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Brazilian Journal of Psychiatry
EDITORIAL • Braz J Psychiatry 41 (6) • Nov-Dec 2019 • https://doi.org/10.1590/1516-4446-2019-0629 copy
A cerebrospinal fluid biosignature for the diagnosis of Alzheimer's disease
Tatiana Barichello
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USALaboratório de Fisiopatologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazilhttp://orcid.org/0000-0001-7776-8454
Vijayasree V. Giridharan
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Felipe Dal-Pizzol
Laboratório de Fisiopatologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
Alzheimer's disease (AD) and other dementia (OD) are major and increasing global health challenges. The World Health Organization (WHO) estimates that around 50 million people worldwide have dementia, of which AD is the most common form, potentially contributing to 60 to 70% of these cases. The alarming global burden of dementia is projected to reach 82 million by 2030 and 152 million people by 2050.11. World Health Organization (WHO). New guide for carers of people with dementia [Internet]. 2019 [cited 2019 Aug 26]. http://who.int/mental_health/neurology/dementia
http://who.int/mental_health/neurology/d...
AD biomarkers play an essential role in detecting the disease in its early stages, thus allowing initiation of treatment. Being in direct contact with the brain and spinal cord, cerebrospinal fluid (CSF) has been known to act as a valuable source of biomarkers that are representative of various biochemical and metabolic profiles of the brain. The established CSF biomarkers for diagnosis of AD are the 42-amino acid form of amyloid-beta (Aβ42) and the total and phosphorylated fractions of tau protein (T-tau and P-tau, respectively). CSF Aβ42 levels are low in patients with AD when compared with healthy controls, due to increased amyloid deposition in the brain of these patients. Tau protein is a microtubule-associated protein expressed in neurons, and is considered as an important biomarker of several disorders in which axonal damage is implicated. In AD, T-tau and P-tau concentrations in the CSF are elevated due to cortical neuronal loss and cortical tangle formation, respectively. The most recent well-established biomarker for AD diagnosis is the neurofilament light chain (NFL) protein. NFL is a marker of neuroaxonal damage, and its levels are elevated in the CSF of patients with AD and other neurological conditions as compared with healthy controls. These high NFL levels in the CSF are due to prominent axonal destruction triggered by neurodegeneration. A recent systematic review and meta-analysis by Olsson et al. recommends using CSF Aβ42, T-tau, P-tau, and NFL levels as a panel of diagnostic biomarkers for AD in clinical practice and research22. Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673-84. (Figure 1).
Cerebrospinal fluid (CSF) biosignature for the diagnosis of Alzheimer's disease.In Alzheimer's disease, levels of the 42-amino acid form of amyloid-beta (Aβ42) are low, while those of total tau protein (T-tau), phosphorylated tau protein (P-tau), and neurofilament light chain (NFL) protein in CSF are high.
In this issue of the Brazilian Journal of Psychiatry, Radanovic et al. evaluated Aβ1-42, P-tau, and T-tau in the CSF of healthy controls (n=54), patients with mild cognitive impairment (MCI) (n=82), patients with AD (n=46), and patients with OD (n=26), and tested for correlation with Mini-Mental State Examination (MMSE) scores. CSF from patients with AD contained higher levels of P-tau and T-tau and lower levels of Aβ1-42, as well as a lower Aβ1-42/P-tau ratio, as compared to healthy controls and those with MCI, but not to the OD group. By evaluating the coefficient of correlation between CSF biomarkers and MMSE, the authors found that the Aβ1-42 levels in the CSF and MMSE scores correlated weakly in the MCI (0.247), moderately in the OD (0.440), and weakly and inversely (-0.145) in the AD group. T-tau CSF levels had a weak, inverse correlation with MMSE scores in the control (-0.284) and MCI (-0.241) groups; this correlation was moderate to high in the OD (-0.665) group. P-tau CSF levels presented a weak negative correlation with the AD group (-0.343) and moderate negative correlation with the OD group (-0.540).33. Radanovic M, Oshiro CA, Freitas TQ, Talib LL, Forlenza OV. Correlation between CSF biomarkers of Alzheimer's disease and global cognition in a psychogeriatric clinic cohort. Braz J Psychiatry. 2019;41:479-84. The authors did not find a strong correlation between CSF biomarkers and MMSE scores; however, an important contribution of this study was to reaffirm the importance of the CSF biomarkers Aβ1-42, P-tau, and T-tau to distinguish patients with AD from controls and OD in the Brazilian population.
The limitations of adopting MMSE scores in AD clinical trials was demonstrated by Chapman et al., who examined the diagnostic accuracy of MMSE and Logical Memory (LM) cutoffs used in AD trials and diagnostic studies, tested using subjects from the NACC database diagnosed with normal cognition (n=10,741), MCI (n=5,883), or AD dementia (n=6,814). The results from this large-cohort study revealed that MMSE and LM scores might not be appropriate tools for the selection of subjects to enroll in multicenter studies designed to develop therapeutics and diagnostic methods for AD.44. Chapman KR, Bing-Canar H, Alosco ML, Steinberg EG, Martin B, Chaisson C, et al. Mini mental state examination and logical memory scores for entry into Alzheimer's disease trials. Alzheimers Res Ther. 2016;8:9.
Another study, by Olsson et al., demonstrated the association between cognition and CSF-NFL levels. Their wide-ranging sample included healthy controls (n=75) and patients with MCI (n=114), AD (n=397), frontotemporal dementia (FTD) (n=96), amyotrophic lateral sclerosis (n=68), Parkinson's disease (PD) (n=41), PD with MCI (n=19), PD dementia (n=29), dementia with Lewy bodies (n=33), corticobasal syndrome (n=21), and progressive supranuclear palsy (n=20). The patients were followed longitudinally for cognitive testing over a period of 1 to 18 years. The CSF biomarkers evaluated included Aβ1-42, P-tau, T-tau, and NFL. Compared to other markers, CSF levels of NFL gradually increased among the control, MCI, and AD groups. These results delineate the increased positive association of NFL with cognitive impairment. As expected, the AD group presented low levels of Aβ42 and high levels of P-tau, T-tau, and NFL compared to the control group. As this study included patients with neurodegenerative disorders, the outcome also emphasizes that CSF NFL levels appear to reflect the intensity of neurodegeneration, and that NFL has the potential to assist in differentiation of AD from FTD.55. Olsson B, Portelius E, Cullen NC, Sandelius Å, Zetterberg H, Andreasson U, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol. 2019;76:318-25.
To date, the biosignature of AD has comprised CSF levels of T-tau, P-tau, and Aβ42, as well as plasma T-tau. However, a growing body of evidence suggests NFL is a strong CSF biomarker that should be included in this biosignature.
The authors thank the University of Texas Health Science Center at Houston (UTHealth), Universidade do Extremo Sul Catarinense (UNESC), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa e Inovação de Santa Catarina (FAPESC). TB has received grants from Alzheimer's Association® (AARGDNTF-19-619645).
World Health Organization (WHO). New guide for carers of people with dementia [Internet]. 2019 [cited 2019 Aug 26]. http://who.int/mental_health/neurology/dementia
» http://who.int/mental_health/neurology/dementia
Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673-84.
Radanovic M, Oshiro CA, Freitas TQ, Talib LL, Forlenza OV. Correlation between CSF biomarkers of Alzheimer's disease and global cognition in a psychogeriatric clinic cohort. Braz J Psychiatry. 2019;41:479-84.
Chapman KR, Bing-Canar H, Alosco ML, Steinberg EG, Martin B, Chaisson C, et al. Mini mental state examination and logical memory scores for entry into Alzheimer's disease trials. Alzheimers Res Ther. 2016;8:9.
Olsson B, Portelius E, Cullen NC, Sandelius Å, Zetterberg H, Andreasson U, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol. 2019;76:318-25.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Disclosure The authors report no conflicts of interest.
How to cite this article: Barichello T, Giridharan VV, Dal-Pizzol F. A cerebrospinal fluid biosignature for the diagnosis of Alzheimer's disease. Braz J Psychiatry. 2019;41:467-468. http://dx.doi.org/10.1590/1516-4446-2019-0629
Figure 1 Cerebrospinal fluid (CSF) biosignature for the diagnosis of Alzheimer's disease.In Alzheimer's disease, levels of the 42-amino acid form of amyloid-beta (Aβ42) are low, while those of total tau protein (T-tau), phosphorylated tau protein (P-tau), and neurofilament light chain (NFL) protein in CSF are high.
Associação Brasileira de Psiquiatria Rua Pedro de Toledo, 967 - casa 1, 04039-032 São Paulo SP Brazil, Tel.: +55 11 5081-6799, Fax: +55 11 3384-6799, Fax: +55 11 5579-6210 - São Paulo - SP - Brazil
E-mail: editorial@abp.org.br


The news on the 2009 elections this week was supposed to be related to the first ballot-access petitions to be filed, and there is news there, with three candidates on the Democratic side filing their petitions with the State Board of Elections on Tuesday, the first day they could be filed. But it was something else that went down on Tuesday that is the source of the latest bit of friction between Democratic Party gubernatorial-nomination candidates Brian Moran and Terry McAuliffe.
"It's offensive to see Terry McAuliffe raising money with the likes of Republican operative and lobbyist Ed Rogers," Moran campaign manager Andrew Roos said in a statement released by the campaign Wednesday morning, in the wake of a report on Politico.com that McAuliffe held a fundraiser Tuesday night at the Washington, D.C., lobbying firm BGR, which was cofounded by Republican pols Ed Rogers and Haley Barbour, the former chair of the Republican National Committee and the current governor of Mississippi.
BGR was all-Republican until it read the writing on the wall in 2008 and started taking on Democratic clients.
According to the Politico.com report, Rogers, a co-chair for the fundraiser, befriended McAuliffe, a former Democratic National Committee chair, in their years of locking horns as TV talking heads in the green rooms offstage, and has said he will "never go against" McAuliffe in his bid to become Virginia's next governor.
McAuliffe might be finding another unexpected ally toward that end – in the conservative Richmond Times-Dispatch, which today fawned over McAuliffe for "raising the bar" in his campaign of "big ideas," as he has styled it.
Back to the story that we thought was going to be the big news of Tuesday – McAuliffe and Moran and lieutenant-governor nomination candidate Jody Wagner all filed their ballot-access petitions with the State Board of Elections yesterday. McAuliffe was first among the gubernatorial candidates, which should mean that his name would appear first on the ballot for the June 9 primary. And for those keeping score at home, McAuliffe had 315 more signatures on his petitions, 17,243, than Moran with his 16,928.
Both were looking up to Wagner's signature haul, though. The former Secretary of Finance submitted petitions with 17,858 signatures to the State Board.


Tonight Henning and managed to make a release of mGTK. We call it a prerelease becase we have not written any documentation, the release has only been tested on my laptop (running Debian Sarge/Sid), and we have not made a Windows port yet. Still, now you can download it from Sourceforge and play with it.
While GTK bindings in itself is very useful for ML, I am wondering whether there is an opportunity to reach a higher level of GUI coding with ML. As far as I can understand your bindings, they present a more or less one-to-one mapping of the existing C api to ML.
How about trying to reach a higher level?
See for instance the Lit Window Library which is an attempt to provide a higher-level C++ GUI library (for WxWindows in this case), providing two new things: automated bindings of GUI elements to (complex) data structures, and use of a constraint system to define GUI rules.
Those two things definately seems like good extensions of the traditional GUI coding. And thinking further along those lines, the next idea could be automatic construction of GUI dialogs to edit (complex) data structures: You basically define a complex data type, pass that to the engine, and it will magically provide a dialog which allows you to edit that data structure.
In other words, use the data structure as a declarative Domain Specific Language for GUI design.
For such an idea to work out, you need a rich type system, and this is where ML kicks in. It has exactly that.
I agree that a higher-level GUI library would be nice to have, and there has been several interesting libraries for both Haskell and SML a newer example is Functional Forms (and slightly dated overview for more Haskell examples). But for mGTK it has been a explicit non-goal to provide a high-level library. Instead we want to focus on giving the SML programmer as much GUI power as the C programmer. That is, we want to give access to all parts of the C API, even the calendar widget.
Only when that goal has been reached will we start to look at making higher-level GUI library. However, if others want to start on such a higher-level GUI library and want to use mGTK as a substrate, then we'll do what we can to support that efford.
Why not start on the higher level library before? Well, I don't know about Henning, but for me the reason is that I'd rather try to produce something which is not just another proof-of-concept library.
I think Ken's approach is the right one, though I will probably want to wait for the high-level, cool interface before I get my head seriously into GUI programming. I've always thought that those systems were far too complicated. (E.g., the claim that being a Windows C++ programmer is much more a test of your knowledge of the MFC hierarchy than it is a test of your C++ skills.
I basically agree with Ken that we don't want yet another proof-of-concept library. It takes a good amount of work to design a library that has the right "functional feel" (look at the Standard ML Basis Library for an example). As Ken puts it: Making a library that feels "completely right" is something entirely different than making a library that is "good enough".
a functional feel (but without the hassle of worrying about functionality at the same time).
I can certainly sympathise with that approach. Full credit for that.
The reason I feel a high level GUI library is interesting is that I think you need a competitive advantage to steal a market. And this advantage has to be substantial.
Ask yourself: Even when you have complete coverage of the C API, you still come up short against the C library, simply because you become out of date too fast. Also, the ML camp will always be behind in regards to XML libraries, network libraries, cryptographic libraries, and so on and so on.
The fundamental problem is that there are so many C people out there, and only so many ML people. If you are trying to compete on breadth and quality, you will always loose.
However, if you compete on efficiency, you have a chance.
So, my take would be to cover as much of the API that is usable in real life. Then go for higher level constructs where there is a chance for a big advantage.
Looking at functional forms, that does have some nice ideas. However, it stills looks too verbose in my opinion. Too much layout fiddling. I believe the computer can do most of the layout itself, and do that fairly decently.
and then one or two lines to bring up the dialog with a nice default layout.
Anyway, talk is cheap. Keep up the good work.
Asger, I understand your point an to some degree I agree with it. But you are far more optimistic about what mGTK could possibly do in the near future than what I am!
I don't think that mGTK will help SML steal any markets in the near future. What mGTK will do is that it will enable SML to stay on the battlefield. SML has traditional had a strong as an language in education, but this "marked" in under serve attack from Java and C#. MGTK will take away one of the substantial advantages Java and C# have over SML: a GUI library.
The above is sounding a bit more negative about SML than what I really feel. And I'm sure that mGTK will enable interesting research, it already has.
I think there is value to following a dual-track approach: leverage existing — and future — technologies by establishing bindings to active development communities, in this case of GTK+ to ML as Henning and Ken have done with mGTK; and build a novel technology on top of existing substrates that provides well-defined 'competitive' advantages.
It appears to me that these advantages in the GUI construction domain could be productivity (more correct GUI functionality per programmer hour) and efficiency (faster and more responsive execution at moderate or no space increases) _simultaneously_. This is not only by attaining a 'functional feel' to integrate GUI programming with, say ML programming, but by leveraging and exploiting properties of functional programming: the applicability of caching, memoization, sharing, coalescing and data identification (by hashing) for purely functional (and thus always light-weight memoizable) computations on immutable (and thus always replicable, sharable, and efficiently identifiable) data. E.g., screen displays could be rendered in a compositional fashion from abstract gui states that in turn are 'views' of (functionally determined by) some 'model' (logical system state), where values are cached, intermediate results memoized, results from different users and different GUI parts shared, and doing so across multiple machines in a network (cache the menu bit map wherever convenient, e.g., both in an applet server and applet clients).


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£1.39 raised for Groundswell
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redpajama_set_name: RedPajamaCommonCrawl


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The Seattle Sounders FC soccer team air their games in English & Spanish on local radio.  The English-language station is Sports Radio 950 KJR-AM while the 3-station Spanish-language network originates at KBRO and airs on the ESPN Deportes affiliates around the Pacific Northwest.  The ESPN Deportes network comprises 3 A.M. stations and 1 F.M. translator.  The Spanish network also includes a 30-minute pregame & 30-minute postgame analysis.

Radio Network (3 stations + 1 F.M. translator)
1280/KLDY: Lacey (2014-)
1480/KNTB: Lakewood (2014-)
1490/KBRO: Bremerton (2014-)
92.1/K221FJ: Tacoma (rebroadcasts KNTB)

Unsure status (2 stations)
1210/KMIA: Auburn-Federal Way
99.3/KDDS-FM: Elma, Washington

References

Radio Network
Sports radio networks in the United States

redpajama_set_name: RedPajamaWikipedia


Stop Napa Oaks Hillside Subdivision...again!
Davidon Homes Informational Meeting Tonight!
Nov 28, 2017 — Important Napa Oaks Meeting—locals please join us!
We need your help. Please join your fellow community members at this public meeting, and raise your questions about the proposed hillside subdivision. This meeting is hosted by the developer, Davidon Homes — this is your chance to ask your questions directly to them. This is an important step as we lead up to the votes by the Planning Commission and the City Council.
We will have extra "Stop Napa Oaks" yard signs if you need one.
Napa Oaks Final EIR Released this week!
Davidon Homes Makes Presentation to the Neighborhood!
This petition made change with 2,167 supporters!


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Governor Ugwuanyi Empowers Three Physically-Challenged Persons Among Groups
The Chairman of Igbo-Etiti Local Government Area, Hon. Ikenna Nwodo, on Friday, led the youths of the council, under the umbrella of 'Peace Ambassadors for Gburus' to the Government House, Enugu, to declare their unanimous support for Governor Ifeanyi Ugwuanyi's senatorial bid and that of the governorship candidate of the Peoples Democratic Party (PDP), Dr. Peter Ndubuisi Mbah and other candidates of the party, declaring that "the sins of the fathers, the mistakes of those before us can never befall us."
Hon. Nwodo, a leader of the PDP in Igbo-Etiti LGA, explained that the group's philosophy reflects the principles of party supremacy, peace and togetherness, stressing: "We are standing together as youths and writing our own future. We are standing together on a platform of peace, a platform of progress, and a platform of prosperity.
"We are telling you (Ugwuanyi) that all Igbo-Etiti youths are solidly behind you to represent Enugu North Senatorial District in the Senate in 2023, our incoming governor by the special grace of God, Barr. Peter Mbah, Hon. Ezenta Ezeani (PDP House of Assembly candidate) and Rt. Hon. Dr. Martins Oke (PDP House of Representatives candidate).
The Council Chairman appreciated the Director General of Peace Ambassadors for Gburus, Hon. Martins Ugwuamadieze, for his immense support and grassroots mobilisation and charged the teeming members of the group to remain focused and committed to the tasks ahead, saying: "It is operation deliver your polling units. We are here not only to support our leader, but to also support all other PDP candidates for the coming elections. It is operation deliver your polling units."
In his speech, the Director General of Peace Ambassadors for Gburus, Hon. Ugwuamadieze, corroborated Hon. Nwodo's statement, adding that they are ready to do the work they have agreed to do satisfactorily.
Stressing that "Igbo-Etiti is PDP and PDP is Igbo-Etiti", the DG reassured Gov. Ugwuanyi that "we are going to come first in the forthcoming general elections because our Digital Mayor, Ikenna Nwodo, is doing all it takes to make sure that everybody supports you and the PDP."
Hon. Ugwuamadieze applauded Gov. Ugwuanyi for the youths' participation in governance, stating that the governor has "given every Igbo-Etiti youth a sense of belonging by the emergence of these young men from our council area.
"It's not only that you have given us hope, you have also given us hope that tomorrow, it may be your (our) turn."
Also at the Government House, Enugu, on a solidarity visit to Gov. Ugwuanyi, were teeming members of Mmagha Support Group for Gburugburu 2023, led by the Director General of the group, Dr. Joel Ugwuoke.
The group equally assured of its unalloyed support for Gov. Ugwuanyi's senatorial bid in 2023, that of the governorship candidate of the PDP, Dr. Mbah and other candidates of the party in recognition of the governor's remarkable achievements and uncommon leadership style.
Delivering the group's message, the DG, Dr. Ugwuoke told Gov. Ugwuanyi, who was with traditional rulers of Enugu North Senatorial District led by the Grand Patron of Enugu State Council of Traditional Rulers, HRH, Igwe Simeon Osisi Itodo, that "we are here to let you know that come 2023 we are solidly behind you and other PDP candidates."
The DG hailed the governor for his administration's fruitful investment drive in Enugu State, disclosing that "I am one of the beneficiaries because you provided the enabling atmosphere for that (investment) and investors are coming to invest in our communities."
He added: "For instance, in my community Eroagu, white men built some factories there because of the enabling environment you created in Enugu State.
"In Nsukka, our sons have attracted the Nollywood Industry because you developed Nsukka. We have good roads and I am proud of it whenever I am inviting visitors and business associates to Nsukka.
"The judiciary buildings we had before were too local and dilapidated but you transformed them by renovating and constructing modern ones.
"Your Excellency, your projects are uncountable. We have taken note of them and when we come for campaign we will list them.
"The number of people you are seeing here are just the numbers that can be contained here. We all have agreed that we will support all the candidates of the PDP. We will deliver in all our polling units.
"So, I will advise that you should never stress yourself but allow us to do the job because your good governance will speak for you and we plead that you continue the good work."
In their separate speeches, the Commissioner for Transport and a staunch member of Mmagha Support Group for Gburugburu, Hon. Andy Peter Omeje, the Zonal Coordinator of the group, Hon. Fidelis Ojobo, the woman and youth leaders, Mrs. Ijeoma and Chinonso Ugwunweze respectively, all expressed gratitude to Gov. Ugwuanyi for his administration's youth-friendly initiatives and developmental strides, particularly the ongoing massive projects at the newly established State University of Medical and Applied Sciences (SUMAS), Igbo-Eno, Enugu State, and the attraction of the Federal Polytechnic, Ohodo, with their inherent benefits to the people of Enugu State, among others.
While addressing the crowd, Gov. Ugwuanyi identified and empowered three physically-challenged persons who were among members of the support groups at the Government House, Enugu financially to enable them establish businesses of their choice, amid jubilation.
The Executive Secretary of Enugu State Christian Pilgrims Welfare Board, Barr. Nestor Ezeme, was at the events.
#EnuguStateIsInTheHandsOfGod
#amokelouis


Australian Opal Yellow Gold Dangle Earrings present these October birthstones in decorative bezels. The detailed royal-like settings are each holding an 8x6mm oval AAA grade white Australian opal. Flashes of colored fire disperse light with each turn or change of light. Every opal has its own special beauty, and these gemstones have long been desirable and sought after! Featuring a shepherd's hook style ear wire, also in yellow gold, this pair is timeless and appropriate for every occasion be it casual or formal. This pair of drops weighs 1.82 grams.