Background

TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.

Objective

To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.

Design, Setting, and Participants

Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.

Main Outcome Measure

We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.

Results

The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.

Conclusions

Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD co-segregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.

Objectives

To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.

Design

Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.

Setting

Inpatient traumatic brain injury unit

Patients or Other Participants

Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.

Main Outcome Measure

Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.

Results

Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.

Conclusion

Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

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

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.

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.

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.

Objective

To analyze the spectrum of neurological manifestations in children hospitalized with pandemic influenza A H1N1 virus of 2009 (pH1N1).

Design

Retrospective case series of children hospitalized from May 1, 2009, through November 30, 2009.

Setting

Tertiary-care children’s hospital in Colorado.

Patients

All hospitalized patients with pH1N1 with neurological consult or diagnosis, lumbar puncture, electroencephalogram, or neuroimaging were selected as suspected cases. These were systematically reviewed and selected for final analysis if confirmed by pre-established definitions as a neurological complication.

Results

Of 307 children with pH1N1, 59 were selected as having suspected cases of neurological complications. Twenty-three children were confirmed to have a neurological complication. Of these 23, 15 (65%) required intensive care monitoring. The median length of stay was 4 days. Seventeen (74%) had a preexisting neurological diagnosis. The most common manifestation was seizure with underlying neurological disease (in 62% of cases) followed by encephalopathy with or without neuroimaging changes (in 26% of cases). Results from a lumbar puncture showed elevated protein levels in 3 of 6 patients but no significant pleocytosis. Seven of the 9 electroencephalograms showed diffuse slowing, and findings from magnetic resonance imaging were abnormal in 5 of 6 children. Deaths occurred in 13% of patients, and short-term disability in 22%.

Conclusions

Children infected with pH1N1 presented with a wide spectrum of neurological manifestations, which occurred primarily in individuals with preexisting neurological conditions. These individuals had a severe disease course, evidenced by need for intensive care services and relatively high rates of mortality or neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.

Objective

To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).

Design

Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.

Setting

Academic medical centers

Patients

45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)

Results

Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.

Conclusions

Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.

Objective

To determine specific type of amyloid from nerve biopsies using laser microdissection (LMD) and mass spectrometry (MS) based proteomic analysis.

Methods

Twenty one nerve biopsies (17 sural, 3 sciatic, 1 root amyloidoma) infiltrated by amyloid were studied. Immunohistochemical subtyping was unable to determine the specific amyloid for these 21 cases, but the clinical diagnosis was made based on additional testing. Clinical diagnosis was made through evaluation of serum monoclonal proteins, biopsy of bone marrow for acquired monoclonal immunoglobulin light-chain amyloidosis (AL) and kindred evaluations with DNA sequencing of transthyretin (TTR) and gelsolin (GSN). Our study included 8 cases of AL-type amyloidosis, 11 cases of TTR amyloidosis (3 Val30Met, 2 Val32Ala, 2 Thr60Ala, 1Ala109Ser, 1 Phe64Leu, 1 Ala97Ser, 1 not sequenced), and 2 cases of gelsolin amyloidosis (1 Asp187Asn, 1 not sequenced). One TTR and one gelsolin amyloidosis patients with no specific mutation identified were diagnosed based on the genetic confirmation in their first degree relative. Congophilic proteins in the tissues of these 21 cases were laser microdissected, digested into tryptic peptides and analyzed utilizing liquid chromatography electrospray tandem mass spectrometry. Identified proteins were reviewed using bioinformatics tools with interpreters blinded to clinical information.

Results

Specific types of amyloid were accurately detected by LMD/MS in all cases (8 AL-type, 2 gelsolin, and 11 transthyretin). Incidental serum monoclonal proteins did not interfere with detection of TTR amyloidosis in two patients. Additionally, specific TTR mutations were identified in ten cases by LMD/MS. Serum amyloid P-component and apolipoprotein E proteins were commonly found among all cases.

Conclusions

Proteomic analysis of nerve tissue using LMD/MS distinguishes specific types of amyloid independent of clinical information. This new proteomic approach will enhance both diagnostic and research efforts in amyloidosis and other neurologic diseases.

Objectives

To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study.

Design

Nested case-control genome-wide association study.

Setting

The Washington Heights–Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.

Participants

Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.

Intervention

The Illumina HumanHap 650Y chip for genotyping.

Main Outcome Measure

Clinical diagnosis or pathologically confirmed diagnosis of LOAD.

Results

The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7 × 10−7), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9 × 10−6 under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.

Conclusions

Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.

Background

Insulin resistance is a causal factor in pre-diabetes and type 2 diabetes (T2D), and also increases the risk of developing Alzheimer’s disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fluorodeoxyglucose positron emission tomography (FDG PET) in parietotemporal, frontal, and cingulate cortex are also associated with increased AD risk, and can be observed years before dementia onset.

Objectives

We examined whether greater insulin resistance as indexed by the homeostasis model assessment (HOMA-IR) would be associated with reduced resting CMRglu in areas known to be vulnerable in AD in a sample of cognitively normal adults with newly diagnosed pre-diabetes or T2D (P-D/T2D). We also determined whether P-D/T2D adults have abnormal patterns of CMRglu during a memory encoding task.

Design

Randomized crossover design of resting and activation [F-18] FDG-PET.

Setting

University Imaging Center and VA Clinical Research Unit.

Participants

Participants included 23 older adults (mean age±SEM=74.4±1.4) with no prior diagnosis of or treatment for diabetes, but who met American Diabetes Association glycemic criteria for pre-diabetes (n=11) or diabetes (n=12) based on fasting or 2-h oral glucose tolerance test (OGTT) glucose values, and 6 adults (mean age±SEM=74.3±2.8) with normal fasting glucose and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment (MCI).

Intervention

Fasting participants rested with eyes open in a dimly lit room and underwent resting and cognitive activation [F-18]FDG PET imaging on separate days, in randomized order, at 9 am. Following a 30-min transmission scan, subjects received an intravenous injection of 5 mCi [F-18]FDG, and the emission scan commenced 40 min post-injection. In the activation condition, a 35-min memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words that were randomly presented in series through earphones. Delayed free recall for items on the word list was assessed once the emission scan was complete.

Main Outcome Measures

HOMA-IR was calculated for each participant using fasting glucose and insulin values obtained during OGTT screening, and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding/activation scan to examine task-related patterns of CMRglu.

Results

Greater insulin resistance as indexed by HOMA-IR was associated with an AD-like pattern of reduced CMRglu in frontal, temporal-parietal, and cingulate regions in adults with P-D/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-h OGTT glucose concentration, or apolipoprotein E-ε4 allele carriage. During the memory encoding task, normal adults showed activation in right anterior and inferior prefrontal cortex, right inferior temporal cortex, and medial and posterior cingulate regions. Compared to the normal group, adults with P-D/T2D showed a different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.

Conclusions

Our results suggest that insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of MCI.

Context

Amyloid β (Aβ) is a key pathophysiological feature of Alzheimer’s disease (AD). Baseline and change values of plasma Aβ have been associated with AD risk.

Objective

To determine if plasma Aβ levels: 1) can be linked to specific cognitive changes which constitute conversion to AD; and 2) correspond to cognitive change independent of dementia.

Setting

Northern Manhattan community.

Design

Longitudinal study including three visits over ~4.5 years (2000–2006).

Participants

880 individuals, from a population based and ethnically diverse sample, who had two plasma Aβ measurements and were dementia-free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired at any point, and 70 converted to AD.

Main Outcome Measures

General Estimating Equations tested the association between plasma Aβ (baseline and change values) and cognitive change (composite score, and memory, language, and visuospatial indices).

Results

High baseline plasma Aβ42 (p=.01)and Aβ40 (p=.01), and decreasing/relatively stable Aβ42 (p=.01) were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (p=.01) and decreasing/relatively stable plasma Aβ42 (p=.01) was associated with faster cognitive decline, primarily in memory.

Conclusions

The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elders also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.

Objectives

To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.

Design

Association study of AD and CLU, PICALM, CR1 and APOE genotypes.

Setting

Academic research institutions in the United States, Canada, and Israel.

Participants

7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.

Results

Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.

Conclusions

We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.

Background

The clinical diagnosis of dementing diseases largely depends upon the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathological findings are unavailable. Nevertheless, research on group decision-making indicates many factors can adversely influence panel performance.

Objective

To determine conditions that improve consensus panel diagnosis.

Design

Comparison of neuropathological diagnoses with individual and consensus panel diagnoses based on clinical summaries, FDG-PET scans, and summaries with scans.

Setting

Expert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of FDG-PET imaging.

Patients and Methods

Forty-five patients with pathologically confirmed Alzheimer’s disease or frontotemporal dementia. Statistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations.

Results

The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.

Conclusions

Using a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding potential pitfalls of group decision-making.

Objective:

The clinical diagnosis of Alzheimer's disease is often based, at least in part, on poor cognitive test performance compared with normative values. The presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease was examined.

Design:

Longitudinal study from 1979 to 2008.

Setting:

Washington University in St. Louis Alzheimer Disease Research Center.

Participants:

Of 78 individuals aged 65 to 101 years enrolled as healthy controls 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD.

Main Outcome Measures:

Criteria for diagnosis of Alzheimer disease based on various cut-points (1.5, 1.0, and 0.5 standard deviations below the mean for robust test norms) for two standard psychometric measures from each of three cognitive domains (episodic memory, visusospatial ability, working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and the last assessment for those who did not.

Results:

Areas under the curve from ROC analyses ranged from .71 to .49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline prior to clinical diagnosis.

Conclusions:

Reliance on divergence from group normative values to determine initial cognitive decline caused by Alzheimer disease results in failure to include people in the initial symptomatic stage of the illness.

Objective

A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson’s disease (PD). There is also increasing evidence that SNPs elsewhere in the gene associate with risk. We sought to further explore the disease association, determine whether evidence of allelic heterogeneity exists, and examine the correlation between PD-associated variants and plasma α-synuclein levels.

Methods

We performed a two-tiered analysis of 1,956 PD patients and 2,112 controls from the NeuroGenetics Research Consortium using a comprehensive tagSNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 cases and 78 controls using a highly sensitive Luminex assay.

Results

Five of the 15 SNPs genotyped were associated with PD under an additive model in Tier 1 (α=0.05). Of these, four were successfully replicated in Tier 2. In the combined sample, the most significant marker was rs356219 (OR, 1.41; CI, 1.28–1.55; p = 1.6 × 10−12) located ~ 9 kb downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r2=0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in cases under an adjusted additive model (p = 0.005).

Conclusions

Our data suggest that one or more unidentified functional SNCA variants modify risk for PD, and that the effect is larger than, and independent of, REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

Objective

To investigate associations between MRI brain morphology, cerebrovascular risk (VR), clinical diagnosis and cognition among elders living in urban Shanghai.

Design

Cross-sectional study.

Setting

Memory Disorders Clinic and community normal control (NC) subject recruitment.

Participants

Ninety-six older subjects, 32 with normal cognition, 30 with amnestic MCI (aMCI) and 34 with dementia.

Main outcome measures

Each subject received medical history, neurological/physical exams, neuropsychological evaluations, brain MRI and apolipoprotein E-ε4 (APOE -ε4) genotype test. MRI volumes were assessed using a semi-automatic method.

Results

Brain volume (BV) was significantly smaller in the demented compared with NC (p < 0.001) or aMCI (p = 0.043). Hippocampal volume (HV) was lower, and white matter hyperintensity volume (WMH) was higher, in aMCI (HV: p = 0.028; WMH: p = 0.041) and dementia (HV: p < 0.001; WMH: p = 0.002) compared with NC. APOE -ε4 presence was significantly associated with reduced HV (p = 0.02). Systolic blood pressure was positively associated with VR score (p = 0.037); diastolic blood pressure (p = 0.021) and VR score (p = 0.036) were both positively associated with WMH. WMH (p = 0.029) and VR (p = 0.031) were both higher among the demented than NC.

Conclusion

MRI brain morphology changes were significantly associated clinical diagnosis, in addition, blood pressure was highly associated with VR score and WMH. These results suggest that MRI is a valuable measure of brain injury in a Chinese cohort and can serve to assess the effects of various degenerative and cerebrovascular pathologies.

Background

Alzheimer's disease (AD) is the most common form of age-related dementia and one of the most serious health problems in the industrialized world. Biomarker approaches to diagnostics would be more time and cost effective and may also be useful for identifying endophenotypes within AD patient populations.

Methods

We analyzed serum protein-based multiplex biomarker data from 197 patients diagnosed with AD and 203 controls from a longitudinal study of Alzheimer's disease being conducted by the Texas Alzheimer's Research Consortium to develop an algorithm that separates AD from controls. The total sample was randomized equally into training and test sets and random forest methods were applied to the training set to create a biomarker risk score.

Findings

The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively and an AUC of 0.91 in detecting AD. When age, gender, education, and APOE status were added to the algorithm, the sensitivity, specificity, and AUC were 0.94, 0.84, and 0.95, respectively.

Interpretation

These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. Of note, a disproportionate number of inflammatory and vascular markers were weighted most heavily in analyses. Additionally, these markers consistently distinguished cases from controls in SAM, logistic regression and Wilcoxon analyses, suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.

3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are among the most prescribed medications in the United States. Statins act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. However, statins decrease other downstream products of the mevalonate pathway, and it is via these pathways that statins may affect inflammation, nitric oxide synthesis, the coagulation cascade, and other processes. Through these pleiotropic effects, statins may have an effect on neurologic diseases, including ischemic and hemorrhagic stroke, Alzheimer disease, Parkinson disease, and multiple sclerosis. This article reviews the basic biochemistry of statins as it relates to these pleiotropic effects, the potential role of statins in several neurologic disorders, and the results of clinical trials performed for several of these conditions.

Background

Harold et al. and Lambert et al. recently published two large genome-wide association studies of late onset Alzheimer’s disease (LOAD) in which CLU, CR1, and PICALM were identified as novel LOAD genes.

Objective

To test for replication of the association between variants in the CLU, CR1 and PICALM genes with Alzheimer’s disease.

Design

Case-control association study

Setting

Community-based ascertainment of patients seen at the Mayo Clinic Jacksonville, FL and Rochester, MN, and autopsy-confirmed cases and controls whose pathology was evaluated at the Mayo Clinic Jacksonville. Additional samples were obtained from the National Cell Repository for Alzheimer’s Disease (NCRAD).

Participants

LOAD case-control series of European descent consisting of 1,829 LOAD cases and 2,576 controls

Main Outcome Measure

Clinical or pathology-confirmed diagnosis of LOAD

Results

In our follow-up study of 1,829 LOAD cases and 2,576 controls, the most significant SNPs in CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179) were tested for allelic association and gave ORs of 0.82, 1.15, and 0.80 respectively that were comparable in direction and magnitude to those originally reported with p values of 8.6×10−5, 0.014, and 1.3×10−5 that were significant even after Bonferroni correction for 3 SNPs tested.

Conclusion

These results showing near perfect replication provide the first additional evidence that CLU, CR1, and PICALM are LOAD genes.

Objectives

To compare the trajectory of motor decline, as measured by gait speed and finger tapping speed, between those who developed mild cognitive impairment (MCI) and those who remained cognitively intact. We also sought to determine the approximate time at which decline in motor function accelerated in those who developed MCI.

Design

Longitudinal cohort study

Participants

Subjects were 204 healthy seniors (58% women) from the Oregon Brain Aging Study evaluated for up to 20 years with annual neurologic, neuropsychological and motor examinations.

Main Outcome Measures

The pattern of motor decline with aging was compared using a mixed-effects model with an interaction term for age and clinical diagnosis of mild cognitive impairment. The time prior to diagnosis of MCI when the change in gait or tapping speed accelerates was assessed with a mixed-effects model with a change point for men and women, separately and combined, who developed MCI.

Results

The rates of change with aging of gait speed (p<0.001) and tapping speed in the dominant hand (p<0.003) and non-dominant hand (p<0.001) were significantly different between MCI converters and non-converters. Using a change-point analysis for MCI converters, the decrease in gait speed accelerated by 0.02 m/s/yr (p<0.001) occurring 12.1 years prior to the onset of MCI. An acceleration of gait speed decline occurred earlier in men than women. For tapping speed, the change point occurred after the onset of MCI for both dominant and non-dominant hands when men and women were combined.

Conclusions

Motor decline as indexed by gait speed accelerates up to 12 years prior to MCI. Longitudinal changes in motor function may be useful in the early detection of dementia during pre-clinical stages when the utility of disease-modifying therapies would be greatest.

Objective

To compare assessment of regional cerebral metabolic changes with DTBZ-PET measurement of regional cerebral blood flow (K1) and FDG-PET measurement of regional cerebral glucose uptake (CMRglc) in a clinically representative sample of mild dementia and mild cognitive impairment (MCI) subjects. We hypothesized that DTBZ-PET K1 and FDG-PET CMRglc provide equivalent information.

Design, Setting, Participants

DTBZ-PET K1 measurement of regional cerebral blood flow and FDG-PET CMRglc measurement of regional cerebral glucose uptake was performed in 50 subjects with either mild dementia (MMSE ≥ 18) or MCI drawn from a university based Cognitive Disorders Clinic. Results were compared with 80 normal control subjects.

Main Outcome Measures

DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K1 deficits and FDG-PET CMRglc deficits were assessed with stereotaxic surface projections (SSP) of parametric images.

Results

DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were highly correlated, both within and between subjects. SSP maps of deficits in DTBZ-PET regional K1 measurements and FDG-PET CMRglcs were markedly similar. DTBZ-PET K1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMRglc maps.

Conclusion

DTBZ-PET K1 and FDG-PET CMRglc provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. K1 measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. K1 assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve of utility of PET imaging in mild dementia and MCI.

Human embryonic stem cells provide a useful source of material for studying basic human development and various disease states. However, ethical issues concerning their procurement limit their acceptance and possible clinical applicability. Recent advances in stem cell technology have provided an alternative source of pluripotent stem cells that do not require the use of an embryo. This review addresses the generation of induced pluripotent stem cells from skin fibroblasts taken from various patient populations, with a specific focus on the pediatric disorder spinal muscular atrophy. These patient-derived cells may help devise more appropriate therapies through a greater understanding of the molecular mechanisms underlying neuron dysfunction and death in a number of diseases. Furthermore, they provide an ideal platform for small molecule screening and subsequent drug development.