Showing papers in "JAMA Neurology in 2013"

Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease

Abstract: Importance Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease. Objective To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity. Design Retrospective observational study from 2007 to 2012. Setting Memory and Aging Center, University of California, San Francisco. Patients We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). Main Outcomes and Measures Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. Results Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform ( P Conclusions and Relevance Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

Sleep Quality and Preclinical Alzheimer Disease

Abstract: Importance Sleep and circadian problems are very common in Alzheimer disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and β-amyloid (Aβ), a key molecule involved in AD pathogenesis. Objective To test whether Aβ deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. Design Cross-sectional study conducted from October 2010 to June 2012. Setting General community volunteers at the Washington University Knight Alzheimer's Disease Research Center. Participants Cognitively normal individuals (n = 145) 45 years and older were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. Valid actigraphy data were recorded in 142. The majority (124 of 142) were recruited from the Adult Children Study, in which all were aged 45 to 75 years at baseline and 50% have a parental history of late-onset AD. The rest were recruited from a community volunteer cohort in which all were older than 60 years and healthy at baseline. Main Outcome Measures Sleep was objectively measured using actigraphy for 2 weeks. Sleep efficiency, which is the percentage of time in bed spent asleep, was the primary measure of sleep quality. Total sleep time was the primary measure of sleep quantity. Cerebrospinal fluid Aβ42 levels were used to determine whether amyloid deposition was present or absent. Concurrent sleep diaries provided nap information. Results Amyloid deposition, as assessed by Aβ42 levels, was present in 32 participants (22.5%). This group had worse sleep quality, as measured by sleep efficiency (80.4% vs 83.7%), compared with those without amyloid deposition, after correction for age, sex, and APOE ϵ4 allele carrier status (P = .04). In contrast, quantity of sleep was not significantly different between groups, as measured by total sleep time. Frequent napping, 3 or more days per week, was associated with amyloid deposition (31.2% vs 14.7%; P = .03). Conclusions and Relevance Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality but not with changes in sleep quantity.

Self-reported Sleep and β-Amyloid Deposition in Community-Dwelling Older Adults

Abstract: Importance Older adults commonly report disturbed sleep, and recent studies in humans and animals suggest links between sleep and Alzheimer disease biomarkers. Studies are needed that evaluate whether sleep variables are associated with neuroimaging evidence of β-amyloid (Aβ) deposition. Objective To determine the association between self-reported sleep variables and Aβ deposition in community-dwelling older adults. Design, Setting, and Participants Cross-sectional study of 70 adults (mean age, 76 [range, 53-91] years) from the neuroimaging substudy of the Baltimore Longitudinal Study of Aging, a normative aging study. Exposure Self-reported sleep variables. Main Outcomes and Measures β-Amyloid burden, measured by carbon 11–labeled Pittsburgh compound B positron emission tomography distribution volume ratios (DVRs). Results After adjustment for potential confounders, reports of shorter sleep duration were associated with greater Aβ burden, measured by mean cortical DVR (B = 0.08 [95% CI, 0.03-0.14];P = .005) and precuneus DVR (B = 0.11 [0.03-0.18];P = .007). Reports of lower sleep quality were associated with greater Aβ burden measured by precuneus DVR (B = 0.08 [0.01-0.15];P = .03). Conclusions and Relevance Among community-dwelling older adults, reports of shorter sleep duration and poorer sleep quality are associated with greater Aβ burden. Additional studies with objective sleep measures are needed to determine whether sleep disturbance causes or accelerates Alzheimer disease.

History, Applications, and Mechanisms of Deep Brain Stimulation

Abstract: Deep brain stimulation (DBS) is an effective surgical treatment for medication-refractory hypokinetic and hyperkinetic movement disorders, and it is being explored for a variety of other neurological and psychiatric diseases Deep brain stimulation has been Food and Drug Administration-approved for essential tremor and Parkinson disease and has a humanitarian device exemption for dystonia and obsessive-compulsive disorder Neurostimulation is the fruit of decades of both technical and scientific advances in the field of basic neuroscience and functional neurosurgery Despite the clinical success of DBS, the therapeutic mechanism of DBS remains under debate Our objective is to provide a comprehensive review of DBS focusing on movement disorders, including the historical evolution of the technique, applications and outcomes with an overview of the most pertinent literature, current views on mechanisms of stimulation, and description of hardware and programming techniques We conclude with a discussion of future developments in neurostimulation

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

Abstract: IMPORTANCE: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING: Eleven centers from sites around the world performing genotyping. PARTICIPANTS: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES: Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

Abstract: Importance We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. Objective To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau 181 ], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. Design, Setting, and Participants Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. Main Outcomes and Measures The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau 181 ; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. Results Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau 181 , α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau 181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau 181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau 181 . Conclusions and Relevance In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau 181 , and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.

Frequency and Characteristics of Isolated Psychiatric Episodes in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Abstract: IMPORTANCE: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown. OBJECTIVE: To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort of patients diagnosed during a 5-year period (median follow-up, 2 years). A total of 571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the University of Pennsylvania and the University of Barcelona, and clinical information was obtained by us or referring physicians. MAIN OUTCOMES AND MEASURES: Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations. RESULTS: Of 571 patients, 23 (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapse. For all 23 patients, age (median, 20 years), sex (91%female), and tumor association (43%; ovarian teratoma in all cases) were similar to the population at large. Predominant symptoms included delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain magnetic resonance imaging findings were abnormal in 10 of 22 patients (45%) and cerebrospinal fluid analysis showed pleocytosis in 17 of 22 patients (77%). Eighty-three percent of the patients had full or substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17 of 18 patients (94%) returned to a similar or better prerelapse functional level. CONCLUSIONS AND RELEVANCE: Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new-onset psychosis, having a history of encephalitis, subtle neurological symptoms, and/or abnormal results on ancillary tests should prompt screening for NMDAR antibodies.

Randomized Clinical Trial of 3 Types of Physical Exercise for Patients With Parkinson Disease

Abstract: Objective To compare the efficacy of treadmill exercises and stretching and resistance exercises in improving gait speed, strength, and fitness for patients with Parkinson disease. Design A comparative, prospective, randomized, single-blinded clinical trial of 3 types of physical exercise. Setting The Parkinson's Disease and Movement Disorders Center at the University of Maryland and the Baltimore Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center. Patients A total of 67 patients with Parkinson disease who had gait impairment were randomly assigned to 1 of 3 arms of the trial. Interventions (1) A higher-intensity treadmill exercise (30 minutes at 70%-80% of heart rate reserve), (2) a lower-intensity treadmill exercise (50 minutes at 40%-50% of heart rate reserve), and (3) stretching and resistance exercises (2 sets of 10 repetitions on each leg on 3 resistance machines [leg press, leg extension, and curl]). These exercises were performed 3 times a week for 3 months. Main Outcome Measures The primary outcome measures were gait speed (6-minute walk), cardiovascular fitness (peak oxygen consumption per unit time [$$⋅VO 2 ], and muscle strength (1-repetition maximum strength). Results All 3 types of physical exercise improved distance on the 6-minute walk: lower-intensity treadmill exercise (12% increase; P = .001), stretching and resistance exercises (9% increase; P 2 (7%-8% increase; P Conclusions The effects of exercise were seen across all 3 exercise groups. The lower-intensity treadmill exercise resulted in the greatest improvement in gait speed. Both the higher- and lower-intensity treadmill exercises improved cardiovascular fitness. Only the stretching and resistance exercises improved muscle strength. Therefore, exercise can improve gait speed, muscle strength, and fitness for patients with Parkinson disease. The combination of treadmill and resistance exercises may result in greater benefit and requires further investigation.

Late-life depression, mild cognitive impairment, and dementia.

Abstract: Objective To evaluate the association of late-life depression with mild cognitive impairment (MCI) and dementia in a multiethnic community cohort. Design and Setting A cohort study was conducted in Northern Manhattan, New York, New York. Participants A total of 2160 community-dwelling Medicare recipients aged 65 years or older were included in the study. Methods Depression was assessed using the 10-item version of the Center for Epidemiological Studies Depression scale (CES-D) and defined by a CES-D score of 4 or more. We used logistic regression for cross-sectional association analyses and proportional hazards regression for longitudinal analyses. Main Outcome Measures Mild cognitive impairment dementia, and progression from MCI to dementia were the main outcome measures. We also used subcategories of MCI (amnestic and nonamnestic), and dementia (probable Alzheimer disease and vascular dementia, including possible Alzheimer disease with stroke). Results Baseline depression was associated with prevalent MCI (odds ratio, 1.4; 95% CI, 1.1-1.9) and dementia (2.2; 1.6-3.1). Baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7; 95% CI, 1.2-2.3) but not with incident MCI (0.9; 0.7-1.2). Persons with MCI and coexisting depression at baseline had a higher risk of progression to dementia (HR, 2.0; 95% CI, 1.2-3.4), especially vascular dementia (4.3; 1.1-17.0), but not Alzheimer disease (1.9; 1.0-3.6). Conclusion The association of depression with prevalent MCI and with progression from MCI to dementia, but not with incident MCI, suggests that depression accompanies cognitive impairment but does not precede it.

Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired National Football League Players: A Cross-sectional Study

Abstract: OBJECTIVES To assess cognitive impairment and depression in aging former professional football (National Football League [NFL]) players and to identify neuroimaging correlates of these dysfunctions. DESIGN We compared former NFL players with cognitive impairment and depression, cognitively normal retired players who were not depressed, and matched healthy control subjects. SETTING Research center in the North Texas region of the United States. PATIENTS Cross-sectional sample of former NFL players with and without a history of concussion recruited from the North Texas region and age-, education-, and IQ-matched controls. Thirty-four retired NFL players (mean age, 61.8 years) underwent neurological and neuropsychological assessment. A subset of 26 players also underwent detailed neuroimaging; imaging data in this subset were compared with imaging data acquired in 26 healthy matched controls. MAIN OUTCOME MEASURES Neuropsychological measures, clinical diagnoses of depression, neuroimaging mea-sures of white matter pathology, and a measure of cerebral blood flow. RESULTS Of the 34 former NFL players, 20 were cognitively normal. Four were diagnosed as having a fixed cognitive deficit; 8, mild cognitive impairment; 2, dementia; and 8, depression. Of the subgroup in whom neuroimaging data were acquired, cognitively impaired participants showed the greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in cognitively impaired and depressed retired players compared with their respective controls. Regional blood flow differences in the cognitively impaired group (left temporal pole, inferior parietal lobule, and superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming, and word finding). CONCLUSIONS Cognitive deficits and depression appear to be more common in aging former NFL players compared with healthy controls. These deficits are correlated with white matter abnormalities and changes in regional cerebral blood flow.

APOE ε4 increases risk for dementia in pure synucleinopathies.

Abstract: Lewy body disease (LBD) en-compasses a spectrum of clinicopathologic entities that include Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). Dementia with Lewy bodies and PDD are differentiated from one another based on clinical criteria. Dementia with Lewy bodies is diagnosed when dementia occurs before or concurrently with parkinsonism, whereas in PDD, parkinsonism precedes dementia by at least 12 months.1 Lewy body disease neuropathologic changes (NCs) include classic histologic inclusions (Lewy bodies) and α-synuclein immunopositive neuronal inclusions and processes (Lewy neurites) in partially overlapping regions of the brain. However, the pathologic classification of DLB is complex because some cases show LBDNCs with no or low levels of Alzheimer disease (AD) NCs, which we refer to as pure DLB (pDLB), while many other cases show LBDNCs with coexistent high levels of ADNCs (LBDAD). Importantly, the pathophysiologic relationship between LBD-AD, pDLB, and PDD has not been delineated, and whether these disorders share common risk factors remains unclear. Humans are unlike other mammals in that we possess 3 common alleles of the apolipoprotein E (APOE) gene that are determined by 2 single nucleotide polymorphisms located in exon 4 at positions 3937 (T/C; rs429358) and 4075 (C/T; rs7412). The corresponding apoE isoforms (299 amino acids) differ at amino acid positions 112 (Cys for apoE2 and apoE3; Arg for apoE4) and 158 (Cys for apoE2; Arg for apoE3 and apoE4), and these isoforms have different functional and biochemical properties.2 The APOE e4 allele is a well-established risk factor for both early-onset and late-onset AD.3,4 We and others have reported an association between e4 and LBD-AD,5–7 but it is unclear whether e4 is a risk factor for pDLB or PDD because interpretations of existing data are limited by methodologic differences between studies. In particular, studies of DLB have often failed to assess for the presence of coexistent ADNCs, thus they have been unable to differentiate LBD-AD from pDLB.8–10 Therefore, it is possible that all genetic risk for DLB associated with the APOE e4 allele is related to its frequent comorbidity with ADNCs and is unrelated to LBDNCs. Furthermore, no studies have directly compared genetic risk factors between pDLB and PDD. To address this gap in knowledge, we genotyped APOE in a clinically and neuropathologically well-characterized sample of control participants and subjects with AD, LBD-AD, pDLB, and PDD.

A 5-Year Follow-up of Rituximab Treatment in Patients With Neuromyelitis Optica Spectrum Disorder

Abstract: Importance A previous 2-year analysis of repeated rituximab treatment in patients with neuromyelitis optica (NMO) revealed significant improvements in relapse rates and disability. We report the findings from the longest follow-up of rituximab treatment in NMO, which provide reassurance regarding the long-term efficacy and safety of rituximab in NMO. Objective To report the results of rituximab treatment in patients with relapsing NMO or NMO spectrum disorder (NMOSD) for a median of 60 months. Design, Setting, and Participants Retrospective case series in an institutional referral center for multiple sclerosis, including 30 patients with relapsing NMO or NMOSD. Interventions After induction therapy, a single infusion of rituximab (375 mg/m 2 ) as maintenance therapy was administered whenever the frequency of reemerging CD27 + memory B cells in peripheral blood mononuclear cells, as measured with flow cytometry, exceeded 0.05% in the first 2 years and 0.1% thereafter. Main Outcomes and Measures Annualized relapse rate (ARR), disability (Expanded Disability Status Scale score), change in anti–aquaporin 4 antibody, and safety of rituximab treatment. Results Of 30 patients, 26 (87%) exhibited a marked reduction in ARR over 5 years (mean [SD] pretreatment vs posttreatment ARR, 2.4 [1.5] vs 0.3 [1.0]). Eighteen patients (60%) became relapse free after rituximab treatment. In 28 patients (93%), the disability was either improved or stabilized after rituximab treatment. No serious adverse events leading to discontinuation were observed during follow-up. Conclusions and Relevance Repeated treatment with rituximab in patients with NMOSD over a 5-period, using an individualized dosing schedule according to the frequency of reemerging CD27 + memory B cells, leads to a sustained clinical response with no new adverse events.

Prognosis of mild cognitive impairment in early Parkinson disease: the Norwegian ParkWest study.

Abstract: Importance Mild cognitive impairment (MCI) is common in Parkinson disease (PD), but the prognostic value of MCI in early PD is unknown. Objective To examine the course of MCI and its progression to dementia in an incident PD cohort. Design Prospective longitudinal cohort study. Setting The Norwegian ParkWest study, an ongoing population-based study of the incidence, neurobiology, and prognosis of PD in western and southern Norway. Participants A population-based cohort of 182 patients with incident PD monitored for 3 years. Main Outcomes and Measures Serial neuropsychological tests of attention, executive function, verbal memory, and visuospatial skills were administered at baseline, 1 year, and 3 years. Patients were classified as having MCI and received a diagnosis of dementia according to published consensus criteria. Results Significantly more patients with MCI than without MCI at baseline (10 of 37 [27.0%] vs 1 of 145 [0.7%]; relative risk, 39.2 [95% CI, 5.2-296.5]; P Conclusions and Relevance Mild cognitive impairment at PD diagnosis predicts a highly increased risk for early dementia. Repeated neuropsychological testing increases the prognostic accuracy of MCI with respect to early dementia development in PD.

Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects.

Abstract: Importance Identifying risk factors for increased β-amyloid (Aβ) deposition is important for targeting individuals most at risk for developing Alzheimer disease and informing clinical practice concerning prevention and early detection. Objective To investigate risk factors for Aβ deposition in cognitively healthy middle-aged and older adults. Specifically, we hypothesized that individuals with a vascular risk factor such as hypertension, in combination with a genetic risk factor for Alzheimer disease (apolipoprotein E ϵ4 allele), would show greater amyloid burden than those without such risk. Design Cross-sectional study. Setting General community. Participants One hundred eighteen well-screened and cognitively normal adults, aged 47 to 89 years. Participants were classified in the hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic, as measured across 7 occasions at the time of study. Intervention Participants underwent Aβ positron emission tomography imaging with radiotracer fluorine 18–labeled florbetapir. Participants were genotyped for apolipoprotein E and were classified as ϵ4 + or ϵ4 − . Main Outcome Measure Amyloid burden. Results Participants in the hypertension group with at least 1 ϵ4 allele showed significantly greater amyloid burden than those with only 1 risk factor or no risk factors. Furthermore, increased pulse pressure was strongly associated with increased mean cortical amyloid level for subjects with at least 1 ϵ4 allele. Conclusions and Relevance Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of risk factors such as hypertension earlier in the life span may be one potential mechanism to ameliorate or delay neuropathological brain changes with aging.

Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease.

Abstract: Apolipoprotein (apo) E was discovered in the early seventies as a protein associated with cholesterol-rich and triglyceride-rich plasma lipoproteins (for review see Mahley et al., 2009).1 ApoE is synthesized by the liver and secreted into the circulation as a protein incorporated into very low density lipoproteins, chylomicron remnants, and a subclass of high density lipoproteins. ApoE regulates transport of cholesterol and lipids throughout the body and mediates clearance of plasma lipoproteins by the low density lipoprotein receptor (LDLR) and other LDLR-related protein family members.1 In the brain, apoE is produced mainly by astrocytes.2 In the cerebrospinal fluid (CSF) and interstitial fluid (ISF) of the central nervous system (CNS), apoE circulates incorporated into small particles and disks resembling high density lipoproteins. Throughout the body and within the CNS, apoE contributes to restorative processes mediating redistribution of lipids to cells that require cholesterol and phospholipids. Human apoE has three alleles located on a single gene locus on chromosome 19q13 encoding three major apoE isoforms, apoE2, apoE3, and apoE4.3 These apoE isoforms differ by single amino acid substitutions at two residues which have a major effect on the structure and function of apoE protein at the molecular and cellular level, and association with neuropathological conditions. ApoE2 has a cysteine residue at position 158, whereas apoE3 and apoE4 each have arginine. It is believed that this confers greater stability of apoE2 protein and is associated with its protective effect against Alzheimer’s disease (AD).4 ApoE4 is a major genetic risk factor for AD3 and possesses an arginine at residue 112, whereas both apoE2 and apoE3 have cysteines. This single amino acid difference is associated with relative instability of apoE4 protein and its multiple pathogenic effects on cells.1 The most common apoE3 isoform has a cysteine residue at position 112 and an arginine at position 158 which provides greater protein stability compared to apoE4, and is associated with much lower risk for neuropathological disorders compared to APOE4 carriers. Diverse neuropathological effects of apoE4 on cells within the CNS include, but are not limited to1, 2: i) direct toxic effects on neurons that could be mediated by impaired neurite outgrowth, cytoskeletal disruption, hyperphosphorylation of tau, mitochondrial dysfunction and impaired synaptogenesis; ii) reduced Alzheimer’s amyloid β (Aβ) clearance from brain; and iii) direct toxic effects on the cerebrovascular system causing and/or contributing to neuronal dysfunction and neurodegnerative changes. Several recent reviews provide an excellent overview on apoE isoform-specific toxic effects on neurons and effects on neuropathological disorders.1, 2, 4 Therefore, focus of the present review is on cerebrovascular effects of apoE. Particularly, I discuss apoE isoform-specific effects on cerebrovascular integrity and Aβ vascular clearance, and how apoE4 acting through the cerebrovascular system contributes to development of cognitive and neuropathological changes related to the onset and progression of AD.

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

Abstract: Importance The apolipoprotein E ( APOE [GenBank,348; OMIM,107741]) e4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. Objective To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. Design, Setting, and Participants A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. Exposures We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. Main Outcomes and Measures Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified. Results During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the e4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the e4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the e4 allele on neurofibrillary tangle density (interaction estimate, −0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. Conclusions and Relevance Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE e4 + individuals.

Mechanisms of protein seeding in neurodegenerative diseases.

Abstract: Most age-associated neurodegenerative diseases involve the aggregation of specific proteins within the nervous system. In Alzheimer disease, the insidious pathogenic process begins many years before the symptoms emerge, and the lesions that characterize the disease—senile plaques and neurofibrillary tangles—ramify systematically through the brain. We review evidence that the β-amyloid and tau proteins, which aggregate to form senile plaques and neurofibrillary tangles, respectively, are induced to misfold and self-assemble by a process of templated conformational change that amplifies a toxic species. Recent data also indicate that the spread of these lesions from one site to another is mediated by the cellular uptake, transport, and release of endogenous seeds formed by the cognate proteins. This simple pathogenic principle suggests that the formation, trafficking, and metabolism of pathogenic protein seeds are promising therapeutic targets for Alzheimer disease and other neurodegenerative disorders.

Incidence of Dementia With Lewy Bodies and Parkinson Disease Dementia

Abstract: RESULTS Among 542 incident cases of parkinsonism, 64 had DLB and 46 had PDD. The incidence rate of DLB was 3.5 per 100 000 person-years overall, and it increased steeply with age. The incidence of PDD was 2.5 overall and also increased steeply with age. The incidence rate of DLB and PDD combined was 5.9. Patients with DLB were younger at onset of symptoms than patients with PDD and had more hallucinations and cognitive fluctuations. Men had a higher incidence of DLB than women across the age spectrum. The pathology was consistent with the clinical diagnosis in 24 of 31 patients (77.4%) who underwent autopsy. CONCLUSIONS AND RELEVANCE The overall incidence rate of DLB is lower than the rate of Parkinson disease. The incidence of DLB increases steeply with age and is markedly higher in men. This men to women difference may suggest different etiologic mechanisms. Our findings may guide health care planning and prompt new studies.

White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease?

Abstract: Importance Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation. Objective To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography–derived amyloid positivity on the clinical expression of AD. Design Baseline PIB–positron-emission tomography values were downloaded from the Alzheimer's Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59). Setting The Alzheimer's Disease Neuroimaging Initiative public database. Participants The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Disease's Neuroimaging Initiative database. Main Outcome Measures Clinical AD diagnosis and WMH volume. Results Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD. Conclusions and Relevance White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

TDP-43 pathology, cognitive decline, and dementia in old age.

Abstract: Importance Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood. Objective To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late-life cognitive decline. Design, Setting, and Participants Longitudinal clinical-pathologic cohort study involving more than 40 Catholic groups across the United States. A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified. Main Outcomes and Measures Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death. Results Transactive response DNA-binding protein 43 pathology, ranging from sparse to severe, was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. Transactive response DNA-binding protein 43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment. Conclusion and Relevance The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.

New Oral Anticoagulants and the Risk of Intracranial Hemorrhage: Traditional and Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials of New Oral Anticoagulants in Atrial Fibrillation

Abstract: Importance Randomized studies have shown a decreased risk of intracranial hemorrhage (ICH) with use of novel oral anticoagulants (NOACs). However, it is unclear whether the magnitude of benefit is similar for all NOACs currently available. Objective To perform a systematic review and meta-analysis to quantitatively assess the rates of ICH within the framework of both conventional and Bayesian statistics. Data Sources The MEDLINE, CENTRAL, CINAHL, and EBSCO databases, supplemented with conference abstracts, were searched up to December 1, 2012, with no language restriction. Study Selection Randomized trials comparing NOACs vs a comparator and reporting on ICH events. Data Extraction and Synthesis The NOACs were pooled to perform a comparison with all comparators and among themselves in both traditional frequentist and Bayesian random-effects models using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled odds ratios and associated 95% confidence intervals as well as numbers needed to treat and 95% credible intervals for the Bayesian analysis. Main Outcomes and Measures Intracranial hemorrhage events associated with NOACs in comparison with comparators, expressed as odds ratios. Results Six studies (1 administering dabigatran etexilate mesylate, 2 administering rivaroxaban, and 3 administering apixaban) enrolling a total of 57 491 patients were included for analysis. The NOACs significantly reduced the risk of ICH against all comparators (odds ratio = 0.49; 95% CI, 0.36-0.65). Each of the 3 drugs reduced the risk of ICH, with Bayesian indirect comparison analysis not revealing a significant credible difference between the specific medications. Conclusions and Relevance Novel oral anticoagulants are uniformly associated with an overall reduced risk of ICH when used for stroke prevention in atrial fibrillation. Any of the currently available NOACs can be considered first line for patients at high risk for ICH.

Randomized Controlled Clinical Trial of “Virtual House Calls” for Parkinson Disease

Abstract: Importance The burden of neurological disorders is increasing, but access to care is limited. Providing specialty care to patients via telemedicine could help alleviate this growing problem. Objective To evaluate the feasibility, effectiveness, and economic benefits of using web-based videoconferencing (telemedicine) to provide specialty care to patients with Parkinson disease in their homes. Design A 7-month, 2-center, randomized controlled clinical trial. Setting Patients' homes and outpatient clinics at 2 academic medical centers. Participants Twenty patients with Parkinson disease with Internet access at home. Intervention Care from a specialist delivered remotely at home or in person in the clinic. Main Outcome Measures The primary outcome variable was feasibility, as measured by the percentage of telemedicine visits completed as scheduled. Secondary outcome measures included clinical benefit, as measured by the 39-item Parkinson Disease Questionnaire, and economic value, as measured by time and travel. Results Twenty participants enrolled in the study and were randomly assigned to telemedicine (n = 9) or in-person care (n = 11). Of the 27 scheduled telemedicine visits, 25 (93%) were completed, and of the 33 scheduled in-person visits, 30 (91%) were completed (P = .99). In this small study, the change in quality of life did not differ for those randomly assigned to telemedicine compared with those randomly assigned to in-person care (4.0-point improvement vs 6.4-point improvement; P = .61). Compared with in-person visits, each telemedicine visit saved participants, on average, 100 miles of travel and 3 hours of time. Conclusion and Relevance Using web-based videoconferencing to provide specialty care at home is feasible, provides value to patients, and may offer similar clinical benefit to that of in-person care. Larger studies are needed to determine whether the clinical benefits are indeed comparable to those of in-person care and whether the results observed are generalizable. Trial Registration clinicaltrials.gov Identifier: NCT01476306

Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy

Abstract: Objective To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). Design Retrospective case series. Setting Neurology department at a tertiary referral center. Patients Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. Main Outcome Measures Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. Results We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4–positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. Conclusions Interleukin 6 receptor–blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Ischemic Stroke and Transient Ischemic Attack in Young Adults: Risk Factors, Diagnostic Yield, Neuroimaging, and Thrombolysis

Abstract: Background Approximately 10% to 14% of ischemic strokes occur in young adults. Objective To investigate the yield of diagnostic tests, neuroimaging findings, and treatment of ischemic strokes in young adults. Design We retrospectively reviewed data from our Get with the Guidelines–Stroke database from 2005 through 2010. Setting University hospital tertiary stroke center. Patients A total of 215 consecutive inpatients aged 18 to 45 years with ischemic stroke/transient ischemic attack. The mean (SD) age was 37.5 (7) years; 51% were male. Results There were high incidence rates of hypertension (20%), diabetes mellitus (11%), dyslipidemia (38%), and smoking (34%). Relevant abnormalities were shown on cerebral angiography in 136 of 203 patients, on cardiac ultrasonography in 100 of 195, on Holter monitoring in 2 of 192; and on hypercoagulable panel in 30 of 189 patients. Multiple infarcts were observed in 31% and were more prevalent in individuals younger than age 35 years. Relevant arterial lesions were frequently detected in the middle cerebral artery (23%), internal carotid artery (13%), and vertebrobasilar arteries (13%). Cardioembolic stroke occurred in 47% (including 17% with isolated patent foramen ovale), and 11% had undetermined stroke etiology. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 0-9) and 81% had good outcome at hospital discharge. Of the 29 patients receiving thrombolysis (median National Institutes of Health Stroke Scale score, 14; interquartile range, 9-17), 55% had good outcome at hospital discharge and none developed symptomatic brain hemorrhage. Conclusions This study shows the contemporary profile of ischemic stroke in young adults admitted to a tertiary stroke center. Stroke etiology can be determined in nearly 90% of patients with modern diagnostic tests. The causes are heterogeneous; however, young adults have a high rate of traditional vascular risk factors. Thrombolysis appears safe and short-term outcomes are favorable.

Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype

Abstract: Objectives To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity. Design Retrospective, case-control study. Settings Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain. Patients Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects. Intervention Glycine receptor α1–transfected cells to test serum or cerebrospinal fluid from cases and control subjects. Main Outcome Measures Frequency of GlyRα1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases. Results Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65–IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG–positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P = .02). The single seropositive control patient had steroid-responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid. Conclusions Glycine receptor α1–IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.

Insights From LGI1 and CASPR2 Potassium Channel Complex Autoantibody Subtyping

Abstract: Objective To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex. Design Retrospective cohort study. Setting Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology. Patients A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive. Results From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54 853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P Conclusions The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.

Cross-sectional and longitudinal analysis of the relationship between Aβ deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease.

Abstract: IMPORTANCE beta-amyloid (A beta) deposition is one of the hallmarks of Alzheimer disease. A beta deposition accelerates gray matter atrophy at early stages of the disease even before objective cognitive impairment is manifested. Identification of at-risk individuals at the presymptomatic stage has become a major research interest because it will allow early therapeutic interventions before irreversible synaptic and neuronal loss occur. We aimed to further characterize the cross-sectional and longitudinal relationship between A beta deposition, gray matter atrophy, and cognitive impairment.

SQSTM1 Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

Abstract: Importance Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. Objective To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. Design A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. Setting Primary care or referral center. Participants An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Main Outcomes and Measures Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. Results We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. Conclusions and Relevance Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people.

Abstract: Importance Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. Objective To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions. Design, Setting, and Participants Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort. Intervention Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning. Main Outcomes and Measures For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11–labeled Pittsburgh compound B positron emission tomography). Results Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention. Conclusions and Relevance Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.

Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone

Abstract: Importance Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities to the infectious prion protein (PrP sc ) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrP sc ND. Objective To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients. Design We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrP sc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature. Setting University-based academic center and agencies of the US Department of Health and Human Services. Participants Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP. Main Outcome Measures Detectable NDAPs in human pituitary sections and death certificate reports of non-PrP sc ND in the NHPP database. Results We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database. Conclusions and Relevance Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrP sc -related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.