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Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals,ABCA7,TREM2, and an intergenic locus at 5q35 were previously implicated. Objective To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures Diagnosis of Alzheimer disease. Results A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking geneEDEM1(3p26;P = 8.9 × 10−7), near the immune response geneALCAM(3q13;P = 9.3 × 10−7), withinGPC6(13q31;P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and withinVRK3(19q13.33;P = 3.5 × 10−7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus nearIGF1Rat 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such asAPI5 at 11p12 (P = 8.8 × 10−8) andRBFOX1at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association ofALCAM, ARAP1, GPC6, andRBFOX1with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, onlyAPOE,ABCA7,TREM2,BIN1,CD2AP,FERMT2, andWWOXwere implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

IMPORTANCE: Neuronal and axonal destruction are hallmarks of neurodegenerativa diseases, but it is difficult to estimate the extent and progress of the damage in the disease process. OBJECTIVE: To Investigate cerebrospinal fluid (CSF) levels of neurofllament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine Its association with longitudinal cognitive decline. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, we Investigated NFL levels In CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016. EXPOSURES: Concentrations of NFL in CSF. MAIN OUTCOMES AND MEASURES: Levels of CSF NFL and correlations with cognition scores. RESULTS: A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398–777] pg/mL), participants with MCI (831 [526–1075] pg/mL), and those with Alzheimer disease (951 [758–1261] pg/mL), indicating that NFL levels increase with Increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, −0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207–7453] pg/mL) and frontotemporal dementia (2094 [230–7744] pg/mL). In Individuals with parkinsonian disorders, NFL concentrations were highest In those with progressive supranuclear palsy (median [range], 1578 [1287–3104] pg/mL) and corticobasal degeneration (1281 [828–2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau Increased accuracy of discrimination of diseases. CONCLUSIONS AND RELEVANCE: Levels of CSF NFL are associated with cognitive Impairments In patients with Alzheimer disease and frontotemporal dementia. In other neurodegenerative disorders, NFL levels appear to reflect the intensity of the neurodegenerative processes.

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.

Importance We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. Objective To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA—in whom either PSP or CBD was eventually confirmed at autopsy—at initial presentation and at 1-year follow-up. Design, Setting, and Participants A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included. Main Outcomes and Measures Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA–4-repeat–tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally. Results Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms. Conclusions and Relevance In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

Objective To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score. Design and Setting Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative. Patients Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease 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 score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging. Results Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model. Conclusions Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.

Transactive response DNA-binding protein 43 (TDP-43) is a nuclear ribonucleo-protein that plays a role in a variety of cellular functions including protein processing, particularly, modulating transcription and exon splicing.1 It is also a major pathological hallmark of ubiquitinated inclusions in amyotrophic lateral sclerosis and forms of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U,2,3 more recently abbreviated FTLD-TDP by Mackenzie et al4). In these conditions, both sporadic and familial cases show abnormal accumulation of hyper-phosphorylated, ubiquitinated, and truncated TDP-43 fragments.2,3 Recently, we developed phosphorylation-specific TDP-43 monoclonal antibodies that recognize only pathological TDP-43, to study the altered phosphorylation patterns of abnormal TDP-43 in amyotrophic lateral sclerosis, FTLD-TDP, and other neurode-generative diseases.5 These and other studies with previously reported anti–TDP-43 antibodies have shown that phosphorylation of S409/410 in TDP-43 is detected in neuronal and glial inclusions of a variety of central nervous system (CNS)–degenerative diseases including Alzheimer disease (AD) as well as in other older individuals with cognitive impairment.5–8 There is also an association between cognitive status and the intensity of TDP-43 pathology in subjects with age-related cognitive impairment.7 Interestingly, in the Nelson et al study,7 there was no association between cognitive status and other pathology, including AD neuropathological features such as amyloid plaque or neurofibrillary tangle burden. Together, these data raise the possibility that TDP-43 plays a significant role in the pathogenic mechanisms underlying cognitive impairment in AD and other age-related brain disorders. Alzheimer disease is the most common neurodegenerative disease affecting cognition, found in increasing numbers in our elderly population. However, only limited study has been performed to investigate TDP-43 pathology and AD.5–7,9 Caspase-cleaved TDP-43 has been variably described in Hirano bodies, neurofibrillary tangles, reactive glia, and dystrophic plaque-associated neurites,10 but further studies are needed to confirm these findings. Taken together, these studies support the notion that TDP-43 may contribute to the pathobiology of AD. However, no studies have been done to look at the presence of TDP-43 inclusions in genetic forms of AD such as familial AD (FAD) and Down syndrome (DS) to determine whether participants with genetic etiologies have similar TDP-43 pathologies. Hence, the current study was undertaken to assess the presence of TDP-43 immunopathology in a series of well-characterized participants with FAD and DS to determine whether this pathobiological feature differs from that of sporadic forms of AD or other types of CNS degeneration.

Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43- and ubiquitin-immunoreactive pathologic lesions.To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis.Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries.Clinical phenotypes and survival patterns of patients.A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P = .005).Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.An academic medical center.We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.Neuronal and glial TDP-43 pathology.We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Background Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP , the gene encoding for TDP-43, a candidate for genetic screening in ALS. Objectives To investigate the presence and frequency of TARDBP mutations in ALS. Design Genetic analysis. Setting Academic research. Participants One hundred thirty-four patients with sporadic ALS, 31 patients with familial non–superoxide dismutase 1 gene (non- SOD1 ) (OMIM147450) ALS, and 400 healthy control subjects. Main Outcome Measures We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment. Results The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges. Conclusions Mutations in TARDBP are a rare cause of familial non- SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.

Background Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. Objective To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. Design Performance of an immunohistochemical whole–central nervous system scan for evidence of pathological TDP-43 in ALS patients. Setting An academic medical center. Participants We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. Main Outcome Measures Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. Results In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. Conclusions These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.

© 2015 American Medical Association. All rights reserved. IMPORTANCE: Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study. OBJECTIVE: To determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)-PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database. MAINOUTCOMES ANDMEASURES: Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures. RESULTS: The values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOE genotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up. CONCLUSIONS AND RELEVANCE: The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.

Importance Recently, a rare variant in the amyloid precursor protein gene ( APP ) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. Objective To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Design, Setting, and Participants Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. Main Outcomes and Measures Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). Results The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. Conclusions and Relevance The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.

Importance Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. Objectives To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. Design, Setting, and Participants The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance–weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. Main Outcomes and Measures Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. Results Analysis confirmed the association of APOE with earlier AAO ( P = 3.3 × 10 −96 ), with associations in CR1 (rs6701713, P = 7.2 × 10 −4 ), BIN1 (rs7561528, P = 4.8 × 10 −4 ), and PICALM (rs561655, P = 2.2 × 10 −3 ) reaching statistical significance ( P APOE contributes to 3.7% of the variation in AAO ( R2 = 0.256) over baseline ( R2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation ( R2 = 0.242). Conclusions and Relevance We confirmed an association of APOE (OMIM107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO . In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Importance Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. Objective To determine whether common variation in the APOE , MAPT , and SNCA genes is associated with cognitive performance in patients with PD. Design, Setting, and Participants We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test–Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE e2/e3/e4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. Main Outcomes and Measures Nine variables derived from 7 psychometric tests. Results The APOE e4 allele was associated with lower performance on the HVLT-R Total Recall ( P = 6.7 × 10 −6 ; corrected P [ Pc ] = 6.0 × 10 −5 ), Delayed Recall ( P = .001; Pc = .009), and Recognition Discrimination Index ( P = .004; Pc = .04); a semantic verbal fluency test ( P = .002; Pc = .02); the Letter-Number Sequencing Test ( P = 1 × 10 −5 ; Pc = 9 × 10 −5 ); and Trail Making Test B minus Trail Making Test A ( P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE e4 allele was associated with lower scores on the HVLT-R Total Recall ( P = .005; Pc = .045) and the semantic verbal fluency ( P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. Conclusions and Relevance Our data indicate that the APOE e4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE e4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Importance Alzheimer disease (AD) is a neurodegenerative disorder with no effective therapies. In 1984, the National Institute on Aging created the first 5 AD centers (ADCs) in an effort to coordinate research efforts into the pathology and treatment of the disease. Since that time, the ADC program has expanded to include 27 centers in major medical schools throughout the United States. A major aim of ADCs is to develop shared resources, such as tissue samples and patient populations, and thereby promote large-scale, high-impact studies that go beyond the capabilities of any single investigator or institution working in isolation. Objective To quantitatively evaluate the performance of the ADC program over the past 25 years. Design and Setting We systematically harvested every article published by ADC investigators and used social network analysis to analyze copublication networks. Results A total of 12170 ADC papers were published from 1985 through 2012. The frequency of collaborations has increased greatly from the time that the ADCs were started until the present, even after the expansion of ADCs and the recruitment of new investigators plateaued. Moreover, the collaborations established within the context of the ADC program are increasingly interinstitutional, consistent with the overall goal of the program to catalyze multicenter research teams. Most important, we determined that collaborative multi-ADC research articles are consistently of higher impact than AD articles as a whole. Conclusions and Relevance The ADC program has successfully fostered high-impact, multiuniversity collaborations; we suggest that its structural and administrative features could be replicated in other fields of patient-oriented research.

Background Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. Objective To determine the frequency of tau mutations in patients with non-Alzheimer dementia. Patients and Methods One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3′ and 5′ untranslated regions, and at least 146 base pairs in the intron following exon 10. Results Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. Conclusions We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.

Importance Biochemical abnormalities present in GBA ( mut/wt ) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD). Objective To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression. Design and Setting Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups. Participants The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA -associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing. Main Outcome Measures Biochemical profiling was available for all 20 GBA -associated PD cases, as well as a subset (87 of 242) of the GBA -negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations. Results Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset ( P = .04) and were more likely to demonstrate cognitive dysfunction ( P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 ( P = .001), monocyte chemotactic protein 1 ( P = .008), and macrophage inflammatory protein 1α ( P = .005). The association between interleukin 8 and GBA mutation status was replicated ( P = .03) in a separate cohort of patients having PD with vs without GBA mutations. Conclusions and Relevance Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.

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.

Objective To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. Design Validation sample. Setting Multisite, referral centers. Participants A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. Main Outcome Measures Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). Results Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. Conclusions A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

BackgroundCerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of antemortem diagnosis.ObjectiveTo test whether CSF biomarker assays differ in their ability to identify true markers of underlying AD pathology (eg, amyloid plaques and/or neurofibrillary tangles) in living individuals.DesignWe compared the performances of the 2 most commonly used platforms, INNOTEST enzyme-linked immunosorbent assay and INNO-BIA AlzBio3, for measurement of CSF β-amyloid (Aβ) and tau proteins to identify the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau, and phosphorylated tau 181 (p-tau181) using the 2 assay platforms were compared with brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent Pittsburgh compound B.SettingThe Knight Alzheimer's Disease Research Center at Washington University in St Louis, Missouri.SubjectsResearch volunteers who were cognitively normal or had mild to moderate AD dementia.ResultsThe 2 assay platforms yielded different (approximately 2- to 6-fold) absolute values for the various analytes, but relative values were highly correlated. The CSF Aβ1-42 correlated inversely and tau and p-tau181 correlated positively with the amount of cortical Pittsburgh compound B binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau to Aβ1-42 and p-tau181 to Aβ1-42 outperformed any single analyte, including Aβ1-42, in discriminating individuals with vs without cortical amyloid.ConclusionsThe INNOTEST and INNO-BIA CSF platforms perform equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cutoff values.

Objectives To examine the effect of specific cerebrospinal fluid (CSF) profiles on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI). Design Total tau (T-tau), tau phosphorylated at threonine 181, and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from patients with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by CSF profiles: (1) normal T-tau and normal Aβ42 (ie, normal–T-tauAβ42), (2) normal T-tau but abnormal Aβ42 (ie, abnormal-Aβ42), (3) abnormal T-tau but normal Aβ42 (ie, abnormal–T-tau), and (4) abnormal T-tau and abnormal Aβ42 (ie, abnormal–T-tauAβ42). Setting Fifty-eight sites in the United States and Canada. Participants One hundred ninety-five patients with MCI. Main Outcome Measures A composite cognitive measure, the Clinical Dementia Rating Scale–sum of boxes subscale, and conversion to AD dementia. Results Patients with MCI with a CSF profile of abnormal-Aβ42 or abnormal–T-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the Clinical Dementia Rating Scale–sum of boxes subscale compared with those with normal–T-tauAβ42. They also had a greater risk of converting to AD dementia relative to the normal–T-tauAβ42 group. In contrast, those with a CSF profile of abnormal–T-tau did not differ from the normal–T-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of tau phosphorylated at threonine 181 and Aβ42 abnormalities. Conclusions β-Amyloid abnormalities but not tau alterations are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal Aβ42 may be prime candidates for drug treatment and clinical trials in MCI.

Objective: To investigate the effect of cerebrospinal fluid (CSF) abnormalities on the rate of decline in everyday function in normal aging, mild cognitive impairment (MCI), and mild Alzheimer disease (AD). Design: Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and-amyloid 1-42 (A42) concentrations were performed in CSF obtained from participants in the Alzheimer’s Disease Neuroimaging Initiative. Random effects regressions were used to examine the relationship among CSF abnormalities, cognitive impairment (assessed with the Alzheimer Disease Assessment Scale–cognitive subscale [ADAS-Cog]), and functional decline (assessed with the Pfeffer Functional Activities Questionnaire) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment. Setting: Fifty-eight sites in the United States and Canada. Participants: One hundred fourteen cognitively intact adults, 195 patients with MCI, and 100 patients with mild AD. Main Outcome Measure: Decline in the Pfeffer Functional Activities Questionnaire score. Results: Abnormalities in all CSF analytes were associated with functional decline in MCI, and all but the t-tau: A42 ratio were associated with functional decline in controls. No abnormal CSF analyte was associated with functional decline in AD. Among controls, p-tau181 concentration was the most sensitive to functional decline, whereas in MCI it was A42 concentration. Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI, whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status. Across all diagnostic groups, persons with both tau and A42 abnormalities exhibited the steepest rate of functional decline. Conclusions: Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI. However, they do not predict further functional degradation in patients with AD. Persons with comorbid tau and A42 abnormalities are at greatest risk of functional loss.

Research in Alzheimer disease (AD) is rapidly moving toward the point of the earliest identification of the underlying disease processes. These include the accumulation of AB plaques, tau tangles and neuron as well as synaptic loss, and it is likely that these do not all occur contemporaneously. Many investigators contend that, by the time the clinical symptoms appear, sufficient AD pathology and neurodegeneration have occurred, which if irreversible, may reduce the efficacy of disease modifying therapy for clinically manifest AD.1 As such, efforts are underway to try to identify the onset of these pathological processes that culminate in clinically manifest AD dementia. However, to accomplish this, the underlying pathology must be detected, possibly through the use of neuroimaging and chemical biomarker measures. In this issue of JAMA, Mattsson and colleagues2 report their evaluation of the utility of cerebrospinal fluid (CSF) markers for AD in a large multicenter study. The investigators from the Swedish Brainpower CSF Initiative enrolled individuals with mild cognitive impairment (MCI) from 12 centers in Europe as well as healthy individuals as controls and those with mild AD for comparison. They identified 750 individuals as having MCI and followed them for at least two years to determine whether the CSF profile at baseline of Aβ42, total tau (T-tau), and phosphorylated tau (P-tau) predicted the ultimate clinical course. They found that CSF Aβ42, T-tau, and P-tau could be used to predict outcomes and thus suggest that these markers may be useful in identifying patients for clinical trials and possibly screening tests in memory clinics. This group of investigators has been studying these issues for several years, and their study represents a tour de force of clinical and laboratory data collections. However, their study also represents several key challenges that need to be addressed before CSF markers are ready for broad clinical applications, although these markers already are being used in clinical trials of disease-modifying therapies for AD. Mild Cognitive Impairment is a heterogeneous condition, and based on the underlying conceptual nature of the condition, this is to be expected.3–4 International consensus meetings have characterized the construct by subtypes into amnestic and non amnestic MCI5–6 in an attempt to explain some of the heterogeneity. Amnestic MCI of a presumed degenerative etiology is generally considered to be the forerunner of clinical AD, and Mattsson et al2 have diagnosed MCI with that presumption. However, the investigators combined clinical data from 12 different memory disorders centers, using different instruments and likely different implementation of the criteria and consequently may have assembled a group of individuals with significant clinical variability. As such, while they present the Mini-Mental State Examination scores and demographic data, without the presentation of the other clinical data a precise comparison of the individuals from the different centers is difficult. The investigators describe that they enrolled a consecutive series of individuals presenting to memory centers with symptoms leading to the diagnoses of MCI or AD. Despite this variability, the investigators reported an annual rate of progression to AD of 11% which is typical for referral center cohorts.7 Similarly, there was likely considerable variability with respect to the CSF collection and assays, and the authors clearly acknowledge that their CSF assays require further standardization. The coefficients of a variation from other sites were discrepant from the primary site, and a formula was used to “correct” these data. This may have made the results comparable in a statistical sense from the various sites; however, it is also likely that the significant variability in the laboratory data could have compounded the problems with the clinical variability. The investigators in this report are accomplished in AD biomarker research and aware of the hurdles that need to be surmounted to bring an AD biomarker from the initial discovery stage to a validated test for AD diagnosis.8 Despite these potential sources of variability, the study documented the utility of CSF biomarkers to predict, with good accuracy, the outcome of individuals with MCI. Moreover, with further mining of their data, Mattsson et al may improve on their CSF biomarker algorithm. Shaw et al9 recently reported that APOE genotype contributed incrementally to test accuracy when combined with measures of CSF Aβ and tau. Thus, the study by Mattsson et al is an important contribution toward the goal of developing disease-modifying therapies based on the use of biomarkers and clinical measures. Despite the considerable clinical and laboratory variability, the results appear plausible and enticing. As the authors indicate, this multicenter study replicated the results of smaller single-center studies, with the caveat that some of the prior study samples were included in this study. The data likely reflect the underlying pathological processes of AD in some individuals with MCI; however, it is premature to recommend application of these techniques in clinical practice. The inherent clinical and laboratory variability precludes the adoption of these measures at this time. Significant refinement of the assay procedures is necessary before these techniques can be recommended for general clinical use along the lines described in previous publications.8–9 An effort in this direction is now underway in North America known as Alzheimer Disease Neuroimaging Initiative (ADNI)9–10 and is complemented by similar studies in Europe, Japan and Australia. This study represents 57 centers in the United States and Canada and was designed to evaluate the utility of neuroimaging and clinical biomarkers in characterizing the course of amnestic MCI with the intention of predicting clinical AD before the full criteria for dementia are met. A major focus of this study also involves reducing variability in the clinical, neuroimaging and laboratory procedures, including refining the clinical criteria for amnestic MCI (it is noteworthy that the clinical cohort recruited in ADNI has identical clinical features and rates of progression to AD as seen in an earlier clinical trial on amnestic MCI11); standardizing neuroimaging procedures for magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (PET), and PiB (Pittsburgh Compound B) PET; and centralizing the laboratory analysis of CSF biomarkers to ensure consistency and reliability. The biomarker data will be integrated with imaging and clinical data with the goal of identifying the optimal panel to use for predictive testing for AD, AD diagnosis, and clinical trial monitoring. Of critical importance, however, is what the clinician and patient will do with such results. The sensitivity and specificity of Aβ42, T-tau, and P-tau in the study by Mattsson et al were sufficient to be used for screening but not as a diagnostic test. Alzheimer disease has no treatment to prevent or alter the course of the disease, so making the diagnosis with good accuracy may aid in planning but also could be devastating news for some patients and families. Furthermore, false positives and false negatives occur as with any screening test. However, as biomarkers become more sophisticated, they are likely to take on an increasingly important role in the diagnosis and management of AD. The study by Mattsson et al2 represents a major step forward in suggesting that biomarkers may have sufficient accuracy to be used in the AD prodromal phase. The report highlights the challenges but also suggests solutions. Subsequent prospective investigations should clarify the true utility of these measures.

Herein, we review advances in understanding a group of disorders collectively known as TAR-DNA binding protein 43 (TDP-43) proteinopathies since the report that TDP-43 is the major disease protein that mechanistically links frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease to amyotrophic lateral sclerosis. Because TDP-43 proteinopathy underlies sporadic and familial forms of FTLD-U and amyotrophic lateral sclerosis, they may share similar mechanisms linked to the abnormal hyperphosphorylation, ubiquitination, and cleavage of pathologic TDP-43 to generate C-terminal fragments in brain and spinal cord affected with FTLD-U and amyotrophic lateral sclerosis. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders in which protein misfolding leads to brain amyloidosis, as pathologic TDP-43 forms neuronal and glial inclusions lacking the features of brain amyloid deposits. We discuss the implications of these distinct aspects of TDP-43 proteinopathies for developing better diagnostics and therapeutics for FTLD-U and amyotrophic lateral sclerosis.

Background Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene ( MAPτ ) and is associated with neuronal or glial tau inclusions. Objectives To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family. Design A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made. Setting Family study. Patients San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members donot have a MAPτ coding or splice regulatory sequence mutation, and the MAPτ is genetically excluded. Main Outcome Measures Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). Results The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAPτ. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and α-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform. Conclusion The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.

Background Tau and β-amyloid (Aβ) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific patholody, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. Objectives To correlate antemortem cerebrospinal fluid (CSF) tau and Aβ levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Aβ. Design Prospective study. Setting Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. Main Outcome Measures Correlation of CSF tau and Aβ with final diagnosis. Results Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Aβ 42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). Conclusions Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean ± 2 SDs of the cognitively normal cohort.

Background α-Synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for α-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms. Objective To investigate the α-synuclein epitope mapping properties of LBs in familial Alzheimer disease. Design and Setting We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the α-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy. Results The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from α-synuclein aggregates that occurred in multiple system atrophy. Conclusions These data suggest that the epitope profiles of α-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of α-synuclein aggregation is the same within cell types but distinctive between cell types.

Background Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. Methods Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. Results We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. Conclusions Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.

The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

Background The cognitive and functional deterioration that is observed in many "poor-outcome" patients with schizophrenia suggests a neurodegenerative process extending into late life. Previous diagnostic studies have excluded known neurodegenerative diseases as explanations for this dementia. However, we hypothesized that relatively small accumulations of age- or disease-related neurodegenerative lesions occurring in an otherwise abnormal brain could result in deterioration in schizophrenia. Methods Postmortem studies were conducted using 23 prospectively accrued elderly persons with chronic schizophrenia for whom clinical ratings had been determined before death, 14 elderly control patients with no neuropsychiatric disease, and 10 control patients with Alzheimer disease. Immunohistochemistry and unbiased stereological counting methods were used to quantify common neurodegenerative lesions (ie, neurofibrillary tangles, amyloid plaques, and Lewy bodies) and cellular reactions to a variety of noxious stimuli (ubiquitinated dystrophic neurites, astrocytosis, and microglial infiltrates) in the ventromedial temporal lobe and the frontal and the calcarine (primary visual) cortices. Results No statistically significant differences were found between the patients with schizophrenia and the control patients without neuropsychiatric disease for the densities of any of the markers, while both groups exhibited fewer lesions than did the control group with Alzheimer disease. Correlation analyses in the schizophrenia sample failed to identify significant correlations between cognitive and psychiatric ratings and densities of any of the neuropathologic markers. Conclusions No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia. Furthermore, the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena.

The presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra pars compacta, as well as neuron loss and gliosis, is a diagnostic hallmark of Parkinson disease (PD), but LBs also are seen in other cortical and subcortical neurons of the PD brain. Additionally, LBs also occur in similar populations of neurons in the brains of patients with the classic clinical and pathological features of Alzheimer disease (AD). Furthermore, the presence of numerous cortical intraneuronal LBs, but only rare AD neurofibrillary tangles and senile plaques in the brains of patients with an AD-like dementia, defines a neurodegenerative disorder known as dementia with LBs (DLB). Ultrastructural examination of LBs has revealed masses of aggregated 7-to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified. Indeed, the biological significance of LBs, especially the role that they might play in the degeneration of neurons in LB disorders, is still enigmatic (Figure).

The search for the defining neuropathological features of schizophrenia continues to be one of the highest priority areas of research on this severely debilitating and very common neuropsychiatric disorder (for recent updates and comprehensive reviews of previous studies of the regional neuropathology of schizophrenia as well as an extensive compilation of the pertinent more general literature on this subject, see Carpenter and Buchanan, 1 Kerwin, 2 Shapiro, 3 and Winn 4 ). There are a number of compelling reasons that justify intense research efforts to delineate the central nervous system (CNS) lesions that constitute a primary "cause" of schizophrenia as well as those secondary events that underlie the varied behavioral symptoms of this highly complex disease. Specifically, the identification of such lesions would markedly enhance the pace of research on schizophrenia by enabling investigators to (1) generate testable hypotheses about the cause and molecular pathogenesis of this disorder; (2) develop specific

Objective. —To assess the potential availability and utility of fetal tissues obtained from spontaneous abortions and from ectopic pregnancies for human transplantation therapy. Design. —Tissue collection and analysis by personnel skilled in tissue banking. Setting. —Procurement programs in five tissue banks located in diverse geographical areas that are funded by the National Institutes of Health. Patients. —All women entering obstetric clinics during 1993 who consented to participate in the study. Interventions. —None. Main Outcome Measures. —Evaluation of the products of conception by standard developmental, histological, microbiological, and cytogenetic criteria. Results. —From 22235 obstetric admissions, 1250 spontaneously aborted embryos and 247 products of ectopic pregnancies were obtained. Of these, seven embryos (0.5%) were potentially useful for human transplantation therapy. Conclusion. —Fetal tissues from spontaneous abortions and from ectopic pregnancies are quite limited as feasible sources for human transplantation therapy. ( JAMA . 1995;273:66-68)