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1.  Plasma sphingolipid changes with autopsy-confirmed Lewy Body or Alzheimer’s pathology 
INTRODUCTION
The clinical and pathological phenotypes of Dementia with Lewy Bodies (DLB) and Alzheimer’s disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology.
METHODS
We identified four groups with available plasma two years prior to death: high (n=12) and intermediate likelihood DLB (n=14) based on the third report of the DLB consortium; dementia with Alzheimer’s pathology (AD; n=18); and cognitively normal with normal aging pathology (n=21). Lipids were measured using ESI/MS/MS.
RESULTS
There were overall group differences in plasma ceramides C16:0, C18:1, C20:0 and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group.
DISCUSSION
Plasma ceramides and monohexosylceramides are elevated in people with dementia with either high likelihood DLB or AD pathology.
doi:10.1016/j.dadm.2016.02.005
PMCID: PMC4852484  PMID: 27152320
Alzheimer’s disease; Lewy body; Autopsy; Lipids; Ceramide
2.  Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy 
Kovacs, Gabor G. | Ferrer, Isidro | Grinberg, Lea T. | Alafuzoff, Irina | Attems, Johannes | Budka, Herbert | Cairns, Nigel J. | Crary, John F. | Duyckaerts, Charles | Ghetti, Bernardino | Halliday, Glenda M. | Ironside, James W. | Love, Seth | Mackenzie, Ian R. | Munoz, David G. | Murray, Melissa E. | Nelson, Peter T. | Takahashi, Hitoshi | Trojanowski, John Q. | Ansorge, Olaf | Arzberger, Thomas | Baborie, Atik | Beach, Thomas G. | Bieniek, Kevin F. | Bigio, Eileen H. | Bodi, Istvan | Dugger, Brittany N. | Feany, Mel | Gelpi, Ellen | Gentleman, Stephen M. | Giaccone, Giorgio | Hatanpaa, Kimmo J. | Heale, Richard | Hof, Patrick R. | Hofer, Monika | Hortobágyi, Tibor | Jellinger, Kurt | Jicha, Gregory A. | Ince, Paul | Kofler, Julia | Kövari, Enikö | Kril, Jillian J. | Mann, David M. | Matej, Radoslav | McKee, Ann C. | McLean, Catriona | Milenkovic, Ivan | Montine, Thomas J. | Murayama, Shigeo | Lee, Edward B. | Rahimi, Jasmin | Rodriguez, Roberta D. | Rozemüller, Annemieke | Schneider, Julie A. | Schultz, Christian | Seeley, William | Seilhean, Danielle | Smith, Colin | Tagliavini, Fabrizio | Takao, Masaki | Thal, Dietmar Rudolf | Toledo, Jon B. | Tolnay, Markus | Troncoso, Juan C. | Vinters, Harry V. | Weis, Serge | Wharton, Stephen B. | White, Charles L. | Wisniewski, Thomas | Woulfe, John M. | Yamada, Masahito | Dickson, Dennis W.
Acta neuropathologica  2015;131(1):87-102.
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
doi:10.1007/s00401-015-1509-x
PMCID: PMC4879001  PMID: 26659578
Aging; ARTAG; Tau astrogliopathy; Tau
3.  Evaluating pathogenic dementia variants in posterior cortical atrophy 
Neurobiology of aging  2015;37:38-44.
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to “posterior Alzheimer’s disease (AD)” pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n=67) or posterior AD neuropathology (n=57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4,300 European-American population controls from the NHLBI Exome Sequencing Project (ESP). We identified two rare variants not previously reported in PCA, TREM2 Arg47His and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report two rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
doi:10.1016/j.neurobiolaging.2015.09.023
PMCID: PMC4688220  PMID: 26507310
PCA; posterior Alzheimer’s disease; dementia; APOE; TREM2; PSEN2; NeuroX
4.  Imaging markers of cerebrovascular pathologies: Pathophysiology, clinical presentation, and risk factors 
Cerebrovascular pathologies (CVPs) are common pathologies associated with age-related cognitive decline along with Alzheimer disease pathologies. The impact of CVP on the prevalence of dementia is increasingly being recognized. The goal of this review is to improve our understanding of the pathophysiological underpinnings and the multimodal magnetic resonance imaging and positron emission tomography imaging changes that are associated with the hallmarks of CVP. This knowledge will facilitate the development of early detection, intervention, and prevention strategies that may contribute to lowering the risk of dementia. In this review, we will first discuss currently known risk factors of CVPs including cardiovascular, lifestyle, genetic, sex differences, and head injury. Next, we will focus on the pathophysiology of CVPs and their impact on neurodegeneration and downstream cognitive impairment. Specifically, we will discuss three of the most common cerebrovascular lesions seen on MRI: white-matter hyperintensity, microbleeds, and infarcts. Finally, we will discuss the unanswered open questions in this field.
doi:10.1016/j.dadm.2016.12.006
PMCID: PMC5198884  PMID: 28054023
Cerebrovascular; Pathophysiology; Imaging; Aging
5.  C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins 
Nature neuroscience  2016;19(5):668-677.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
doi:10.1038/nn.4272
PMCID: PMC5138863  PMID: 26998601
6.  Transmission of Soluble and Insoluble α-Synuclein to Mice 
The neurodegenerative synucleinopathies, which include Parkinson disease, multiple system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation is fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months post-injection. Disease-associated deposits accumulated both near and distal to the site of the injection suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogenous within a single patient but might exist in both soluble and insoluble isoforms.
doi:10.1097/NEN.0000000000000262
PMCID: PMC4654695  PMID: 26574670
α-Synuclein; Lewy body disease; Parkinson disease; Prion; Prion-like; Soluble prion
7.  Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72 
Acta neuropathologica  2015;130(6):863-876.
The loss of chromosome 9 open reading frame 72 (C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers (n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay (n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e-05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches.
doi:10.1007/s00401-015-1480-6
PMCID: PMC4655160  PMID: 26437865
C9ORF72; Frontotemporal dementia; Frontotemporal lobar degeneration; Motor neuron disease; Amyotrophic lateral sclerosis; Disease modifier
8.  Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease 
Human Molecular Genetics  2015;24(22):6492-6504.
Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5′-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.
doi:10.1093/hmg/ddv358
PMCID: PMC5007609  PMID: 26358770
9.  Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies 
Neurology  2015;85(19):1680-1686.
Objective:
To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.
Methods:
In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.
Results:
The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63–2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62–20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04–12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85–25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.
Conclusions:
Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.
doi:10.1212/WNL.0000000000001946
PMCID: PMC4653108  PMID: 26333800
10.  TDP-43 and pathological subtype of Alzheimer’s disease impact clinical features 
Annals of neurology  2015;78(5):697-709.
Objective
To determine whether the frequency of TDP-43 deposition in Alzheimer’s disease (AD) differs across pathologically defined AD subtypes (Hippocampal sparing [HpSp]; Typical and Limbic), and to further examine the relationship between TDP-43, pathological subtype, and clinical features in AD.
Methods
We identified all cases with pathologically-confirmed AD (NIA-Reagan intermediate-high probability, Braak stage IV–VI) independent of cognitive status (n=188). Neurofibrillary tangle counts were performed using thioflavin-S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD Pathology (n=19); Typical AD Pathology (n=136); Limbic AD Pathology (n=33). TDP-43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP-43 and TDP-43 stage. All cases were clinically sub-classified at presentation as Amnestic AD Dementia versus Atypical AD Dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP-43, accounting for possible interactions between pathological subtype and TDP-43.
Results
TDP-43 deposition was frequent in Typical (59%) and Limbic AD pathologies (67%), but not HpSp AD Pathology (21%) (p=0.003). The observed associations of TDP-43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p=0.01), but not TDP-43 (p=0.69).
Interpretation
Although the frequency of TDP-43 deposition in AD varies by pathological subtype, the observed effects of TDP-43 on clinical/MRI features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP-43.
doi:10.1002/ana.24493
PMCID: PMC4623932  PMID: 26224156
TDP-43; Alzheimer’s disease; hippocampal sparing; memory; amnestic; atypical
11.  An MRI‐Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease 
Journal of Neuroimaging  2016;26(3):264-268.
ABSTRACT
BACKGROUND AND PURPOSE
Pathologic diagnosis is the gold standard in evaluating imaging measures developed as biomarkers for pathologically defined disorders. A brain MRI atlas representing autopsy‐sampled tissue can be used to directly compare imaging and pathology findings. Our objective was to develop a brain MRI atlas representing the cortical regions that are routinely sampled at autopsy for the diagnosis of Alzheimer's disease (AD).
METHODS
Subjects (n = 22; ages at death = 70‐95) with a range of pathologies and antemortem 3T MRI were included. Histology slides from 8 cortical regions sampled from the left hemisphere at autopsy guided the localization of the atlas regions of interest (ROIs) on each subject's antemortem 3D T1‐weighted MRI. These ROIs were then registered to a common template and combined to form one ROI representing the volume of tissue that was sampled by the pathologists. A subset of the subjects (n = 4; ages at death = 79‐95) had amyloid PET imaging. Density of β‐amyloid immunostain was quantified from the autopsy‐sampled regions in the 4 subjects using a custom‐designed ImageScope algorithm. Median uptake values were calculated in each ROI on the amyloid‐PET images.
RESULTS
We found an association between β‐amyloid plaque density in 8 ROIs of the 4 subjects (total ROI n = 32) and median PiB SUVR (r 2 = .64; P < .0001).
CONCLUSIONS
In an atlas developed for imaging and pathologic correlation studies, we demonstrated that antemortem amyloid burden measured in the atlas ROIs on amyloid PET is strongly correlated with β‐amyloid density measured on histology. This atlas can be used in imaging and pathologic correlation studies.
doi:10.1111/jon.12341
PMCID: PMC4848115  PMID: 27017996
Alzheimer's disease; atlas; MRI; pathology
12.  A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration 
Acta neuropathologica  2015;130(1):145-157.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for α-internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co-localization of SOD1 and α-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved.
doi:10.1007/s00401-015-1431-2
PMCID: PMC5039014  PMID: 25917047
amyotrophic lateral sclerosis; electron microscopy; frontotemporal lobar degeneration; immunohistochemistry; internexin-alpha; neurofilament; superoxide dismutase 1
13.  A novel tau mutation, p.K317N, causes globular glial tauopathy 
Acta neuropathologica  2015;130(2):199-214.
Globular glial tauopathy (GGT) are 4-repeat tauopathies neuropathologically characterized by tau-positive, globular glial inclusions, including both globular oligodendroglial inclusions (GOI) and globular astrocytic inclusions (GAI). No mutations have been found in 25 of the 30 GGT cases reported in the literature who have been screened for mutations in microtubule associated protein tau (MAPT). In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55–83 years) and mean age at symptomatic onset of 66 years (50–77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at amino acid residue 317 was used to assess functional significance of the variant on microtubule assembly and tau filament formation. Recombinant p.K317N tau had reduced ability to promote tubulin polymerization. Recombinant 3R and 4R tau bearing the p.K317N mutation showed decreased 3R tau and increased 4R tau filament assembly. These results strongly suggest that the p.K317N variant is pathogenic. Sequencing of MAPT should be considered in patients with GGT and a family history of dementia or movement disorder. Since several individuals in our series had a positive family history but no MAPT mutation, genetic factors other than MAPT may play a role in disease pathogenesis.
doi:10.1007/s00401-015-1425-0
PMCID: PMC5039015  PMID: 25900293
FTDP-17; globular glial tauopathy (GGT); hereditary tauopathies; tau biochemistry; tau gene (MAPT)
15.  Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease 
Alzheimer's & Dementia  2016;12(8):862-871.
Introduction
The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.
Methods
We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.
Results
We confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).
Discussion
We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.
doi:10.1016/j.jalz.2016.01.010
PMCID: PMC4982482  PMID: 26993346
Posterior cortical atrophy; Alzheimer's disease; Genetics; GWAS; Selective vulnerability; APOE
16.  TREM2 p.R47H substitution is not associated with dementia with Lewy bodies 
Neurology: Genetics  2016;2(4):e85.
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.1,2 At autopsy, α-synuclein–positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease–related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.2 The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.3 These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD.
doi:10.1212/NXG.0000000000000085
PMCID: PMC4946771  PMID: 27458607
17.  An autoradiographic evaluation of AV-1451 Tau PET in dementia 
Background
It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.
Methods
Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.
Results
AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. “Off-target” binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.
Conclusions
Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of “off-target” binding.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-016-0315-6
PMCID: PMC4906968  PMID: 27296779
AV-1451; Tau; Alzheimer’s disease; TDP-43; Pick Disease; Corticobasal degeneration; Progressive supranuclear palsy; Tauopathy; Pick’s disease; Atypical Alzheimer’s disease; Frontotemporal dementia
18.  Intraneuronal amyloid-β accumulation in basal forebrain cholinergic neurons: a marker of vulnerability, yet inversely related to neurodegeneration 
Brain  2015;138(6):1444-1445.
This scientific commentary refers to ‘Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease’, by Baker-Nigh et al. (doi: 10.1093/brain/awv024).
doi:10.1093/brain/awv097
PMCID: PMC4614122  PMID: 26013803
19.  A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer's disease severity 
NeuroImage : Clinical  2016;11:802-812.
Alzheimer's disease (AD) researchers commonly use MRI as a quantitative measure of disease severity. Historically, hippocampal volume has been favored. Recently, “AD signature” measurements of gray matter (GM) volumes or cortical thicknesses have gained attention. Here, we systematically evaluate multiple thickness- and volume-based candidate-methods side-by-side, built using the popular FreeSurfer, SPM, and ANTs packages, according to the following criteria: (a) ability to separate clinically normal individuals from those with AD; (b) (extent of) correlation with head size, a nuisance covariatel (c) reliability on repeated scans; and (d) correlation with Braak neurofibrillary tangle stage in a group with autopsy. We show that volume- and thickness-based measures generally perform similarly for separating clinically normal from AD populations, and in correlation with Braak neurofibrillary tangle stage at autopsy. Volume-based measures are generally more reliable than thickness measures. As expected, volume measures are highly correlated with head size, while thickness measures are generally not. Because approaches to statistically correcting volumes for head size vary and may be inadequate to deal with this underlying confound, and because our goal is to determine a measure which can be used to examine age and sex effects in a cohort across a large age range, we thus recommend thickness-based measures. Ultimately, based on these criteria and additional practical considerations of run-time and failure rates, we recommend an AD signature measure formed from a composite of thickness measurements in the entorhinal, fusiform, parahippocampal, mid-temporal, inferior-temporal, and angular gyrus ROIs using ANTs with input segmentations from SPM12.
Highlights
•Evaluate thickness- and volume-based quantitative measures of AD severity•Volume- and thickness-based measures perform similarly for separating by diagnosis.•Volume-based measures are correlated with head size; thickness-based mostly aren't.•We recommend an AD signature measure formed from cortical thickness measures.•We recommend thicknesses using ANTs software with input segmentations from SPM12.
doi:10.1016/j.nicl.2016.05.017
PMCID: PMC5187496  PMID: 28050342
20.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
doi:10.1093/brain/awv050
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
21.  CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia 
Nature Communications  2016;7:11253.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNF gene product affects ubiquitination and protein degradation in cultured cells.
doi:10.1038/ncomms11253
PMCID: PMC4835537  PMID: 27080313
22.  Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS 
Nature neuroscience  2015;18(8):1175-1182.
Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS cases (8,224 AS, 1,437 APA), including changes in ALS-associated genes (e.g. ATXN2 and FUS), and cases of sporadic ALS (sALS; 2,229 AS, 716 APA). Furthermore, hnRNPH and other RNA-binding proteins are predicted as potential regulators of cassette exon AS events for both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS.
doi:10.1038/nn.4065
PMCID: PMC4830686  PMID: 26192745
23.  Plasma sphingolipid changes with autopsy-confirmed Lewy body or Alzheimer's pathology 
Introduction
The clinical and pathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology.
Methods
We identified four groups with available plasma 2 years before death: high (n = 12) and intermediate-likelihood DLB (n = 14) based on the third report of the DLB consortium; dementia with Alzheimer's pathology (AD; n = 18); and cognitively normal with normal aging pathology (n = 21). Lipids were measured using ESI/MS/MS.
Results
There were overall group differences in plasma ceramides C16:0, C18:1, C20:0, and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high-likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group.
Discussion
Plasma ceramides and monohexosylceramides are elevated in people with dementia with either high-likelihood DLB or AD pathology.
doi:10.1016/j.dadm.2016.02.005
PMCID: PMC4852484  PMID: 27152320
Alzheimer's disease; Lewy body; Autopsy; Lipids; Ceramide
24.  The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer’s disease in Hispanics in Florida 
Mutations in the gene encoding the presenilin-1 protein (PSEN1) were first discovered to cause Alzheimer’s disease (AD) 20 years ago. Since then more than 200 different pathogenic mutations have been reported, including a p.Gly206Ala founder mutation in the Hispanic population. Here we report mutation analysis of known AD genes in a cohort of 27 early-onset (age of onset ≤65, age of death ≤70) Hispanic patients ascertained in Florida. The PSEN1 p.Gly206Ala mutation was identified in 13 out of 27 patients (48.1%), emphasizing the importance of this specific mutation in the etiology of early-onset AD in this population. One other patient carried the known PSEN1 p.Gly378Val mutation. Genotyping of the PSEN1 p.Gly206Ala and p.Gly378Val mutations in 63 late-onset Hispanic AD patients did not identify additional mutation carriers. All p.Gly206Ala mutation carriers shared rare alleles at two microsatellite markers flanking PSEN1 supporting a common founder. This study confirms the p.Gly206Ala variant as a frequent cause of early onset AD in the Hispanic population and for the first time reports the high frequency of this mutation in Hispanics in Florida.
PMCID: PMC4788736  PMID: 27073747
Alzheimer’s disease; early-onset; presenilin 1; founder mutation; diagnosis; Hispanic
25.  Similarities between familial and sporadic autopsy-proven progressive supranuclear palsy 
Neurology  2013;80(22):2076-2078.
Progressive supranuclear palsy (PSP) is a relatively common neurodegenerative tauopathy clinically characterized by parkinsonism, axial rigidity, and supranuclear gaze palsy. Pathologic findings of PSP are neuronal loss, gliosis, and neurofibrillary tangles in basal ganglia, diencephalon, and brainstem; there is increasing recognition of clinicopathologic variants of PSP.1
doi:10.1212/WNL.0b013e318294b2eb
PMCID: PMC3716405  PMID: 23635960

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