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NASCAR, Watch
WATCH: NASCAR Fans Cheer Loudly as Air Force 1 Touches Down at Daytona
by btctipme
President Trump is set to deliver the "start your engines" command at the Daytona 500 on Sunday. Though, the crowd in attendance isn't waiting for the start of the race to start getting loud.
Air Force 1 made it's dramatic flyover and landing at Daytona, to the trill of thousands who immediately began cheering loudly.
Crowd cheers as Air Force One, containing President @realDonaldTrump and @FLOTUS Melania Trump, flyover of the Daytona speedway. #DAYTONA500 pic.twitter.com/3r0BeZc0cH
— The Hill (@thehill) February 16, 2020
Loud chants of "U.S.A. U.S.A.!" could be heard as the president's plane flew overhead.
"Trump will bask in the appreciation of thousands of NASCAR fans, becoming the second president to attend the Daytona 500 after President George W. Bush, who also appeared at the race during his reelection year," the Associated Press reports.
"Trump's reelection campaign will run a TV ad during the Fox broadcast of the race and fly an aerial banner near the speedway. About 100,000 people are expected to attend this year's race and millions more will watch on television. About 9 million people took in last year's race on television.
"Trump tweeted Sunday morning: "Getting ready to go to the Daytona 500. Will be GREAT!"'
The president has made appearances at the World Series, college football national championships, and a UFC fight.
Follow Dylan Gwinn on Twitter @themightygwinn


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Jack and the Giant Tantrum
Imprint: Ladybird
Dimensions: 251mm x 6mm x 251mm
Little monsters, big problems.
Series: Monster Town
Louis Growell
Chris Jevons (Illustrator)
A story about dealing with temper tantrums when tiny monsters don't get their way.
Welcome to Monster Town! The monsters here are perfectly friendly, but they're not always very well-behaved . . .
Jack is sweet and kind most of the time, but throws the BIGGEST tantrums Monster Town has ever seen when he gets upset. Will he ever learn how to keep his temper?
With playful illustrations and reassuring text, this picture book series is perfect for adults and children to enjoy together, and provides practical tips to help manage tricky toddler behaviours.
Louis Growell Chris Jevons
Louis Growell lives in the UK and this is their debut book!
Chris Jevons
Chris has always enjoyed doodling and scribbling characters since childhood. Inspired by Disney films, Pixar animation and picture books, he pursed a career as a children's book illustrator. Since gaining representation by The Bright Agency, Chris has illustrated over 60 books in his career so far. He now spends his days drawing animals, monsters and aliens for picture books and fiction titles. Chris lives and works in Harrogate UK. Clients include: Hachette, Hodder, Penguin Random house, Ladybird, Egmont, Faber and Faber, Bloomsbury and Walker Books.
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redpajama_set_name: RedPajamaCommonCrawl


WUZHEN - Chinese government is actively promoting internet infrastructure of Belt and Road countries, said officials and company representatives at the third World Internet Conference (WIC) in Wuzhen, East China's Zhejiang province.
China-Pakistan cross-border cable project, a project under the China-Pakistan Economic Corridor (CPEC), has been under construction since May.
"The CPEC is the shortest route that links China to the Middle East, Africa, and Asia," said Amir Azeem Bajwa, Major General of the Special Communication Organization of Pakistan. "We call it the 'digital Silk Road'."
There are 135 million mobile phone users in Pakistan, huge potential for telecom cooperation with China. Yang Xiaowei, general manager of the China Telecommunications Corporation, said at WIC that the company would cooperate with operators in the Belt and Road countries on a Pan-Asia network.
Chen Zhaoxiong, vice minister of industry and information technology, pointed out that China is working on unifying standards for cross-border e-commerce in Belt and Road countries to tackle technological challenges and expand new industries.
According to the International Telecommunication Union (ITU), the information level of Asian Pacific and Africa are both below the global average.
In 2011, China's leading telecom company China Unicom initiated the Asia-Africa-Europe-1 (AAE-1), a 25,000 km submarine cable system which ventures to link 19 nations and regions across Asia, Africa and Europe.
In order to boost big data and cloud computing in the Middle East and North Africa, Aliyun, Alibaba's cloud computing subsidiary, set up a joint venture with Dubai's Meraas in May 2015. This joint venture will offer system integration services to help private companies and governments in the region to reduce IT spending.
"There are ample opportunities for Belt and Road countries to cooperate on information infrastructure, Internet applications, information content exchange, big data and intelligent manufacturing," said Yang Xiaoya, an official from ITU.


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Aboriginal Law
The Yukon's Open Entry Mining System Declared a Breach of the Duty to Consult with First Nations: Ross River Dena Council v Government of the Yukon 2012 YKCA 14
by Tessa Crosby · January 28, 2013
As Canada's MPs return to the House of Commons today they will be greated by jingle dancers on Parliament Hill. The gathering is one of more than thirty to be held across Canada as part of a national day of action in support of the Idle No More movement. Among other things, the movement seeks to raise awareness about aboriginal rights, treaty rights and self governance.
The equitable resolution of these issues is becoming more urgent as resource development becomes increasingly important to the Canadian economy. Much of the natural resources are found in treatied territory, traditional territory of First Nations, or areas of asserted but unproven land claims. In addition to having a strong moral and equitable interest in what development – if any – occurs on these lands, many First Nations (as inhabitants of remote regions) are uniquely placed to either support the development by providing much needed labour, or disrupt these activities through non cooperation. Moral arguments aside, arriving at an equitable arrangement is increasingly just good business sense.
While many of these issues must be addressed politically, the courts are increasingly asked to determine the scope of aboriginal rights. In the context of resource development, much of the litigation centers on the duty to consult with First Nations. As established in Haida Nation v British Columbia, 2004 SCC 73 [Haida], the duty requires the Crown to consult with First Nations where proposed Crown conduct may adversely affect claims to aboriginal interests in land.
In Ross River Dena Council v Government of the Yukon, 2012 YKCA 14 the Yukon Court of Appeal ("YKCA") found that the Yukon Government had breached its duty to consult with Ross River Dena First Nation. The breach occurred when the Government registered new mining claims under the Quartz Mining Act, SY 2003 c 14 [Quartz Mining Act]. Registration has two effects which the Ross River Dena Council ("RRDC") submits trigger the duty to consult:
It transfers subsurface rights to claims holders, arguably threatening the RRDC's asserted aboriginal title; and
It entitles the claimholder to engage in class 1 exploration activities without further permission or notice, arguably threatening the RRDCs surface aboriginal rights (of which hunting is the most important).
The YKCA upheld the lower court finding that the registration system does not meet the Haida consultation requirements. However, it disagreed with the lower court on the question of what regime would satisfy the duty; while the lower court held that the duty would be discharged if the Yukon Government were to notify the RRDC of any newly recorded quartz mining claims, the YKCA held that mere notice is insufficient. It also accepted that the duty was triggered both by the threat posed to aboriginal title by the transfer of subsurface rights and the threat to aboriginal rights by class 1 exploration activities. While declining to specify an appropriate consultation mechanism, the Court of Appeal ruled that consultation must occur before the adverse impact.
The decision is particularly damaging to the Yukon Government coming as it did just weeks after the repeal of provisions in the Yukon Oil and Gas Act, RSY 2002, c 162, which required the prior consent of any First Nation who has not concluded a land claim agreement to the disposition of oil and gas rights in its traditional territory. The repeal was unsuccessfully opposed by the RRDC, one of three Yukon First Nations which has not yet signed a land claim agreement.
The Open Entry Mining System in the Yukon
Under the Quartz Mining Act, a claim to resource rights is acquired by staking the parcel. The system is "open entry", meaning any individual may claim un-staked land without prior approval by the government. A staked claim must be registered with the Mining Recorder, but registration may only be refused on technical grounds.
Once the claim is registered, the claim holder is entitled to all minerals in the bounds of the staked claim for a year, subject to annual renewals. This entitles the claim holder to undertake class 1 exploration on the claim without notice to or approval by the Yukon Government or affected First Nation(s). Class 1 exploration activities include: clearing the land, constructing lines, corridors and trails, using explosives and removing subsurface rock.
Mining is big business in the Yukon. As the sector expands, the risk of conflict between First Nations and exploration companies increases. The issues are complex. On the one hand, there are the rights of increasingly powerful First Nations, some of whom have land claims agreement and others who have unresolved but strong claims to Aboriginal title. The interests of individual First Nations vary but most are interested in First Nation participation in and control over the resource development which take place on their land.
Although frequently characterized as a conflict between First Nations who oppose resource development and industry which craves it, the conflict is more complex than that. For example, the RRDC is not opposed to resource development; on January 30 it was announced that it has signed an exploration agreement with Golden Predator Corp. What the RRDC objects to is resource development without their consent, participation, and ultimate benefit.
On the other hand, there are the interests of resource companies and those which would benefit from the economic development promised by mining. Mining companies, as represented in this case by the intervenor Yukon Chamber of Mines, argue that an open entry registry system is essential the Yukon mining industry due to the secret nature of mineral staking claims. If a mining company must publicize its interest in a particular claim before it actually acquires rights in it, it becomes vulnerable to predatory competitors who seek to acquire the rights first.
The Yukon Chamber of Mines' argument about the absolute necessity of open entry claims is undermined by the fact that Alberta does not have an open entry mining system. Despite this apparent deficiency, the Fraser Institute Survey of Mining Companies 2011/2012 ranked Alberta as the third most attractive jurisdiction to mining companies in the world.
The Duty to Consult
The triggering event for the duty to consult was restated in Rio Tinto Alcan Inc v Carrier Sekani Tribal Council, 2010 SCC 43 [Rio Tinto] as follows:
The Crown has knowledge, actual or constructive, of a potential aboriginal claim or right; and
There is contemplated Crown conduct; and
There is potential for the contemplated conduct to adversely affect the aboriginal claim or right.
The Yukon Government conceded that it had actual knowledge of the RRDC's interest in the territory. The two parties have been involved in land claims negotiations for several decades.
On the second branch of the Rio Tinto test, the Yukon Government submitted that registering a claim does not qualify as "contemplated Crown conduct". They point to how the Recorder has no discretion under the statute to refuse to register a claim, and argue that the position is merely ministerial.
In the Yukon Government's submission, if the duty were triggered it could only have been when the Yukon legislature passed the Quartz Mining Act, and not when an individual claim is registered. The question of whether legislative action may trigger the duty to consult was left open by the Supreme Court of Canada in Rio Tinto. The Yukon Government submitted that this was not an appropriate case to decide the issue, or in the alternative that the legislative action cannot or did not trigger the duty.
While declining to determine the legislative action question, the YKCA found that the duty to consult had been triggered in this case. Transferring mineral rights to claim holders by registration is Crown conduct capable of triggering the duty, regardless of the discretion of the Recorder under the legislation. As the duty to consult lies upstream of legislation, the terms of the legislation are no defence to a First Nation's claim that the duty has been triggered and breached. The failure to provide discretion in the legislation is not an answer to the First Nations claim but rather the source of the problem.
The YKCA further noted that the legislation does give the government broad discretion to prohibit the staking of claims on particular lands. This discretion could have been used to prohibit any staking in the disputed Ross River territory. If the Government wishes to permit claim staking in the territory, it may only do so if it respects the rights (including the right to be consulted) of the RRDC.
On the third point, the Court acceptedtwo separate types of adverse effect. Firstly, transferring the mineral rights had an adverse effect on the aboriginal title claims of the RRDC. This is exceedingly interesting , as it accepts that subsurface rights may be included in aboriginal title. While aboriginal title has not yet been proven in a Canadian court, the jurisprudence is growing and this finding may prove important.
The second adverse effect is on aboriginal rights to use the land, most importantly hunting. Carrying out class 1 exploration activities has the potential to adversely affect these rights by restricting access and influencing local wildlife.
What is Adequate Consultation?
Where the duty to consult is triggered, the consultation must be bona fide with a view to accommodating the claimed interests. The nature of the consultation depends on the apparent strength of the aboriginal claim and the degree of intrusion by the proposed conduct. Appropriate consultation can range from notification to full consent.
In this case, the RRDC's claim to aboriginal title and aboriginal rights is strong; they have occupied the territory since time immemorial and have never ceded it in treaty. While the degree of intrusion of class 1 exploration into aboriginal rights is considerable, it is surpassed by the intrusion into aboriginal title caused by the transfer of mineral rights.
On the question of what constitutes sufficient consultation in this case, the YKCA rejected the trial judge's holding that notice may be sufficient. It found the trial judge had given too much weight to arguments about the importance of an open entry system to the Yukon mining industry, a factor which is irrelevant to determining appropriate consultation. Consultation is a constitutional imperative which cannot be limited by ordinary legislation to accommodate non-constitutional concerns.
While declining to specify an appropriate consultation scheme, the Court of Appeal made two statements which will be useful in designing an appropriate scheme.
Mere notice is insufficient in the circumstances, given the strength of the RRDC's asserted aboriginal rights and title, and the intrusiveness of class 1 explorations and the transfer of subsurface rights.
Consultation must occur before claimed aboriginal title and rights are adversely affected. Ex poste facto consultation does not satisfy the duty.
In amending the Quartz Mining Act in light of this decision, the Government of the Yukon would be wise to consider the experience of Ontario. In 2009 the open entry system of the Mining Act, RSO 1990 c M.14, was amended, partly in response to concerns about potential claims of First Nations. Although it does not impose a duty to consult prior to the transfer of mineral rights, the new Mining Act recognizes and affirms existing treaty and Aboriginal rights including the duty to consult and includes detailed consultation requirements at each stage in the mining process, including early exploration. Additionally, First Nations must be notified when mining claims are recorded within their traditional territories, and they may apply to have sites of cultural significance withdrawn from claim staking.
The Yukon Government will likely introduce similar provisions to provide for consultation before class 1 exploration adversely affects aboriginal rights. There is no similar roadmap for consultation prior to adverse effect on aboriginal rights. Although eleven of the fourteen Yukon First Nations have surrendered their aboriginal title in land claims agreements, large portions of the resource rich territory remain subject to unsurrendered aboriginal title claims. Inventing an adequate consultation mechanism – which is required in order to grow the resource economy of the territory – will require considerable innovation and creativity.
Next story Clarifying Jurisdiction Over Metis and Non-Status Indians in Canada: The Federal Court in Daniels v The Queen
Previous story Peeling Back the Court's Decision in R v NS


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NeuroImage: Clinical 13 (2017) 330–338
Contents lists available at ScienceDirect
NeuroImage: Clinical journal homepage: www.elsevier.com/locate/ynicl
Longitudinal changes in microstructural white matter metrics in Alzheimer's disease Chantel D. Mayoa, Erin L. Mazerolle b, Lesley Ritchie c, John D. Fisk d,e,f,g, Jodie R. Gawryluk a,⁎, for, the, Alzheimer's Disease Neuroimaging Initiative1: a
Department of Psychology, University of Victoria, PO Box 1700 STN CSC, Victoria, BC V8W 2Y2, Canada Department of Radiology and the Hotchkiss Brain Institute, University of Calgary, HSC 2905, 3330 Hospital Dr NW, Calgary, AB T2N 1N4, Canada Department of Clinical Health Psychology, University of Manitoba, 350-771 Bannatyne Avenue, Winnipeg, MB R3E 3N4, Canada d Psychology, Nova Scotia Health Authority, Queen Elizabeth II Health Centre, 4066, 4th Floor, Abbie J. Lane Memorial Building, 5909 Veterans' Memorial Lane, Halifax, NS B3H 2E2, Canada e Department of Psychiatry, Dalhousie University, 4066, Abbie J. Lane Memorial Building, 5909 Veterans' Memorial Lane, Halifax, NS B3H 2E2, Canada f Department of Psychology & Neuroscience, Dalhousie University, 4066, Abbie J. Lane Memorial Building, 5909 Veterans' Memorial Lane, Halifax, NS B3H 2E2, Canada g Department of Medicine, Dalhousie University, 4066, Abbie J. Lane Memorial Building, 5909 Veterans' Memorial Lane, Halifax, NS B3H 2E2, Canada b c
a r t i c l e
Article history: Received 15 September 2016 Received in revised form 12 December 2016 Accepted 13 December 2016 Available online 16 December 2016 Keywords: Alzheimer's disease Aging Diffusion tensor imaging Magnetic resonance imaging White matter
a b s t r a c t Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current avenues of AD research focus on pre-symptomatic biomarkers that will assist with early diagnosis of AD. The majority of magnetic resonance imaging (MRI) based biomarker research to date has focused on neuronal loss in grey matter and there is a paucity of research on white matter. Methods: Longitudinal DTI data from the Alzheimer's Disease Neuroimaging Initiative 2 database were used to examine 1) the within-group microstructural white matter changes in individuals with AD and healthy controls at baseline and year one; and 2) the between-group microstructural differences in individuals with AD and healthy controls at both time points. Results: 1) Within-group: longitudinal Tract-Based Spatial Statistics revealed that individuals with AD and healthy controls both had widespread reduced fractional anisotropy (FA) and increased mean diffusivity (MD) with changes in the hippocampal cingulum exclusive to the AD group. 2) Between-group: relative to healthy controls, individuals with AD had lower FA and higher MD in the hippocampal cingulum, as well as the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; and tapetum. Conclusion: The current results indicate that sensitivity to white matter microstructure is a promising avenue for AD biomarker research. Additional longitudinal studies on both white and grey matter are warranted to further evaluate potential clinical utility. © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Abbreviations: AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; DTI, diffusion tensor imaging; FA, fractional anisotropy; FSL, Functional MRI of the Brain Software Library; HC, healthy controls; MCI, mild cognitive impairment; MD, mean diffusivity; MRI, magnetic resonance imaging; MMSE, Mini Mental Status Exam; ROI, region of interest; TBSS, Tract-Based Spatial Statistics; WMS, Wechsler Memory Scale. ⁎ Corresponding author at: Cornett Building, Department of Psychology, University of Victoria, PO Box 1700 STN CSC, Victoria, BC V8W2Y2, Canada. E-mail addresses: [email protected] (C.D. Mayo), [email protected] (E.L. Mazerolle), [email protected] (L. Ritchie), [email protected] (J.D. Fisk), [email protected] (J.R. Gawryluk). 1 Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_ to_apply/ADNI_Acknowledgement_List.pdf.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Pathologically, AD is characterized by extracellular aggregation of amyloid-beta into senile plaques and hyper-phosphorylated tau protein accumulation in intraneuronal neurofibrillary tangles (Beach et al., 2012). Clinically, AD is characterized by progressive cognitive decline that typically presents with memory loss as the initial and primary concern (Alzheimer's Association, 2014). Worldwide, approximately 47.5 million individuals are living with dementia, the majority of which suffer from Alzheimer's disease (World Health Organization, 2016). Emerging research has focused on the identification of biomarkers that will assist with early diagnosis of AD and allow for the evaluation of potential disease modifying treatments (Dubois et al., 2010). Considerable effort has been devoted to the development of PET molecular
http://dx.doi.org/10.1016/j.nicl.2016.12.012 2213-1582/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
C.D. Mayo et al. / NeuroImage: Clinical 13 (2017) 330–338 Table 1 Participant demographics at baseline and year one. Baseline
Age # of males # of females Education
AD vs. HC⁎ AD
AD vs. HC⁎
75.8 ± 7.6 24 10
p = 0.104 76.9 ± 7.7 p = 0.113 – –
74.1 ± 6.5 – –
p = 0.114 – –
15.7 ± 2.9
p = 0.347 –
⁎ t-Tests used to obtain p-values.
neuroimaging biomarkers of amyloid and tau in AD (e.g. Wang et al., 2016), however, magnetic resonance imaging (MRI) continues to offer a non-invasive and easily repeatable method of examining neuropathological changes associated with AD. To date, the majority of MRI-based research in AD has focused on tissue loss in grey matter structures (Cash et al., 2014). These findings indicate widespread whole brain grey matter atrophy in individuals with AD, including enlarged ventricles and decreased hippocampal volume (Gold, 2012; Hampel et al., 2014; Perl, 2010; Teipel et al., 2010). In terms of white matter changes, the Amyloid Cascade Hypothesis (Hardy and Higgins, 1992) suggests that axonal degeneration arises as a result of Wallerian degeneration. However, the close association of tau with both axonal integrity and with the cognitive symptoms of AD suggests that white matter changes may occur independently and perhaps prior to changes in grey matter. Furthermore, the retrogenesis model proposed by Bartzokis et al. (2007) hypothesizes that white matter degeneration in AD follows a reverse pattern to that observed in early myelination. These ideas lend support to the notion of white matter changes in AD as biomarkers
that may be particularly helpful in earlier identification of AD (see Amlien and Fjell, 2014 for a review). One promising tool to detect early white matter alterations in the brain is diffusion tensor imaging (DTI; Alexander et al., 2007; Soares et al., 2013). Currently, fractional anisotropy (FA) and mean diffusivity (MD) are the most frequently reported DTI metrics (Amlien and Fjell, 2014). FA is a measure of the degree of directionality of water diffusion, thought to be driven by microstructure such as cellular boundaries and myelin (Alexander et al., 2007; Amlien and Fjell, 2014; Soares et al., 2013), while MD is a measure of the mean water diffusion rate (Soares et al., 2013). These metrics can provide information regarding changes or differences in restriction to diffusion that may reflect myelination and axonal integrity. Specifically, decreases in FA and increases in MD are indicative of decreased myelination and loss of axons, as a consequence of neurodegeneration (Bosch et al., 2012; Kantarci, 2014; Serra et al., 2010). The majority of published AD research has used a cross sectional design and consistently revealed low FA and high MD in widespread white matter regions including the frontal, parietal, and temporal lobes (including hippocampal regions), as well as the corpus callosum and longitudinal association tracts (Acosta-Cabronero and Nestor, 2014; Sexton et al., 2011; Stebbins and Murphy, 2009; Stoub et al., 2014). Microstructural water diffusion changes are not unique to AD, however. In fact, some of these changes occur during the healthy aging process. For example, Burzynska et al. (2010) examined DTI indices from young and older adults and found an age-related reduction in FA within a number of white matter structures. These findings are consistent with recent reviews that discuss degeneration of white matter tracts with age, which may result from cerebrovascular changes or other common underlying health conditions (e.g. Lockhart and Decarli, 2014). Recent studies that have utilized a longitudinal design to investigate microstructural changes in AD via DTI have revealed decreased FA in the
Table 2 Number and percentage of total significant voxels in regions with significantly (decreased) fractional anisotropy and/or (increased) mean diffusivity at year one compared to baseline in individuals with Alzheimer's disease and in healthy controls. Alzheimer's disease
Healthy controls
White matter regions
Corpus callosum
5842 (77.3%) 2868 (59.8%) 2195 (70.7%) 3710 (49.7%) 1809 (80.8%) 1775 (56.5%) 3 (30.0%) 758 (77.4%) 272 (70.1%) 393 (56.9%) 338 (54.7%) 90 (75.0%) 38 (95.0%) 227 (55.4%) 2402 (65.2%) 873 (66.3%)
3715 (49.2%) 1769 (36.9%) 1017 (32.8%) 1794 (24.0%) 1351 (60.3%) 312 (9.9%) 3 (30.0%) 239 (24.4%) 0 (0.0%) 322 (46.6%) 290 (46.9%) 30 (25.0%) 14 (35.0%) 157 (38.3%) 1834 (49.8%) 756 (57.4%)
3700 (49.0%) 2368 (49.4%) 1297 (41.8%) 3079 (41.2%) 996 (44.5%) 953 (30.3%) 5 (50.0%) 305 (31.2%) 0 (0.0%) 333 (48.2%) 212 (34.3%) 0 (0.0%) 9 (47.5%) 183 (44.6%) 1381 (37.5%) 647 (49.1%)
Internal capsule External capsule Corona radiata Posterior thalamic radiations Longitudinal fasciculi Fronto-occipital fasciculi Cingulum (white matter of cingulate gyri) Hippocampal cingulum Fornix Corticospinal tract Uncinate Fasciculus Tapetum Medial lemniscus Cerebellar peduncle Cerebral peduncle
C.D. Mayo et al. / NeuroImage: Clinical 13 (2017) 330–338
uncinate fasciculus (Kitamura et al., 2013) as well as FA and MD changes in the fornix, corpus callosum, and inferior cingulum, over time in individuals with AD (Genc et al., 2016; Norwrangi et al., 2013). The current study is the first to use the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to investigate changes in diffusion tensor imaging (DTI) metrics over time. The ADNI database has collected and made available DTI data from individuals with AD and healthy controls at multiple sites across North America. The overarching aim of the current study was to determine if DTI, as a measure of microstructural white matter integrity, has potential as a biomarker of AD. The study had two specific objectives: 1) to examine within-group microstructural white matter changes in individuals with AD and healthy controls at baseline and year one; and 2) to evaluate between-group differences in individuals with AD and healthy controls at both time points. It was hypothesized that 1) individuals with AD would have decreased FA and increased MD across time and that 2) individuals with AD would have lower FA and higher MD as compared to healthy controls at both time points. A whole brain exploratory approach was taken to capture differences between groups in any region, however, it was predicted that medial temporal regions would be more greatly affected in AD, compared to healthy controls, given that this is one of the first affected regions in the progression of AD grey matter pathology (Braak and Braak, 1991; Gold, 2012; Hampel et al., 2014; Perl, 2010; Teipel et al., 2010).
2. Method and materials All data were obtained from the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) database (http://adni.loni.usc.edu). The ADNI, led by Principal Investigator Dr. Michael W. Weiner, was launched in 2003 with the goal of testing whether longitudinal brain imaging, biological markers, and neuropsychological assessment can be used together to measure the progression of AD. For more information, please see www.adni-info.org.
2.1. Participants Full eligibility criteria for the ADNI are described in the ADNI2 procedures manual (Alzheimer's Disease Neuroimaging Initiative, 2008). Briefly, individuals with AD met NINCDS/ADRDA criteria for probable AD (McKhann et al., 1984), demonstrated abnormal memory function on the Wechsler Memory Scale (WMS) II (≤ 8 for 16 years education and above), had a MMSE score between 20 and 26, and had a Clinical Dementia Rating of 0.5 (very mild) or 1.0 (mild). Healthy controls were required to be free of subjective memory concerns, to have a score within the normal range on the WMS Logical Memory II (≥9 for 16 years of education and above), have a MMSE score between 24 and 30, and a Clinical Dementia Rating of 0 (none).
Fig. 1. Results of within-group Tract-Based Spatial Statistics white matter analysis showing pattern of reduced fractional anisotropy (red) overlaid on the white matter skeleton (green) at year one compared to baseline in individuals with Alzheimer's disease (panel A) and in healthy controls (panel B; p b 0.05, corrected for multiple comparisons).
Individuals from the ADNI database were included in the present study if data was available at both baseline and year one. Data were retrieved from 34 individuals with AD (mean age = 75.8 ± 7.6; 10 females; MMSE = 23.59 ± 1.74; Logical Memory II = 1.65 ± 1.94) and 33 healthy age-matched controls (mean age = 73.0 ± 6.6; 16 females; MMSE = 29.03 ± 1.26, Logical Memory II = 11.70 ± 2.84). There were no significant differences between the two groups with respect to age, gender, or education (Table 1). The mean number of days from baseline to year one was not significantly different between groups (394 ± 25 for AD, and 403 ± 54 for healthy controls). All ADNI participants provided informed written consent approved by each sites' Institutional Review Board. Secondary data use for the current study was approved by the Human Research Ethics Board at the University of Victoria, in British Columbia, Canada.
There were 46 images acquired for each scan: 41 diffusion-weighted images (b = 1000 s/mm2) and 5 non-diffusion-weighted images (b = 0 s/mm2). Repetition time varied across scanning sites, but was approximately 12,500 to 13,000 ms. 2.3. Data analysis 2.3.1. Image preprocessing All data analyses were performed in Functional MRI of the Brain Software Library (FSL) version 5.0 (Analysis Group, FMRIB, Oxford, UK, http://fsl.fmrib.ox.ac.uk; Smith et al., 2004). Diffusion weighted images were corrected for eddy current distortions and head movement using Eddy Correct and non-brain tissue was removed using Brain Extraction Tool (Smith, 2002). Brain-extracted images were then visually inspected to confirm accurate results.
2.2. Image acquisition MRI data were downloaded from the ADNI2 database. All participants underwent whole-brain MRI scans according to the ADNI protocol. Images were acquired from 3 T MRI scanners (GE Medical Systems) from seven North American sites. Axial diffusion weighted image data were acquired with a spin echo planar imaging sequence. Scan parameters are as follows: acquisition matrix = 256 × 256, voxel size = 1.4 × 1.4 × 2.7 mm3, flip angle = 90°, number of slices = 59.
2.3.2. Image analysis FA maps were created using DTIfit and input into Tract-Based Spatial Statistics (TBSS) to obtain a projection of all participants' FA data onto a mean FA skeleton (Smith et al., 2006). First, all participants' FA data were non-linearly aligned to a common space (FMRIB58_FA). Then, the mean FA image was created and thresholded (FA N 0.2) to create the mean FA skeleton. Next, each participant's FA data was projected onto the thresholded mean FA skeleton. Voxelwise statistical analysis
Fig. 2. Results of within-group Tract-Based Spatial Statistics white matter analysis showing pattern of increased mean diffusivity (blue) overlaid on the white matter skeleton (green) at year one compared to baseline in individuals with Alzheimer's disease (panel A) and in healthy controls (panel B; p b 0.05, corrected for multiple comparisons).
of the white matter skeleton was performed using Randomise, FSL's nonparametric permutation inference tool. Threshold free cluster enhancement was used to correct for multiple comparisons (p b 0.05). TBSS was also performed for MD; non-linear registration estimated from the FA images was applied to MD data and each participant's MD image was projected onto the mean FA skeleton before applying voxelwise statistics. 2.3.3. Statistical comparisons Within-group comparisons were made for individuals with AD from baseline to year one, and for healthy controls from baseline to year one. Additionally, between-group contrast comparisons were made between individuals with AD and healthy controls at both baseline and at year one. White matter regions were identified with Johns Hopkins University's white matter atlas available in FSL (Mori et al., 2008; Wakana et al., 2007). 3. Results 3.1. Within-group microstructural white matter changes in individuals with AD and healthy controls at baseline and year one The within-group FA analysis showed that individuals with AD had reductions in FA in multiple regions, including the hippocampal cingulum, at year one compared to baseline (Table 2; Fig. 1A). Healthy controls also had reduced FA in similar regions across time, but these alterations were less extensive (as is visible in Fig. 1), and did not include the hippocampal cingulum (Fig. 1B). There were no significant increases in FA at year one compared to baseline in either group. The within-group MD analysis showed that individuals with AD also had increased MD in multiple regions including the hippocampal
cingulum at year one compared to baseline (Table 2; Fig. 2A). Healthy controls also had increased MD at year one compared to baseline, but once again, these alterations were less extensive than in AD, and did not include the hippocampal cingulum (Fig. 2B). There were no significant decreases in MD at year one compared to baseline in either group. 3.2. Between-group differences in individuals with AD and healthy controls at baseline and year one At baseline, between-group TBSS revealed that individuals with AD had lower FA relative to healthy controls (Table 3; Fig. 3A). At year one, individuals with AD also had lower FA relative to healthy controls, and these alterations appeared more widespread than at baseline (Fig. 3B). The between-group TBSS also revealed that individuals with AD had higher MD relative to healthy controls at baseline (Table 3; Fig. 4A). At year one, individuals with AD had higher MD relative to healthy controls in similar regions as baseline, but there were also patterns of higher MD in the hippocampal cingulum, not seen at baseline (Fig. 4B). No regions demonstrated greater FA or lower MD in HC compared to AD for either time point. 4. Discussion The current study is the first to examine longitudinal white matter changes using DTI data from the ADNI2 cohort. DTI indices of FA and MD were focused on in the current study, given that these are the most commonly reported metrics and can be interpreted in the context of recent literature (Amlien and Fjell, 2014). The primary objective of the current study was to examine longitudinal white matter changes in individuals with AD and healthy aging.
Table 3 Number and percentage of total significant voxels in regions with low fractional anisotropy and high mean diffusivity in individuals with Alzheimer's disease (AD) compared to healthy controls (HC) at baseline and at year one. Baseline White matter regions Corpus callosum Internal capsule External capsule Corona radiata Posterior thalamic radiation Longitudinal fasciculi Fronto-occipital fasciculi Cingulum (white matter of cingulate gyri) Hippocampal cingulum Fornix Corticospinal tract Uncinate fasciculus Tapetum Medial lemniscus Cerebellar peduncle Cerebral peduncle
AD b HC FA
AD N HC MD
4378 (57.9%) 555 (11.6%) 845 (27.2%) 2981 (39.9%) 1233 (55.1%) 909 (28.9%) 0 (0.0%) 597 (61.0%) 351 (90.5%) 339 (49.1%) 0 (0.0%) 70 (58.3%) 38 (95.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
5076 (67.2%) 1264 (26.3%) 927 (29.9%) 5678 (76.0%) 1092 (48.8%) 1826 (58.1%) 2 (20.0%) 423 (43.2%) 0 (0.0%) 297 (43.0%) 0 (0.0%) 43 (35.8%) 39 (97.5%) 0 (0.0%) 0 (0.0%) 9 (0.7%)
6306 (83.0%) 1675 (34.8%) 1800 (58.1%) 3566 (48.1%) 1496 (66.4%) 1535 (48.7%) 0 (0.0%) 856 (90.4%) 142 (35.3%) 581 (85.7%) 70 (11.4%) 94 (77.7%) 36 (97.3%) 251 (64.5%) 1662 (47.1%) 751 (56.9%)
6327 (83.3%) 1468 (30.5%) 1327 (42.8%) 6424 (86.6%) 1096 (48.7%) 2135 (67.7%) 4 (40.0%) 535 (56.5%) 168 (41.8%) 356 (52.5%) 0 (0.0%) 69 (57.0%) 37 (100.0%) 0 (0.0%) 0 (0.0%) 3 (0.2%)
Significant changes in FA and MD were observed both in individuals with AD as well as in healthy controls at one year follow up. As expected, individuals with AD demonstrated decreased FA and increased MD in widespread white matter tracts (see Table 2 and Figs. 1 and 2), including the hippocampal cingulum at year one compared to their baseline assessment. While healthy controls also exhibited decreased FA and increased MD in widespread white matter tracts (see Table 2 and Figs. 1 and 2), these changes were less extensive than those observed in AD participants. Furthermore, healthy controls did not demonstrate FA or MD changes in the hippocampal cingulum as were observed in those with AD. Thus, the relatively widespread changes in larger white matter tracts seen in healthy controls may reflect age-related health factors such as vascular risk factors and the accumulation of other co-morbid health conditions (e.g., Vassilaki et al., 2016). However, changes in microstructural integrity for the hippocampal cingulum over short time intervals (i.e. one year) may more specifically reflect ongoing degenerative process due to AD. The second objective of the current study was to investigate between-group differences in individuals with AD and healthy controls at both baseline and year one. As predicted, significant between-group differences in FA and MD were observed in multiple regions at both time points (Table 3, Figs. 3 and 4), including regions of the medial temporal lobe (e.g., hippocampal cingulum). Such between-group white matter differences are in line with previous cross-sectional studies that have observed DTI alterations in the same regions (i.e. corpus callosum, superior or inferior longitudinal fasciculus; cingulate; cingulum; fornix; and uncinate fasciculus) when comparing individuals with AD to age-matched healthy controls (Agosta et al., 2011; Bosch et al., 2012; Douaud et al., 2011; Lim et al., 2012; Liu et al., 2011; Parente et al., 2008; Salat et al., 2010; Serra et al., 2010; Shu et al., 2011; Sousa Alves et al., 2012; Stricker et al., 2009). Lower FA and higher
MD in AD relative to controls at each time point likely reflects the more extensive and pathological neurodegeneration observed in AD. In particular, lower FA and higher MD in the hippocampal region is consistent with the early pathological progression of AD (Braak and Braak, 1991; Hampel et al., 2014) as well as memory loss as an initial and primary concern (Alzheimer's Association, 2014). Although there have been few longitudinal DTI studies on individuals with AD, our findings are largely consistent with those published to date (Genc et al., 2016; Kitamura et al., 2013; Norwrangi et al., 2013), demonstrating that such findings may be generalizable across AD populations — especially, given ADNI's multi-site collection. Furthermore, these findings are consistent with the pathological progression observed in AD. In particular, the observed decreases in FA and increases in MD likely reflect the progressive loss of the water diffusionrestricting barriers in white matter (e.g., decreased level of myelination, loss of axons) as a consequence of neurodegeneration (Bosch et al., 2012; Kantarci, 2014; Serra et al., 2010). Currently, the mechanisms underlying white matter pathology in AD are not well understood. It is hypothesized that some damage to white matter may occur secondarily to grey matter pathology via Wallerian degeneration, but additional white matter alterations may also occur independent from grey matter pathology, as put forth by the retrogenesis hypothesis, for example (Amlien and Fjell, 2014; Bartzokis et al., 2007). In summary, the current whole brain DTI study found evidence of a higher rate of decline in FA and increase in MD over approximately one year in individuals with AD versus matched healthy controls. These differential changes were seen in a number of white matter regions that correspond to regions know to be affected in AD. Importantly however, these DTI changes were evident in the hippocampal cingulum only in those with AD and not healthy controls, a finding that is
Fig. 3. Results of between-group baseline (panel A) and year one (panel B) Tract-Based Spatial Statistics white matter analysis showing pattern of lower fractional anisotropy (red) overlaid on the white matter skeleton (green) in individuals with Alzheimer's disease compared to healthy controls (p b 0.05, corrected for multiple comparisons).
consistent with the known pattern of progression of AD pathology in the grey matter of medial temporal regions (Braak and Braak, 1991). Volume reduction in the hippocampal grey matter is well documented in previous AD research (Hampel et al., 2014). The current findings suggest there are microstructural alterations in hippocampal white matter as well. It is currently unknown whether microstructural changes can be detected earlier than volumetric changes. Thus, future work should focus on both hippocampal grey and white matter, given that the observed hippocampal changes appear specific to AD relative to aging. A potential limitation of the current study concerns the criteria used to diagnose AD. There are varying definitions of AD, and the inclusion/ exclusion criteria may differ across studies, making cross-study comparisons and generalizations to all individuals with AD challenging. Furthermore, there is heterogeneity in the ADNI AD sample; disease stage may not be equivalent in the baseline scans and there is no pathological verification of diagnosis for all members of the AD cohort. White matter hyperintensities (WMH) of presumed vascular origin were not accounted for in the current analysis. This represents a potential limitation as WMH are common in older adults and have been shown to be related to lower FA and higher MD relative to normal appearing white matter (e.g., Munoz Maniega et al., 2015). However, the ADNI database has previously been shown to have participants with lower levels WMH relative to other large-scale data sources (Ramirez et al., 2016). Future DTI studies in aging populations may consider including WMH to overcome this limitation. Additionally, although the ADNI2 database includes neuroimaging data from individuals diagnosed with mild cognitive impairment (MCI), the current study did not examine this group, as the primary objective was to characterize white matter in AD, specifically.
Approximately 10 to 15 percent of individuals with MCI progress to AD annually (Gong et al., 2013), in contrast to the 1 to 2 percent of healthy older adults who progress to AD per year (Petersen, 2004). Thus, future studies of longitudinal DTI changes in those with MCI may be helpful in determining whether the DTI changes noted in our AD sample represent sensitive and specific neuroimaging biomarkers of AD pathophysiologic processes in individuals in the prodromal stages of this disease. It is important to recognize that MCI cannot be considered synonymous with early AD (Balthazar et al., 2009). As noted by Dubois (2000), MCI applies to a heterogeneous group of aging adults with cognitive concerns, regardless of the underlying etiology or symptom progression. Future studies are likely to require relatively large and well-characterized study samples, longer follow up periods to adequately observe conversion from MCI to AD, as well as multimodal imaging protocols in order to adequately address this issue. Data collection for ADNI2 is currently ongoing. As new data are added to the database, the current findings should provide support for additional analyses of DTI white matter changes to assist in the development of potential biomarkers of AD. Future studies that draw from the ADNI database will benefit from these multi-year longitudinal data (up to five years). Not only will the number of participants in each study group grow as additional participants are recruited, the trajectory of the disease progression can be better tracked across longer time periods as data collection with the current cohort continues. 5. Conclusion A major focus of research on AD centres on the investigation of biomarkers. To date, most studies have focused on changes in grey matter
Fig. 4. Results of between-group baseline (panel A) and year one (panel B) Tract-Based Spatial Statistics white matter analysis showing pattern of mean diffusivity (blue) overlaid on the white matter skeleton (green) in individuals with Alzheimer's disease compared to healthy controls (p b 0.05, corrected for multiple comparisons).
and taken a cross sectional approach. The current study is the first to examine longitudinal white matter changes using the ADNI2 cohort. The results revealed that changes in FA and MD occurred over a one year period in both patients with AD and healthy controls, although the changes were more extensive in AD and more specific to the medial temporal lobe. DTI holds potential as an AD biomarker though multi-year tracking of brain imaging and AD clinical signs at different diagnostic stages are needed to fully evaluate its clinical utility. Ultimately, better characterization of longitudinal microstructural white matter changes may lead to pre-symptomatic detection and better outcomes for individuals with AD. Funding Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The current study was also supported by the Canadian Institutes of Health Research (Competition: 201310): Catalyst Grant for the Secondary Analyses of Neuroimaging Databases and the Canada Graduate Scholarships [grant number CSE 133352]; Natural Sciences and Engineering Research Council of Canada [grant number PDF-454132-2014] and CREATE; Alberta Innovates - Health Solutions [grant number 201300567]. Acknowledgements Thank you to Dr. Mauricio Garcia-Barrera for the thoughtful comments during the writing of this manuscript. References Acosta-Cabronero, J., Nestor, P.J., 2014. Diffusion tensor imaging in Alzheimer's disease into the limbic-diencephalic network and methodological considerations. Front. Aging Neurosci. 6, 1–21. Agosta, F., Pievani, M., Sala, S., Geroldi, C., Galluzzi, S., Frisoni, G., Filippi, M., 2011. White matter damage in Alzheimer disease and its relationship to gray matter atrophy. Neuroradiology 258, 853–863. Alexander, A.L., Lee, J.E., Lazar, M., Field, A.S., 2007. Diffusion tensor imaging of the brain. Neurotherapeutics 7, 316–329. Alzheimer's Disease Neuroimaging Initiative, 2008. ADNI 2 Procedures Manual. Retrieved from. https://adni.loni.usc.edu/wp-content/uploads/2008/07/adni2-proceduresmanual.pdf. Alzheimer's Association, 2014. 2014 Alzheimer's disease facts and figures. Alzheimers Dement. 10, e47–e92. Amlien, I.K., Fjell, A.M., 2014. Diffusion tensor imaging of white matter degeneration in Alzheimer's disease and mild cognitive impairment. Neuroscience 276, 206–215.
Balthazar, M.L.F., Yasuda, C.L., Pereira, R.F., Pedro, T., Damasceno, B.P., Cendes, F., 2009. Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease. Eur. J. Neurol. 16, 468–474. Bartzokis, G., Lu, P.H., Mintz, J., 2007. Human brain myelination and amyloid beta deposition in Alzheimer's disease. Alzheimers Dement. 3, 122–125. Beach, T.G., Monsell, S.E., Phillips, L.E., Kukull, W., 2012. Accuracy of the clinical diagnosis of Alzheimer's disease at National Institute on Aging Alzheimer's disease centers. J. Neuropathol. Exp. Neurol. 71, 266–273. Bosch, B., Arenaza-Urquijo, E.M., Rami, L., Sala-Llonch, R., Junque, C., Sole-Padulles, C., Pena-Gomex, C., Bargall, N., Molinuevo, J.L., Bartres-Fax, D., 2012. Multiple DTI index analysis in normal aging, amnestic MCI and AD: relationship with neuropsychological performance. Neurobiol. Aging 33, 61–74. Braak, H., Braak, E., 1991. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259. Burzynska, A.Z., Preuschhof, C., Backman, L., Nyberg, L., Li, S.C., Lindenberger, U., Heekeren, H.R., 2010. Age-related differences in white matter microstructure: region-specific patterns of diffusivity. NeuroImage 49, 2104–2112. Cash, D.M., Rohrer, J.D., Ryan, N.S., Ourselin, S., Fox, N.C., 2014. Imaging endpoints for clinical trials in Alzheimer's Disease. Alzheimers Res. Ther. 6, 1–10. Douaud, G., Jbabdi, S., Behrens, T.E., Menke, R.A., Monsch, A.U., Rao, A., Whitcher, B., Kindlmann, G., Matthews, P.M., Smith, S., 2011. DTI measures in cross-fibre areas: increased diffusion anisotropy reveals early white matter alternation in MCI and mild Alzheimer's disease. NeuroImage 55, 880–890. Dubois, B., 2000. Prodromal Alzheimer's disease: a more useful concept than mild cognitive impairment? Curr. Opin. Neurol. 13, 367–369. Dubois, B., Feldman, H., Jacova, C., Cummings, J.L., DeKosky, S.T., Barberger-Gateau, P., Delacourte, A., Frisoni, G., Fox, N.C., Galasko, D., Gauthier, S., Hampel, H., Jicha, G.A., Meguro, K., O'Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, S., Sarazin, M., de Souza, L.C., Stern, Y., Visser, P.J., Scheltens, P., 2010. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 9, 1118–1127. Genc, S., Steward, C.E., Malpas, C.N.B., Velakoulis, D., O'Brien, T.J., Desmond, P.M., 2016. Short-term white matter alterations in Alzheimer's disease characterized by diffusion tensor imaging. J. Magn. Reson. Imaging 3, 627–634. Gold, B.T., 2012. White matter integrity and vulnerability to Alzheimer's disease: preliminary findings and future directions. Biochim. Biophys. Acta 1822, 416–422. Gong, N., Wong, C., Chan, C., Leung, L., Chu, Y., 2013. Correlations between microstructural alterations and severity of cognitive deficiency in Alzheimer's disease and mild cognitive impairment: a diffusional kurtosis imaging study. Magn. Reson. Imaging 31, 688–694. Hampel, H., Lista, S., Teipel, S.J., Garaci, F., Nistico, R., Blennow, K., Zetterberg, H., Bertram, L., Duyckaerts, C., Bakardijan, H., Drzezga, A., Colliot, O., Epelbaum, S., Broich, K., Lehericy, S., Brice, A., Khachaturian, Z.S., Aisen, P.S., Dubois, P.S., 2014. Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: a long-range point of view beyond 2020. Biochem. Pharmacol. 88, 426–449. Hardy, J.A., Higgins, G.A., 1992. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185. Kantarci, K., 2014. Fractional anisotropy of the fornix and hippocampal atrophy in Alzheimer's disease. Front. Aging Neurosci. 6, 1–4. Kitamura, S., Kiuchi, K., Taoka, T., Hashimoto, K., Ueda, S., Yasuno, F., Morkawa, M., Kichikawa, K., Kishimoto, 2013. Longitudinal white matter changes in Alzheimer's disease: a tractography-based analysis study. Brain Res. 1515, 12–18. Lim, H.K., Kim, S.J., Choi, C.G., Lee, J., Kim, S.Y., Kim, H.J., Kim, N., Jahng, G., 2012. Evaluation of white matter abnormality in mild Alzheimer disease and mild cognitive impairment using diffusion tensor imaging: a comparison of tract-based spatial statistics with voxel-based morphometry. J. Korean Soc. Magn. Resonan. Med. 16, 115–123. Liu, Y., Spulber, G., Lehtimaki, K.K., Kononen, M., Hallikainen, I., Grohn, H., Kivipelto, M., Hallikain, M., Vanninen, R., Soininen, H., 2011. Diffusion tensor imaging and tractbased spatial statistics in Alzheimer's disease and mild cognitive impairment. Neurobiol. Aging 32, 1558–1571. Lockhart, S.N., Decarli, C., 2014. Structural imaging measures of brain aging. Neuropsychol. Rev. 24, 271–289. Munoz Maniega, S., Valdes Hernandez, M.C., Clayden, J.D., Royle, N.A., Murray, C., Morris, Z., Aribisala, B.S., Gow, A.J., Starr, J.M., Bastin, M.E., Deary, I.J., Wardlaw, J.M., 2015. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol. Aging 36, 909–918. McKhann, G., Drachman, D., Folster, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Service task force on Alzheimer's disease. Neurology 34, 939–944. Mori, S., Oishi, K., Jiang, H., Jiang, L., Li, X., Akhter, K., Hua, K., Faria, A.V., Mahmood, A., Woods, R., Toga, A., Puke, B., Rosa Neto, P., Evans, A., Zhang, J., Huang, H., Miller, M.I., van Zijl, P., Mazziotta, J., 2008. Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. NeuroImage 40, 570–582. Norwrangi, M.A., Lyketsos, C.G., Leoutsakos, J.M.S., Oishi, K., Albert, M., Mori, S., Mielke, M.M., 2013. Longitudinal, region-specific course of diffusion tensor imaging measures in mild cognitive impairment in Alzheimer's disease. Alzheimers Dement. 9, 519–528. Parente, D.B., Gasparetto, E.L., Celso Hygino, d., Cruz, L., Cortez Domingues, R., Baptistta, A.C., Carvalho, A.C.P., Cortes Domingues, R., 2008. Potential role of diffusion tensor MRI in the differential diagnosis of mild cognitive impairment and Alzheimer's disease. AJ. Am. J. Roentgenol. 190, 1369–1374. Perl, D.P., 2010. Neuropathology of Alzheimer's disease. Mt Sinai J. Med. 77, 32–42. Petersen, R.C., 2004. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194. Ramirez, J., McNeely, A.A., Scott, C.J.M., Masellis, M., Black, S.E., Alzheimer's Disease Neuroimaging Initiative, 2016. White matter hyperintensity burden in elderly cohort
studies: The Sunnybrook Dementia Study, Alzheimer's Disease Neuroimaging Initiative, and three-city study. Alzheimers Dement. 12, 203–210. Salat, D.H., Tuch, D.S., van der Kouwe, A.J.W., Greve, D.N., Pappu, V., Lee, S.Y., Hevelone, N.D., Zaleta, A.K., Growdon, J.H., Corkin, S., Fischel, B., Rosas, H.D., 2010. White matter pathology isolates the hippocampal formation in Alzheimer's disease. Neurobiol. Aging 31, 244–256. Serra, L., Cercignani, M., Lenzi, D., Perri, R., Fadda, L., Caltagirone, C., Macaluso, E., Bozzali, M., 2010. Grey and white matter changes at different stages of Alzheimer's disease. J. Alzheimers Dis. 19, 147–159. Sexton, C.E., Kalu, U.G., Filippini, N., MacKay, C.E., Ebmeier, K.P., 2011. A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease. Neurobiol. Aging 32, 2322.e5–2322.e18. Shu, N., Wang, Z., Qi, Z., Li, K., He, Y., 2011. Multiple diffusion indices reveals white matter degeneration in Alzheimer's disease and mild cognitive impairment: a tract-based spatial statistics study. J. Alzheimers Dis. 26, 275–285. Smith, S.M., 2002. Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143–155. Smith, S.M., Jenkinson, M., Woolrich, M.W., Beckmann, C.F., Behrens, T.E.J., Johansen-Berg, H., Bannister, P.R., De Luca, M., Drobnjak, I., Flitney, D.E., Niazy, R.K., Saunders, J., Vickers, J., Zhang, Y., De Stefano, N., Brady, J.M., Matthews, P.M., 2004. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23, S208–S219. Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Zaheer Cader, M., Matthews, P.M., Behrens, T.E.J., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31, 1487–1505. Soares, J.M., Marques, P., Alves, V., Sousa, N., 2013. A hitchhiker's guide to diffusion tensor imaging. Front Neurosci. 7, 1–14. Sousa Alves, G.S., O'Dwyer, L., Jurcoane, A., Oertel-Knochel, V., Knochel, C., Prvulovic, D., Sudo, F., Alves, C.E., Valente, L., Moreira, D., Fuber, F., Karakaya, T., Pantel, J., Engelhardt, E., Laks, J., 2012. Different patterns of white matter degeneration using
multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients. PLoS One 7, e52859. Stebbins, G.T., Murphy, C.M., 2009. Diffusion tensor imaging in Alzheimer's disease and mild cognitive impairment. Behav. Neurol. 21, 39–49. Stricker, N.H., Schweinsburg, B.C., Delano-Wood, L., Wierenga, C.E., Bangen, K.J., Haaland, K.Y., Frank, L.R., Salmon, D.P., Bondi, M.W., 2009. Decreased white matter integrity in late-myelinating fibre pathways in Alzheimer's disease supports retrogenesis. NeuroImage 45, 10–16. Stoub, T.R., deToledo-Morrell, L., Dickerson, B.C., 2014. Parahippocampal white matter volume predicts Alzheimer's risk in cognitively normal old adults. Neurobiol. Aging 35, 1855–1861. Teipel, S.J., Meindl, T., Wagner, M., Stieltjes, B., Reuter, S., Hauenstein, K.H., Filippi, M., Ernemann, U., Reiser, M.F., Hampel, H., 2010. Longitudinal changes in fiber tract integrity in healthy aging and mild cognitive impairment: a DTI follow-up study. J. Alzheimers Dis. 22, 507–522. Vassilaki, M., Aakre, J.A., Mielke, M.M., Geda, Y.E., Kremers, W.K., Alhurani, R.E., Machulda, M.M., Knopman, D.S., Petersen, R.C., Lowe, V.J., Jack, C.R., Roberts Jr., R.O., 2016. Multimorbidity and neuroimaging biomarkers among cognitively normal persons. Neurology 86, 2077–2084. Wakana, S., Caprihan, A., Panzenboeck, M.N., Fallon, J.H., Perry, M., Gollub, R.L., Hua, K., Zhang, J., Jiang, H., Dubey, P., Blitz, A., van Zijl, P., Mori, S., 2007. Reproducibility of quantitative tractography methods applied to cerebral white matter. NeuroImage 36, 630–644. Wang, L., Benzinger, T.L., Su, Y., Christensen, J., Friedrichsen, K., Aldea, P., McConathy, J., Cairns, N.J., Fagan, A.M., Morris, J.C., Ances, B.M., 2016. Evaluation of tau imaging in staging Alzheimer's disease and revealing interactions between b-amyloid and taupathy. JAMA Neurol. [epub ahead of print]. World Health Organization, 2016. Dementia Fact Sheet. WHO Media Centre. http://www. who.int/mediacentre/factsheets/fs362/en/.
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Women get their periods every month — and it's incredibly expensive
Jane Onyanga-Omara
LONDON – Scotland could become the first country to ban "period poverty" to help women and girls who can't afford feminine hygiene products such as maxi-pads and tampons.
The issue is rarely spoken about in public, but it affects millions of women and girls around the world, including the United States.
At least 500 million women and girls are estimated to lack the means to manage their monthly periods, according to a 2015 report by UNICEF and the World Health Organization. Many drop out of school or miss days of class as a result.
In Britain, the problem came to the forefront with a 2015 petition calling for the government to ax the "tampon tax" — a 5% sales tax on sanitary products. The government voted the following year to scrap the tariff, but it hasn't been dropped — caught up in Brexit negotiations to separate from the European Union.
In the USA, most states charge sales tax for women's pads and tampons. Nine states have dropped the tampon tax — Minnesota, Illinois, Pennsylvania, New York, Massachusetts, Maryland, New Jersey, Connecticut and Florida, according to NPR. Seven other states have introduced such legislation, most recently Nebraska, Virginia and Arizona.
An attempt in California to eliminate a tax on tampons failed in January.
Women for Independence, a Scottish grass-roots group, published a survey in March that said nearly one in five women in Scotland have been unable to afford sanitary products and improvised with such items as newspapers, toilet paper, socks and old clothes.
One in 10 British girls and women ages 14 to 21 cannot afford sanitary protection, according to the humanitarian charity Plan International U.K.
Monica Lennon, a lawmaker from Scotland's opposition Labour Party, plans to introduce a bill that would allow anyone in need to get free sanitary products at food banks, schools, colleges and universities. A six-month pilot program began in July.
"Women in general don't talk about their periods and how they manage them," Lennon told USA TODAY. "I'm glad it's out in the open."
She noted that condoms and other forms of contraception can be accessed free in Scotland and the rest of Britain, so "why can't we get that for pads and tampons?"
Lennon said that once the problems were explained to her male colleagues, they were "quite horrified" and then supportive.
Progress has been made in Wales, where the Welsh government announced in March $1.4 million to help address period poverty.
Tina Leslie, a public health worker from Leeds in northern England, started Freedom4Girls to deliver washable, reusable sanitary packs to Kenyan women and girls two years ago.
"Last year, a colleague of mine who knew what I was doing in Kenya said: 'Do you realize it's happening in your own city? I've got five girls who are missing school because their parents don't have money to buy sanitary protection.' I thought, 'Let me do something about it.'"
The charity now collects and delivers environmentally friendly washable pads and menstrual cups to schools, refugee agencies and women's shelters in Leeds and has set up stations so the public can donate products in supermarkets and offices.
"If you can't afford food, you can't afford sanitary protection," Leslie said.
Camilla Wirseen set up the Cup Foundation to provide menstrual cups to girls in Kenya. She says the foundation has helped about 15,000 girls with the cups, which last for 10 years.
Wirseen, from Sweden, lives in Kenya's capital, Nairobi. She said she founded the organization in 2015 after learning that up to half of the girls in the Nairobi slums have sex in return for pads.
"Poverty is poverty wherever you are. If you can't afford it, you can't afford it," Wirseen said. "The menstrual cup shouldn't be something you hide."
Men have an important role to help end period poverty. "We try to take away the taboo of menstruation — for me that means including men," Wirseen said.
In India, Arunachalam Muruganantham was shocked to find his wife used rags during her periods. That prompted him to invent a simple pad-making machine so women in rural areas could make their own affordable sanitary protection. His story has been turned into a Bollywood movie, Pad Man.
"Why aren't we talking about it?" Leslie said. "Half the population in the world menstruates. Boys want to know what their girlfriends are going through, and men want to know what their wives are going through."


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Top Freelance Websites For Beginners
Are you looking to quit your 9 to 5 job and work as a freelancer? It has never been a better time to start out as an entrepreneur or freelancer in India. The population of freelancers is growing across India as the next generation is looking for flexible working hours and creative working environments. Co-working hubs have opened in Bangalore, Mumbai and Delhi to cater to this niche emerging segment.
The average freelancer in India is in his mid 20's and earns between Rs 20,000 to Rs 30,000 every month. Their population is concentrated in the urban areas of Delhi NCR, Mumbai, Bangalore, Hyderabad and Chennai. Most of these youth bid for projects online on marketplaces. Once they bag a project, they focus on completing the project and getting paid.
The top category of freelancer jobs online are in data entry work, logo and graphic design, web design, building mobile apps, software development, digital marketing and search engine marketing. Anybody can start working on these project once you sign up at different portals.
Freelancer – https://www.freelancer.com
The company began it's operations in 2009 and has it's headquarters in Sydney, Australia.. Most of Freelancer.com users come from the US, India, Philippines and Pakistan. In the last couple of years, the parent company has acquired more than a dozen different domain names targeted at niche overseas markets. The company also owns escrow.com. Freelancer.com is the market leader and competes with Upwork.com for the top freelancer website in the world.
Guru – http://www.guru.com
Guru.com was initially founded in 1998 in Pittsburgh as eMoonlighter.com. The website boasts of more than 1.5 million registered freelancers who are listed in their directories. It is by far the most popular website among newbies who are still learning to freelance. You will meet many experienced professionals on this website from whom you can learn the tricks of the trade.
People Per Hour – https://www.peopleperhour.com
Has a community of curated experts who are willing to work remotely on your projects at the click of a button. The UK based company was founded in 2007 by Xenios Thrasyvoulou and Simos Kitiris. The company was named among Europe's top 100 hottest startups in 2012. The companies focus is on getting your work done at the earliest at the cheapest possible rate.
Toptal – https://www.toptal.com
Toptal claims to be an exclusive network of only the best freelance developers and designers. The company counts Hewlett Packard, Airbnb, JP Morgan, Emirates, Zendesk and Pfizer as some it's clients. The company seeks to help both small and large companies in finding the best talent without straining their financial resources. It does this by providing a no-risk trial to companies looking to hire freelancers on it's website.
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Why Compensation Committees Need Your Help
CPAs can play an important role in developing effective pay policies.
BY RANDY MYERS
WHETHER WORKING IN THE FINANCE DEPARTMENT of a public company or advising that company as an outside consultant, CPAs are in a unique position to guide compensation committees in their role as corporate overseers and to help them better align compensation practices with shareholder interests.
CPAs CAN ADD VALUE TO COMPENSATION COMMITTEES in these four areas: helping to ensure compliance with relevant laws and regulations, setting performance goals and benchmarks for the incentive portion of executive pay packages, calculating the value of stock options where companies treat options as expenses on income statements and evaluating alternatives to traditional stock option payouts.
CPAs WON'T BE ABLE TO ADVISE some clients on compensation matters. The Sarbanes-Oxley Act of 2002 prohibits CPAs from providing many nonaudit services to their audit clients, including management or human resources functions, appraisal or valuation services, "expert services" unrelated to the audit and any other service the soon-to-be-created oversight board finds impermissible.
CPAs CAN HELP COMPENSATION COMMITTEES set the performance goals to which incentive pay is linked. CPAs also can assist in calculating any adjustments to bonus payouts that may be required due to circumstances outside the CEO's control.
THE INTERNATIONAL ACCOUNTING STANDARDS BOARD has already proposed that companies using its standards start expensing stock options in 2004, and FASB said it will consider revisiting the issue and produce its own proposal.
RANDY MYERS is a freelance financial writer who lives in Dover, Pennsylvania. His e-mail address is randy@randymyers.net .
ompanies have yet to solve the riddle of executive compensation—at least to the satisfaction of investors and legislators. Dismayed by reports of CEOs cashing in stock options worth millions of dollars amid a tumbling stock market and a rash of corporate scandals, Congress and financial market regulators have introduced new rules designed to make it harder for top executives at public companies to reap windfall profits at shareholders' expense .
Executive stock option programs—hailed in the 1990s as the best way to align the interests of executives with those of shareholders—face a growing public outcry. This new climate presents a raft of challenges for board members who serve on compensation committees and for the CPAs who advise them. Whether working in the finance department of a public company or acting as an outside consultant, CPAs are in a unique position to guide compensation committees in their role as corporate overseers and to help them design and implement pay packages more in line with shareholder interests.
Compensation committees draw their members from the ranks of nonmanagement directors. They are responsible for setting the compensation packages of the CEO, other senior executives and for the directors themselves. In addition, they approve the size of the bonus pool for the remainder of the workforce, allowing management to decide how to allocate that money. The committee also determines how far down in the employment ranks to extend incentive compensation such as stock option awards. Finally, compensation committees must decide how to use a company's pay philosophy to best advance its overall business principles and goals.
Top Executive Pay
Of the 100 top performing companies in the S&P 500 stock index, annual net total compensation for CEOs ranged from $6 million to $13.5 million.
Source: Compensation Committee Handbook, by James F. Reda, John Wiley & Sons Inc., Hoboken, New Jersey, reda.jf@buckconsultants.com , 2002.
CPAs who advise compensation committees can add value to these undertakings in four distinct areas:
Helping to ensure the committee acts in compliance with the latest laws and regulations.
Setting the performance goals and benchmarks that are the basis for the incentive portion of most executive pay packages.
Calculating the value of traditional stock options for the growing number of companies electing to treat the issuance of options as an expense on their income statement.
Considering alternatives—in terms of their costs and tax implications—to traditional stock option awards.
FOLLOW NEW LEGISLATION
Compensation committees work in a complex and ever changing environment and need expert accounting and legal advice. Thus a critical task for CPAs who counsel them is to keep abreast of pertinent laws and regulations. Compensation committee conduct became even more sharply circumscribed on July 30 when President Bush signed the Sarbanes-Oxley Act of 2002. Besides sweeping reforms affecting public company audits and how such companies conduct business, the act bans a formerly common practice whereby companies granted, and their boards approved, loans to executives. (For more information see " Regulations Under the Sarbanes-Oxley Act, " JofA , Oct.02, page 33.)
Under section 402(a) of the act, it is illegal for public companies to extend credit, directly or indirectly, to directors or officers, except for certain loans available to the general public in the ordinary course of the company's business. (A bank, for example, can still provide mortgages to its officers and directors.) But virtually all of the loans commonly found in executive compensation packages appear to be prohibited, such as those made to help an executive purchase company stock, fund a split-dollar life insurance arrangement, meet an extraordinary expense or relocate. Because the specific intent of the act is unclear in this area, CPAs must wait for interpretive guidance from regulators.
If a company must restate its financial statements due to its failure to comply with disclosure requirements, section 304 of the act requires the CEO and CFO to forfeit any bonuses, incentive or equity-based compensation, as well as any profits from the sale of the company's securities, within the year after the company issues any noncompliant financial statement.
Other new regulations are on the horizon. In August the New York Stock Exchange filed proposed new "corporate accountability" rules with the SEC. (For more information on the new NYSE listing standards, see www.nyse.com/about/report and " NYSE Sets Audit Committees on New Road, " JofA , Nov.02, page 51). These amendments to its listing requirements—if the SEC approves them—would
Require public company boards to have a compensation committee that is composed entirely of independent directors, with tough new definitions for what constitutes independence.
Mandate the committee have a written charter and produce an annual report on executive compensation for inclusion in the company's annual proxy statement.
Specify that compensation committees must consider their companies' performance and relative shareholder returns when setting executive pay.
Provide shareholders the opportunity to vote on all equity compensation plans, except inducement awards and option plans in a merger or acquisition. In situations where equity-based compensation plans don't require shareholder approval, the compensation committee must OK them.
Give the compensation committee the sole authority to retain and terminate any compensation consulting firm and approve its fees and contract terms.
Congress has still more legislation in mind. Senators Carl Levin (D-Michigan) and John McCain (R-Arizona) have sponsored a bill (S 1940) that would require a company to treat stock options on its tax returns the same way it treats them on its financial statements. (Currently, companies can take a tax deduction for the value of options without recording them as an expense on their income statement.) "It's a new ball game," concludes Jim Reda, a principal and compensation practice leader with Buck Consultants in Atlanta. With all of the new rules and pending legislation, "there are a lot more things CPAs need to be knowledgeable about." (See " Where to Go for Help, " at the end of this article.)
Foremost on that list is understanding that CPAs won't be able to advise some clients on compensation matters. Sarbanes-Oxley prohibits CPAs from providing many nonaudit services to audit clients, including management or human resources functions, appraisal or valuation services, "expert services" unrelated to the audit and any other service the Public Company Accounting Oversight Board (PCAOB) finds impermissible. Given the vagueness of that language, says Steven Schaffer, a partner with the law firm Powell Goldstein Frazer & Murphy LLP in Atlanta, it's difficult to say with certainty the degree to which the new law prohibits CPAs from advising audit clients on compensation issues. This provision of Sarbanes-Oxley won't take effect until 180 days after the PCAOB is up and running—which isn't expected until April of 2003. "In the current climate, and with the volatile issues facing the accounting profession right now, I think CPAs have to be very circumspect in rendering these additional services," Schaffer says.
Of course, CPAs who work for audit firms would still be able to provide consulting services to companies that are not audit clients, as would CPAs who work for compensation consultants and in corporate finance departments.
SET GOALS AND BENCHMARKS
Most public company CEOs and other senior executives have four components to their pay packages: an annual salary, an annual incentive bonus pegged to short-term corporate performance, a long-term incentive program typically structured around the issuance of stock options and a nonqualified deferred compensation program which supplements qualified retirement plan benefits. CPAs can help compensation committees establish the performance goals incentive pay is linked to, says Mike Kesner, CPA, an executive compensation consultant and managing partner of the Chicago office of Deloitte & Touche. For example, suppose a company wants to pay its CEO a bonus only if the company's performance exceeds a specified measure such as the average earnings-per-share gain of comparably sized companies in the same industry. CPAs can advise the compensation committee on which companies to include in that peer group and also handle the calculations necessary to figure out how the client company performed relative to the peer group.
CPAs also can help calculate any adjustments to bonus payouts that may be required due to circumstances outside the CEO's control, such as a fire in a major production facility that had a negative impact on earnings. Because a company's directors are responsible for making such decisions, "whether the CPA has any business opining on making the adjustment is debatable," Kesner says. "However, these bonus plans often provide for many discretionary adjustments and a lot of financial analysis needs to be done as a result; somebody has to objectively handle those adjustments." He also says that under IRC section 162(m)(4)(C)(iii), compensation committees, in awarding a performance-based bonus, must certify the company met the relevant performance goals. Here, too, CPAs can be of service. "Compensation committees don't crunch the numbers themselves," Kesner explains. "They typically use an internal CPA to calculate the numbers and then the compensation committee signs off on them."
CALCULATE STOCK OPTION VALUES
The vast majority of public companies follow APB Opinion no. 25, Accounting for Stock Issued to Employees, in accounting for employee incentive stock options. Under Opinion no. 25, as subsequently clarified by FASB Interpretation no. 44, Accounting for Certain Transactions Involving Stock Compensation, a company calculates the cost of those options based on their intrinsic value—the difference between the strike price of the option and the market value of the stock. Since most options are issued "at the market," they have no intrinsic value on the date of issuance, so the cost to the company is zero.
In 2002, however, bowing to pressure from shareholder activists and high-profile leaders such as Warren Buffet, several dozen companies announced they would begin to voluntarily count the fair value of stock options, not the intrinsic value, as an expense on their income statement. They include Coca-Cola, General Electric, Citigroup and Procter & Gamble. FASB Statement no. 123, Accounting for Stock-Based Compensation, recommends this approach but allows companies that comply with Opinion no. 25 and Interpretation no. 44 to merely disclose in the notes to the financial statements what the effect on net income and earnings per share would have been if they had expensed the options at fair value.
Many accounting experts think it is only a matter of time before companies will have to report stock options as an expense at fair value. The International Accounting Standards Board (IASB), for example, has already proposed that companies using its standards start expensing stock options in 2004, and FASB said it will consider revisiting the issue and produce its own proposal. In any event the current trend already is creating demand for the services of CPAs who can calculate the value of executive stock options and suggest economically viable alternative compensation strategies now that some companies have decided to expense options.
Unfortunately, compensation experts find valuing executive stock options isn't as straightforward as valuing options traded in the financial markets. The Black-Scholes model is the most commonly used strategy to value exchange-traded options, but that method doesn't factor in some of the complicating features of executive options, such as their illiquidity and the vesting requirements most incorporate. Partly for that reason, Coca-Cola, in announcing it would expense stock options beginning in the fourth quarter of 2002, also said it would not use Black-Scholes. Instead, the company said it would hire two independent financial institutions to calculate, as best they could, a fair market value for the options.
Whatever method financial advisers use, a company's decision to expense stock options at fair value immediately raises another issue for the compensation committee: what alternative pay programs it should consider. "The primary reason stock options became so popular was because of the lack of an accounting charge," observes James Scannella, a CPA and associate principal with Buck Consultants in New York City. "Once you've accepted the accounting charge, that puts options pretty much on a level playing field with other incentives. The tax field is also quite level, meaning companies that expense options will be free to pick the incentive that makes the most sense for their business. That's the way it should be, with tax and accounting issues very much in the background," says Scannella.
EVALUATE ALTERNATIVES
CPAs can recommend an alternative to issuing plain vanilla options—options with a fixed strike price equal to the market price on the date of issue—by suggesting a company issue options indexed to the performance of a stock-market benchmark, whether a custom index of peer group companies, a third-party industry index or a broad-market measure such as the S&P 500. With this type of option, the strike price—the price at which the executive can exercise the option—moves up in lockstep with the specified index. Accordingly, the option becomes worth exercising only if the company's stock outperforms the index. This eliminates complaints from investors and corporate governance experts that even mediocre corporate performance can result in handsome rewards for stock-option recipients when the stock market as a whole is rising.
To date, relatively few companies have issued indexed options because of their accounting treatment. APB no. 25 requires charging the intrinsic value of indexed options against the issuing company's earnings each year. However, if companies adopt the preferred method under Statement no. 123 and expense options in the year they issue them, the variable accounting requirement is eliminated. With that concern out of the way, employers and shareholders find they generally prefer performance-linked options, since they pay only for exceptional, above-market results. For that reason these options also have less value upon issuance and result in a lower charge to earnings than fixed-price options. Companies can choose to issue standard fixed-price options with a strike price higher than the stock's current market price—postponing the point at which variable accounting treatment is required.
Yet another compensation alternative is to issue stock itself rather than options. Although there is no universal agreement on the matter, many shareholder activists and corporate governance gurus argue that stock, especially restricted stock (the recipient cannot sell it for a predetermined period of time), better than options aligns the interests of executives and shareholders. Their argument is that options present the executive only with upside potential, since they either go up in value or expire worthless, while stock offers both an upside and a material downside. With stock the executive "feels the pain" of a declining stock price along with other shareholders. On a share-for-share basis, restricted stock will have far greater value than any type of stock option. CPAs advising compensation committees will want to point this out so companies switching to restricted stock awards can reduce the size of the award, on a per-share basis, by an appropriate amount.
RIDE HERD ON CHANGE
CPAs who stay on top of changing rules and shifting public opinion will find they can help compensation committees with what John Boma, CPA and senior vice-president at Mullin Consulting, a Minneapolis-based benefits consultant, says may be their biggest challenge—simply to take advantage of the new climate to better adjust compensation philosophy with corporate culture. "Take the issue of stock options," says Boma. "Three years ago companies often had to dump options on people just to attract and retain key executives. For many it was more a matter of keeping up with the Joneses than an expression of corporate culture. Now they have a chance to make compensation programs fit corporate goals." One example: A high-tech company subject to volatile year-over-year performance may favor stock options with strike prices well above the current market price as a way to encourage management to meet lofty goals. A more conservative company in a less volatile industry may prefer to issue either options priced at the market or restricted stock.
"Compensation committees really have to take a step back and ask themselves what is reasonable for the company to pay its executives," says Judy Thorp, a CPA and Chicago-based partner of KPMG LLP in charge of the firm's Midwest compensation and benefits practice. "The whole concept of reasonableness has gotten little attention in the last several years."
Boma, like many other compensation experts, does not foresee a material decline in what CEOs and other top executives receive in the form of salary over the next few years. But he does anticipate a decline in total compensation for two reasons: The weak economy likely will lead to lower incentive-linked bonus payouts, and outstanding stock options are less likely to produce outsized gains now that the stock market no longer is banging out double-digit returns.
By helping compensation committees understand the issues that are driving executive pay trends today, as well as the alternative solutions available, CPAs can guide them through this new and rocky terrain in 2003 and beyond. This is an important task because the stakes are so high. Investor confidence in management depends on setting compensation at fair levels. And compliance with new laws and regulations is crucial as Congress, the SEC and other regulators focus increased attention on corporate governance, of which compensation is only one small, albeit very important, part.
These organizations offer information about compensation issues, corporate governance, the role of the board and independent directors and various shareholder issues.
The American Society
for Corporate Secretaries 521 Fifth Ave.
New York, NY 10175 212-681-2000 www.ascs.org
Business Roundtable 1615 L St. NW
Washington, D.C. 20037 202-872-1260 www.brt.org
California Public Employees
Retirement System (CalPERS) Lincoln Plaza
400 P St.
Sacramento, CA 96814 916-326-3000 www.calpers.org
The Corporate Library 1200 G St. NW
Washington, D.C. 20005 202-434-8723 www.thecorporatelibrary.com
Council of Institutional
Investors 1730 Rhode Island Ave. NW
Washington, D.C. 20036 202-822-0800 www.cii.org
Investor Responsibility
Research Center 1350 Connecticut Ave.
Washington, D.C. 20036 202-833-0700 www.irrc.org
Nasdaq 1500 Broadway
New York, NY 10036 212-858-5200 www.nasdaq.com
National Association of
Corporate Directors 1707 L St. NW
Washington, D.C. 20036 202-775-0509 www.nacdonline.org
Stock Plan Professionals P.O. Box 21639
Concord, CA 94521 925-685-9271 www.naspp.com
The National Center for
Employee Ownership 1736 Franklin St.
Oakland, CA 94612-1217 510-208-1300 www.nceo.org
National Investor
Relations Institute 8045 Leesburg Pike
Vienna, VA 22182 703-506-3570 www.niri.org
New York Stock Exchange 11 Wall St.
New York, NY 10005 212-656-3000 www.nyse.com
TIAA-CREF 730 Third Ave.
New York, NY 10017 212-490-9000 www.tiaa-cref.org