54, 1.00; P=0.049), relative to non-users. A significant association was observed in participants who were aged <60 years at baseline (adjusted pooled RR=0.31, 95% CI: 0.11, 0.86; P=0.02), but not among those who were older (adjusted pooled RR=0.83, 95% CI: 0.60, 1.14; P=0.25) (p for interaction=0.03).
Conclusions
We found that regular use of statins was associated with a modest reduction in PD risk. The possibility that some statins may reduce PD risk deserves further consideration.
doi:10.1001/archneurol.2011.1060
PMCID: PMC3398841  PMID: 22410446
4.  A Mediterranean-Style Diet and White Matter Hyperintensity Volume: the Northern Manhattan Study 
Archives of Neurology  2012;69(2):251-256.
Objective
To examine the association between a Mediterranean-style diet (MeDi) and brain MRI white matter hyperintensities (WMH). The MeDi has previously been associated with a reduced risk of cardiovascular morbidity, possibly including stroke. A greater understanding of modifiable risk factors for small vessel damage may facilitate the prevention of stroke and cognitive decline.
Design
A cross-sectional analysis within a longitudinal population-based cohort study. A semi-quantitative food frequency questionnaire was administered and a score (range 0-9) was calculated to reflect increasing similarity to the MeDi pattern.
Setting
The Northern Manhattan Study.
Participants
1,091 participants, of which 966 had dietary information (mean age 72, 59% women, 65% Hispanic, 16% White, 17% Black).
Main outcome measures
WMH volume was measured by quantitative brain MRI. Linear regression models were constructed to examine the relation between the MeDi score and the log-transformed WMH volume as a proportion of total cranial volume, controlling for sociodemographic and vascular risk factors.
Results
On the MeDi scale, 12% scored 0-2, 16 scored 3, 23% scored 4, 23% scored 5, 26% scored 6-9. Each 1-point increase in MeDi score was associated with a lower log WMH volume (β=-0.04, p=0.02). The only MeDi score component that was an independent predictor of WMH volume was the ratio of monounsaturated to saturated fat (β=-0.20, p=0.001).
Conclusions
A Mediterranean-style diet was associated with a lower WMH burden, a marker of small vessel damage in the brain. However, white matter hyperintensities are etiologically heterogenous and can include neurodegeneration. Replication by other population-based studies is needed.
doi:10.1001/archneurol.2011.548
PMCID: PMC3281550  PMID: 22332193
5.  Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System 
Archives of Neurology  2011;69(1):51-58.
Objective
The amyloid hypothesis predicts that increased production or decreased clearance of amyloid beta (Aβ) leads to amyloidosis, ultimately culminating in Alzheimer’s disease (AD). Dynamic changes in human CNS Aβ levels may be altered by aging or AD pathology and contribute to the risk of AD.
Designs
In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, PIB PET amyloid status and electroencephalography (EEG) and video recording data.
Results
Linear increases of CSF Aβ concentrations over time were observed in younger control participants and older Amyloid- participants, but not in older Amyloid+ participants. Significant CSF Aβ circadian patterns were observed in younger control participants; however circadian amplitudes were decreased in both Amyloid- and Amyloid+ older participants. Aβ diurnal concentrations were correlated to the amount of sleep, but not various awake activities.
Conclusions
Decreased linear rise of CSF Aβ levels associated with amyloid deposition, and decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics, and may contribute to AD.
doi:10.1001/archneurol.2011.235
PMCID: PMC3254706  PMID: 21911660
6.  Autosomal Recessive Causes Likely in Early-Onset Alzheimer Disease 
Archives of Neurology  2011;69(1):59-64.
Background
There is a widespread belief that dominant mutations cause most cases of early-onset Alzheimer's Disease (onset ≤ 60 years, EOAD) yet epidemiologic evidence suggests they explain ≤ 10% of all EOAD cases.
Objective
To determine the genetic contribution to the remaining ~90% of non-autosomal dominant EOAD cases and identify the likely mechanism of inheritance in those cases.
Design, Subjects
A liability threshold model of disease was used to estimate heritability of EOAD and late-onset AD (LOAD) using concordance for AD among parent-offspring pairs. Individuals with probable AD and detailed parental history (n =5,370) were identified in the Uniform Dataset (UDS) whose participants were collected from 32 Alzheimer's Disease Centers.
Results
For LOAD (n = 4,302), we found sex-specific parent–offspring concordance that ranged from ~10-30% resulting in a heritability of 69.8% (95% CI: 64.6–75.0%) and equal heritability for both sexes regardless of parental gender. For EOAD (n = 702), we found that the parent–offspring concordance is ≤ 10% and concordance among siblings is 21.6%. EOAD heritability is 92–100% for all likely values of EOAD prevalence.
Conclusion
We confirm LOAD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the pattern of observed concordance for parent–offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that ~90% of EOAD cases are due to autosomal recessive causes.
doi:10.1001/archneurol.2011.221
PMCID: PMC3332307  PMID: 21911656
7.  Outcome Measures Utilized in Pediatric Stroke Studies – A Systematic Review 
Archives of Neurology  2012;69(1):23-27.
Because no “gold standard” outcome measure or measures exist to allow comparison of pediatric stroke study outcomes in clinical trials, we designed a systematic review of the literature to survey the current use of pediatric stroke outcome measures. Studies that used at least one standardized measure to assess the outcome of children with ischemic or hemorrhagic stroke, ages full-term newborn to 18 years were included. Though 34 studies were included, an additional 36 studies could not be included because ad hoc, author-generated outcome measures were utilized. Excluding those measures in neuropsychological batteries, 38 unique outcome measures were used. The Wechsler Intelligence Scales, Pediatric Stroke Outcome Measure, and Bayley Scales of Infant Development were among the most used, but 79% of outcome measures were used by no more than two studies. Though many utilized measures have been validated for use in children with other medical conditions or for adults with stroke, only one measure has been specifically validated for use in pediatric ischemic stroke. To maximize comparability of future clinical trial results, agreement regarding a preferred pediatric stroke outcome scale or battery of measures is paramount; these measures should be reliable, responsive to change, and specifically validated for use in children with stroke.
doi:10.1001/archneurol.2011.1015
PMCID: PMC3397390  PMID: 22232344
8.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
Objective
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Design
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
Setting
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Subjects
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
Results
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Conclusions
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
doi:10.1001/archneurol.2011.725
PMCID: PMC3290902  PMID: 22159053
9.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Background
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
Objectives
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
Design/Methods
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Results
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Conclusions
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
doi:10.1001/archneurol.2011.535
PMCID: PMC3346179  PMID: 22084131
10.  A Controlled Study of Medial Arterial Calcification of Legs 
Archives of Neurology  2011;68(10):1290-1294.
Background
Diabetes mellitus (DM) is associated with an increased prevalence of peripheral arterial disease and medial arterial calcification (MAC), possibly related to prevalence and severity of diabetic polyneuropathy (DPN).
Objective
To assess the prevalence, risk covariates, and implication of MAC in a controlled study of healthy subjects and patients with DM.
Design
Masked evaluation of radiographs.
Setting
Olmsted County, Minnesota.
Patients
Ambulatory volunteers with DM from the Rochester Diabetic Neuropathy Study cohort (n=260) and matched healthy subjects from the Rochester Diabetic Neuropathy Study–Healthy Subject cohort (n=221).
Methods
Patients and controls underwent standard radiographs of distal legs and feet from January 1, 1995, through December 31, 2002. The radiographs were independently read by masked, experienced radiologists for vessel calcification. Medial arterial calcification prevalence, risk covariates, correlation with peripheral arterial disease, and implication for distal, length-dependent sensorimotor polyneuropathy (DSPN) were studied.
Results
Of 481 study participants, MAC was found in 66 (13.7%): 55 of 260 (21.2%) in patients with DM and 11 of 221 (5.0%) in healthy subjects (P<.001). Inter-rater agreement of MAC was 94.1% (κ coefficient of 0.7). Medial arterial calcification was significantly associated with DSPN (P<.001). In stepwise logistic regression analysis, the significant risk covariates for MAC were advancing age, male sex, DM, and stage of microvessel disease (retinopathy).
Conclusions
Medial arterial calcification of legs was approximately 4 times as prevalent in population-representative ambulatory persons with DM as in healthy subjects. Advancing age, male sex, DM, and retinopathy were the significant risk covariates for MAC of legs. Medial arterial calcification of legs, although significantly associated with DSPN, was not a useful surrogate marker of DSPN. Also, MAC was not shown to be a risk covariate for late worsening of DSPN, although other lines of evidence suggest that peripheral arterial disease may worsen DSPN.
doi:10.1001/archneurol.2011.211
PMCID: PMC3271858  PMID: 21987542
11.  Cerebrospinal Fluid Aβ and Tau Level Fluctuation in an Older Clinical Cohort 
Archives of Neurology  2012;69(2):246-250.
Objective
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Design
Biomarker validation in a clinical cohort.
Setting
University hospital inpatient unit.
Participants
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
Results
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
Conclusion
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
doi:10.1001/archneurol.2011.732
PMCID: PMC3310240  PMID: 22332192
12.  Clinical correlates of white matter tract degeneration in PSP 
Archives of Neurology  2011;68(6):753-760.
Objective
Progressive supranuclear palsy (PSP) is associated with degeneration of white matter tracts that can be detected using diffusion tensor imaging (DTI). However, little is known about whether tract degeneration is associated with the clinical symptoms of PSP. The aim of this study was to use DTI to assess white matter tract degeneration in PSP and to investigate correlates, between tract integrity and clinical measures.
Design
Case-control study
Setting
Tertiary care medical centre
Patients
Twenty subjects with probable PSP and 20 age and gender-matched healthy controls. All PSP subjects underwent standardized clinical testing, including the Frontal Behavioral Inventory and Frontal Assessment Battery to assess behavioral change; the PSP Rating Scale to measure disease severity, the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (parts I, II and III) to measure motor function, and the PSP Saccadic Impairment Scale to measure eye movement abnormalities.
Main outcome measures
Fractional anisotropy and mean diffusivity measured using both region-of-interest analysis and Track Based Spatial Statistics.
Results
Abnormal diffusivity was observed predominantly in superior cerebellar peduncles, body of the corpus callosum, inferior longitudinal fasciculus and superior longitudinal fasciculus in PSP compared to controls. Fractional anisotropy values in the superior cerebellar peduncles correlated with disease severity; inferior longitudinal fasciculus correlated with motor function, and superior longitudinal fasciculus correlated with severity of saccadic impairments.
Conclusions
These results demonstrate that PSP is associated with degeneration of brainstem, association and commissural fibers and that this degeneration likely plays an important role in clinical dysfunction.
doi:10.1001/archneurol.2011.107
PMCID: PMC3401587  PMID: 21670399
13.  Effect of APOE ε4 Status on Intrinsic Network Connectivity in Cognitively Normal Elderly 
Archives of Neurology  2011;68(9):1131-1136.
Objective
To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age, gender and education-matched older adults.
Design
Case-control study.
Setting
Community-based sample
Subjects
Fifty-six cognitively normal APOE ε4 carriers and 56 age, gender and education-matched cognitively normal APOE ε4 non-carriers.
Main Outcome Measure
Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared to APOE ε4 non-carriers ranging from 63 to 91 years of age.
Results
A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 non-carriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network, including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs. non-carriers. There were no group-wise differences in brain anatomy.
Conclusions
We found reductions in posterior default mode network connectivity but increased salience network connectivity in elderly cognitively normal APOE ε4 carriers relative to APOE ε4 non-carriers at rest. The observation of functional alterations in connectivity in the absence of structural changes between APOE e4 carriers and non-carriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.
doi:10.1001/archneurol.2011.108
PMCID: PMC3392960  PMID: 21555604
14.  Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease 
Archives of Neurology  2010;67(1):27-32.
Background
Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
Objective
To examine the effects of a dopamine agonist on the motor response to levodopa.
Design
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Setting
Ambulatory academic referral center.
Patients
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Interventions
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Results
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Conclusions
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
Trial Registration
clinicaltrials.gov Identifier: NCT00666653
doi:10.1001/archneurol.2009.287
PMCID: PMC3390306  PMID: 20065126
15.  Effect of Low Concentrations of Apomorphine on Parkinsonism in a Randomized, Placebo-Controlled, Crossover Study 
Archives of Neurology  2008;65(2):193-198.
Objective
To determine whether low concentrations of a dopamine agonist worsen parkinsonism, which would suggest that activation of presynaptic dopamine autoreceptors causes a super-off state.
Design
Randomized, double-blind, placebo-controlled, crossover clinical trial.
Setting
Academic movement disorders center.
Patients
Patients with Parkinson disease and motor fluctuations.
Intervention
Fourteen patients with Parkinson disease and motor fluctuations were randomized to receive 1 of 6 possible sequences of placebo, low-dose (sub-threshold) apomorphine hydrochloride, and high-dose (threshold to suprathreshold) apomorphine hydrochloride infusions. Subthreshold doses of apomorphine hydrochloride (12.5 μg/kg/h every 2 hours and 25 μg/kg/h every 2 hours), threshold to suprathreshold doses of apomorphine hydrochloride (50 μg/kg/h every 2 hours and 100 μg/kg/h every 2 hours), and placebo were infused for 4 hours daily for 3 consecutive days.
Main Outcome Measures
Finger and foot tapping rates.
Results
There was no decline in finger or foot tapping rates during the low-dose apomorphine hydrochloride infusions relative to placebo. The high-dose infusions increased foot tapping (P<.001) and trended toward increasing finger tapping compared with placebo infusions.
Conclusions
Subthreshold concentrations of apomorphine did not worsen parkinsonism, suggesting that pre-synaptic dopamine autoreceptors are not important to the motor response in moderate to advanced Parkinson disease.
doi:10.1001/archneurol.2007.58
PMCID: PMC3390309  PMID: 18268187
16.  Evidence for Ordering of Alzheimer’s Disease Biomarkers 
Archives of Neurology  2011;68(12):1526-1535.
Objective
To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
Design
Validation sample
Setting
Multi-site, referral centers
Patients
We studied 401 elderly cognitively normal (CN), Mild Cognitive Impairment (MCI) and AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative. We compared the proportions of three AD biomarkers – CSF Aβ42, CSF total tau (t-tau), and hippocampal volume adjusted by intra-cranial volume (HVa) - that were abnormal as cognitive impairment worsened. Cut-points demarcating normal vs. abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.
Interventions
None
Main Outcome measures
AD biomarkers
Results
Within each clinical group in the entire sample (n=401) CSF Aβ42 was abnormal more often than t-tau or HVa. Among the 298 subjects with both baseline and 12 month data, the proportion of subjects with abnormal Aβ42 did not change from baseline to 12 months in any group. The proportion of subjects with abnormal t-tau increased from baseline to 12 months in CN (p=0.05) but not in MCI or dementia. In 209 subjects with abnormal CSF AB42 at baseline, the percent abnormal HVa, but not t-tau, increased from baseline to 12 months in MCI.
Conclusions
Reduction in CSF Aβ42 denotes a pathophysiological process that significantly departs from normality (i.e., becomes dynamic) early, while t-tau and HVa are biomarkers of downstream pathophysiological processes. T-tau becomes dynamic before HVa, but HVa is more dynamic in the clinically symptomatic MCI and dementia phases of the disease than t-tau.
doi:10.1001/archneurol.2011.183
PMCID: PMC3387980  PMID: 21825215
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; CSF tau; CSF Abeta; Alzheimer’s disease staging
17.  Elevated Serum Pesticide Levels and Risk of Parkinson Disease 
Archives of Neurology  2009;66(7):870-875.
Background
Exposure to pesticides has been reported to increase the risk of Parkinson disease (PD), but identification of the specific pesticides is lacking. Three studies have found elevated levels of organochlorine pesticides in postmortem PD brains.
Objective
To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD.
Design
Case-control study.
Setting
An academic medical center.
Participants
Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease.
Main Outcome Measures
Levels of 16 organochlorine pesticides in serum samples.
Results
β-Hexachlorocyclohexane (β-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of β-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of β-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67–11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum β-HCH and PD.
Conclusions
These data suggest that β-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of β-HCH as a etiologic agent for some cases of PD.
doi:10.1001/archneurol.2009.89
PMCID: PMC3383784  PMID: 19597089
18.  Dissociation of Neuropathologic Findings and Cognition 
Archives of Neurology  2007;64(8):1193-1196.
Background
The apolipoprotein E (APOE) ε2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.
Objective
To describe a dissociation between findings neuropathologic with normal cognition in a woman with severe Alzheimer disease with the APOE ε2/ε2 genotype.
Design
Case report from a community based prospective study of persons 90 years or older (The 90+ Study).
Participant
A 92-year-old woman without dementia with the APOE ε2/ε2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.
Intervention
Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.
Results
Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.
Conclusions
The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE ε2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.
doi:10.1001/archneur.64.8.1193
PMCID: PMC3378248  PMID: 17698712
19.  An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1 
Archives of Neurology  2010;68(1):37-44.
Objective
To evaluate the safety and tolerability of recombinant human insulin-like growth factor-1 (rhIGF-1) complexed with IGF binding protein-3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1).
Design
Open-label dose-escalation clinical trial.
Setting
University medical center.
Participants
Fifteen moderately affected ambulatory participants with genetically-proven DM1.
Intervention
Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 over 24 weeks followed by a 16 week washout period.
Outcome Measures
Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks on rhIGF-1/rhIGFBP-3 treatment.
Results
All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual energy x-ray absorptiometry increased by 1.95 kg (p=0.0007) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (p=0.002), a mean increase in HDL levels of 5.0 mg/dL (p=0.03), a mean reduction in HbA1c of 0.15% (p=0.03), and a mean increase in testosterone level (in men) of 203 ng/dL (p=0.002) while on rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (n=9 participants), as did mild transient hypoglycemia (n=3), lightheadedness (n=2), and transient papilledema (n=1).
Conclusions
rhIGF-1/rhIGFBP-3 treatment was generally well tolerated in DM1. rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease.
doi:10.1001/archneurol.2010.227
PMCID: PMC3374954  PMID: 20837825
20.  Progenitor Cell–Based Treatment of the Pediatric Myelin Disorders 
Archives of Neurology  2011;68(7):848-856.
The childhood leukodystrophies are characterized by neonatal or childhood deficiencies in myelin production or maintenance; these may be due to hereditary defects in genes for myelin maintenance, as in Pelizaeus-Merzbacher disease, or to enzymatic deficiencies resulting in substrate misaccumulation or misprocessing, as in the lysosomal storage disorders. Regardless of their respective etiologies, these disorders are essentially all manifested by a profound deterioration in neurological function with age. A congenital deficit in forebrain myelination is also noted in children with the periventricular leukomalacia of cerebral palsy, which yields a more static morbidity. In light of the wide range of disorders to which congenital hypomyelination or postnatal demyelination may contribute, and the relative homogeneity of oligodendrocytes and their progenitors, the leukodystrophies may be especially attractive targets for cell-based therapeutic strategies. As a result, glial progenitor cells, which can give rise to new myelinogenic oligodendrocytes, have become of great interest as potential vectors for the restoration of myelin to the dysmyelinated brain and spinal cord. In addition, by distributing throughout the neuraxis after perinatal graft, and giving rise to astrocytes as well as oligodendrocytes, glial progenitor cells may be of great utility in rectifying the dysmyelination-associated enzymatic deficiencies of the lysosomal storage disorders.
doi:10.1001/archneurol.2011.46
PMCID: PMC3358919  PMID: 21403006
21.  Differential Involvement of Optineurin in Amyotrophic Lateral Sclerosis With or Without SOD1 Mutations 
Archives of Neurology  2011;68(8):1057-1061.
Background
Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS).
Objective
To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1-linked ALS.
Design
Clinical case series.
Setting
Academic referral center.
Subjects
We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z.
Results
We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z.
Conclusion
The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non-SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS.
doi:10.1001/archneurol.2011.178
PMCID: PMC3357952  PMID: 21825243
22.  A Comprehensive Genetic Association Study of Alzheimer Disease in African Americans 
Archives of Neurology  2011;68(12):1569-1579.
Objectives
To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites.
Design
We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population.
Subjects
Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects.
Setting
Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study.
Results
Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P=.0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes.
Conclusions
Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific.
doi:10.1001/archneurol.2011.646
PMCID: PMC3356921  PMID: 22159054
23.  Frequency of known mutations in early onset PD; implication for genetic counseling: the CORE-PD study 
Archives of Neurology  2010;67(9):1116-1122.
Objective
To assess the frequency and clinical characteristics of carriers of previously identified mutations in six genes associated with early onset Parkinson disease (EOPD) and provide empirical data that can be used to inform genetic counseling.
Methods
Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2 and GBA were assessed in 953 individuals with EOPD ascertained based on age at onset (AAO) ≤50 years. Participants included 77 Hispanics and 139 of Jewish ancestry. A validated family history interview and the Unified Parkinson’s Disease Rating Scale (UPDRS) were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status.
Results
One hundred and fifty eight (16.6%) had mutations including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA and one (0.2%) DJ1. Mutation carriers were more frequent among cases with AAO ≤30 than among cases with AAO between 31 and 50 (40.6% vs. 14.6% p<0.001), Jews compared to non-Jews (32.4% vs. 13.7% p<0.001) and those reporting a first degree family history of PD than among those who did not (23.9% versus 15.1% p=0.012). Hispanics were more likely to be PRKN carriers than non-Hispanics (15.6% versus 5.9% p=0.003). The GBA L444P mutation was associated with a higher mean UPDRS-III score after adjustment for covariates.
Conclusion
EOPD individuals of Jewish or Hispanic ancestry, those with AAO ≤ 30, and those with a family history of PD in a first-degree relative may benefit from genetic counseling.
doi:10.1001/archneurol.2010.194
PMCID: PMC3329730  PMID: 20837857
24.  Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study 
Archives of Neurology  2010;67(6):731-738.
Background
Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson’s disease (EOPD). Results from a multi-center study of cases with PD systematically sampled by age at onset (AAO) have not been reported.
Objective
To determine risk factors associated with carrying mutations in the parkin gene.
Design
Cross-sectional observational study
Setting
13 movement disorders centers
Participants
956 EOPD cases defined as AAO <51.
Main Outcome Measures
Presence of heterozygous, homozygous or compound heterozygous parkin mutations.
Results
14.7% of cases reported a family history of PD in a first-degree relative using a previously validated interview. Sixty-four cases (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygotes, 2.2% compound heterozgyotes). Copy Number Variation (CNV) was present in 52.3% (31.6% of heterozygotes, 83.3% of homozygotes, 81.0% of compound heterozygotes). Deletions in exons 3–4 and 255delA, were common in Hispanics, and specifically, in the Puerto Rican population. Earlier AAO, Hispanic ethnicity (OR compared to White non-Hispanic 2.7 95% CI 1.3–5.7, p<0.009) and family history of PD in a first-degree relative (OR 2.8 95%CI 1.5–5.3, p<0.002) were associated with carrying any mutation in the parkin gene (heterozygous, homozygous, compound heterozygous). Hispanic ethnicity was associated with carrying a heterozygous mutation (OR compared to non-Hispanic Caucasian 2.8 95%CI 1.1–7.2, p<0.03) after adjustment for covariates.
Conclusion
AAO, Hispanic ethnicity and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation in Hispanics warrants further study.
doi:10.1001/archneurol.2010.95
PMCID: PMC3329757  PMID: 20558392
25.  Clinical Characterization of a Kindred with a Novel Twelve Octapeptide Repeat Insertion in the Prion Protein Gene 
Archives of Neurology  2011;68(9):1165-1170.
Objective
To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene (PRNP).
Design
Clinical description of a kindred.
Setting
Mayo Clinic Alzheimer’s Disease Research Center (Rochester).
Subjects
Two pathologically-confirmed cases and their relatives.
Main outcome measures
Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses and neuropathological features.
Results
The proband presented with clinical and neuroimaging features of atypical frontotemporal dementia (FTD) and ataxia. Generalized tonic-clonic seizures developed later in her course, and electroencephalography revealed spike and wave discharges but no periodic sharp wave complexes. Her affected sister and father also exhibited FTD-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in their course. Genetic analyses in the proband identified a novel defect in PRNP with one mutated allele carrying a 288 base pair insertion (BPI) consisting of 12 octapeptide repeats. Neuropathologic examination of the sister and proband revealed PrP-positive plaques and widespread tau-positive tangles.
Conclusion
This kindred has a unique combination of clinical and neuropathologic features associated with the largest BPI identified to date in PRNP, and underscores the need to consider familial prion disease in the differential diagnosis of a familial FTD-like syndrome.
doi:10.1001/archneurol.2011.187
PMCID: PMC3326586  PMID: 21911696
frontotemporal dementia; FTD; nonfluent aphasia; Gerstmann–Straüssler–Scheinker syndrome (GSS); Creutzfeldt-Jakob disease (CJD); prion; PRNP

Results 1-25 (35)