Objective

To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.

Design

Observational, retrospective case series.

Setting

Mayo Clinic Health System.

Patients

Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.

Intervention

Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.

Main Outcome Measure

Seizure frequency.

Results

After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.

Conclusion

When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.

Objective

To determine Parkinson disease (PD) life expectancy in the United States and identify demographic, geographic and clinical factors that influence survival.

Design

Retrospective cohort study of 138,000 Medicare beneficiaries with incident PD were identified in 2002 and followed through 2008.

Main Outcome Measures

Confounder adjusted six year risk of death as influenced by three groups of factors: 1) race, sex, age at diagnosis 2) geography, environmental factors 3) clinical conditions. We examined hospitalization diagnoses in terminal PD, compared PD mortality to that of other common diseases.

Results

Thirty-five percent of PD cases lived more than six years. Sex and race significantly predicted survival: female (HR 0.74, 0.73– 0.75), Hispanic (HR 0.72, 0.65–0.80) and Asian (HR 0.86, 0.82–0.91) cases had a lower adjusted risk of death than white males. Dementia/cognitive impairment, diagnosed in 69.6% of cases, most often in Blacks (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR 1.72, 1.69–1.75). PD cases had greater mortality than many common life threatening diseases. Terminal PD patients were hospitalized frequently for cardiovascular disease (15.06%) and infection (29.52%), rarely for PD related illness (4.2%). Regional survival rates were similar, but urban PD cases living in a high industrial metal emission area had a slightly higher adjusted risk of death (HR 1.19, 1.10–1.29).

Conclusions

Demographic and clinical factors impact PD survival. Dementia is highly prevalent in PD and is associated with a significant increase in mortality. More research is needed to understand if environmental exposures influence PD course or survival.

Objective

To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.

Design

Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Patients

Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.

Main Outcome Measures

The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).

Results

Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.

Conclusions

Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.

Increasing evidence shows that the central nervous system and the immune system interact in complex ways, and better insight into these interactions may be relevant to the treatment of patients with stroke and other forms of central nervous system injury. Atherosclerosis, autoimmune disease, and physiological stressors, such as infection or surgery, cause inflammation that contributes to vascular injury and increases the risk of stroke. In addition, the immune system actively participates in the acute pathogenesis of stroke. Thrombosis and hypoxia trigger an intravascular inflammatory cascade, which is further augmented by the innate immune response to cellular damage occurring in the parenchyma. This immune activation may cause secondary tissue injury, but it is unclear whether modulating the acute immune response to stroke can produce clinical benefits. Attempts to dampen immune activation after stroke may have adverse effects because central nervous system injury causes significant immunodepression that places patients at higher risk of infections, such as pneumonia. The activation of innate immunity after stroke sets the stage for an adaptive immune response directed against brain antigens. The pathogenic significance of adaptive immunity and its long-term effects on the postischemic brain remains unclear, but it cannot be ruled out that a persistent autoimmune response to brain antigens has deleterious and long-lasting consequences. Further research will be required to determine what role, if any, immunity has in long-term outcomes after stroke, but elucidation of potential mechanisms may open promising avenues for the development of new therapeutics to improve neurological recovery after brain injury.

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.

Objective

APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.

Method

APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.

Subjects

201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.

Results

APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.

Conclusion

Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.

Objective

To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).

Design

Conditional logistic regression models and survival analysis.

Setting

Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.

Participants

Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.

Main Outcome Measures

Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.

Results

In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P<.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.

Conclusions

APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

Objective

Alexander disease typically results from dominant mutations in GFAP that arise de novo. However, several instances of multigenerational familial cases have been reported, with some of the most extensive having been described prior to the identification of GFAP as the related gene. These historically seminal families continue to be of interest due to their clinical variability and suggestions of recessive inheritance or germline mosaicism. We here describe genetic analyses of the two most thoroughly studied historical families, as well as one newly discovered family.

Design

Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin embedded surgical samples.

Subjects

Affected and unaffected adult members of three families and affected children were included.

Results

Family A contains four siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include one unaffected adult, one juvenile onset, and two adult onset. Family B spans four generations, including the first described adult-onset patient originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains three generations. We detected a novel p.Gln426Leu mutation that is the farthest C-terminal mutation known.

Conclusions

These families display clear evidence of variable phenotypes, but do not support recessive inheritance. While germline mosaicism cannot be excluded for one family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.

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.

Objective

To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS).

Design

Retrospective, cross-sectional cohort study.

Setting

Academic MS center.

Patients

Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort.

Main Outcome Measures

Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire. Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated.

Results

Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P<.001) and more severe on a 10-point scale (5.38 vs 1.85; P <.001). Pain remained more common after controlling for disability and number of spinal cord segments (P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS (75.9% vs 37.8%; P<.001), often requiring more than 1 medication (65.5% vs 15.2%; P<.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006).

Conclusions

Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.

Background

Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.

Objective

To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.

Patients

An American kindred of Northern European and Cherokee American Indian descent.

Results

Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.

Conclusions

Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.

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

Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.

Design

11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.

Setting

ADRC and HIV clinic

Participants

16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).

Main Outcome Measure(s)

Mean and regional 11C-PiB binding potentials

Results

Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).

Conclusions

Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.

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.

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.

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.

Objective

To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.

Design

Prospective cohort study.

Setting

Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.

Participants

Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.

Main Outcome Measures

We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.

Results

Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.

Conclusion

In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Objective

To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.

Design

Population-based, prospective cohort study.

Patients

A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.

Intervention

Patients underwent mutational analysis for SOD1, FUS, and TARDBP.

Results

Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94–single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.

Conclusions

The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.

Objectives

To evaluate associations between mid- and late-life obesity and risk of dementia.

Design

Prospective cohort followed 5.4 years from 1992/4 through 1999.

Setting

Community-dwelling sample in four US sites recruited from Medicare eligibility files.

Participants

2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.

Main Outcome Measures

Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.

Results

Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.

Conclusions

These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.

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.

Objective

To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.

Design

Cohort study.

Setting

Academic multiple sclerosis center.

Patients

Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.

Main Outcome Measures

Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).

Results

An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).

Conclusions

Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.

Objective

To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.

Methods

First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer’s Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplo-type analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing.

Results

One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio,−0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer’s Disease data set or the Caribbean His-panic data set. The corresponding haplotypes were also associated with AD risk (.01< P<.05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P<.05 to P<.01) compared with the scrambled small-hairpin RNA condition.

Conclusions

These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate γ-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.

Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer’s disease (AD). As a result, much work has been done investigating the potential use of lipid-lowering agents (LLAs), particularly statins, as preventive or therapeutic agents for AD. While epidemiology and preclinical statin research (described in Part 1 of this review) have generally supported an adverse role of high cholesterol regarding AD, human studies of statins (reviewed here) show highly variable outcomes, making it difficult to draw firm conclusions. We identify several confounding factors among the human studies, including differing blood-brain barrier permeabilities among statins, the stage in AD at which statins were administered, and the drugs’ pleiotropic metabolic effects, all of which contribute to the substantial variability observed to date. We recommend that future human studies of this important therapeutic topic 1) take the blood-brain barrier permeabilities of statins into account when analyzing results, 2) include specific analyses of effects on low-density and high-density lipoprotein cholesterol, and most importantly, 3) conduct statin treatment trials solely in mild AD patients, who have the best chance for disease modification.