Thursday, 31 July 2008

The Long Good-Bye - A World News America Series on Alzheimer's

The Long Good-bye – Part 1: The First Instalment in a World News America Series on Alzheimer's Looks at Hope Behind New Research.


The old lady stared blankly, not a hint of recognition on her face.


Next to her on the bed sat two of her closest relatives - her daughter and grandson.


They hugged her, teased her, squeezed her hand: nothing.


They talked of hobbies, and pets, and adventures from her past: not a word.


Then - briefly - the haunted expression grew into a smile and both planted kisses on her pallid skin.

For Dianne Kerley and her son Mike it was the best they could hope for.


Fifteen years ago Dianne's 78-year-old mother Flossie (Mike's grandmother) was diagnosed with Alzheimer's disease.


Since then she has lost not only her memory, but the ability to look after herself, as well as the ability to walk and talk.


Dianne and Flossie Kerley's long struggle with Alzheimer's.


Traumatic deterioration


They say that Alzheimer's begins with forgetting your keys and ends with you forgetting what your keys are for, but it is a whole lot worse than that.


Before long Flossie's sense of balance and co-ordination will be compromised.


In the final stages of the disease so too will her ability to breathe.


Until then all Dianne and Mike can do is undertake a heartbreaking weekly pilgrimage to a nursing home in eastern Missouri and watch her fade away before their eyes.


"It was two years ago - at Thanksgiving," said Dianne, recalling the last time her mother recognised her.


"Ten or 12 seconds and then it was gone."


"She was like: 'Well hi! How are you?' and I'm like: 'Well, we sure do miss you,' and she was like: 'You do?. Then all of a sudden the fog just went over - and that was it."


It is difficult to imagine a slower, more agonising death.


Alzheimer's leaves the patient a prisoner in their own body whilst systematically eroding everything about them that makes them human.


What should be the golden years are marked by blank stares and tragically unrequited expressions of love.


My own grandmother


Sprightly and independent, she was like a granny from central casting - white hair, glasses, rocking chair and slippers.


She came to live with us shortly after my parents married and she was a hoot.

She helped out at children's tea parties, always had the best biscuits in the house, and allowed me to watch shows on her black and white TV that my mother frowned on.


But as the years went by, Granny started to change.


Not only would she say the same things, she would do the same things, time and time again.

She would list the names of everyone in the family before arriving at mine, come in to tell us something and then forget what she had come to say.


All the time she was becoming befuddled by tasks which once seemed second nature.


Slowly but surely her sharp mind and sense of fun began to fade like a tropical sunset.


When she lost control of her bladder my mother decided she could not cope and we put her in a home.

The first time I visited she barely recognised me.


A few more trips and she had lost the ability to speak.


Months later a nurse rang to say granny had faded away in her sleep.


We shed a tear then breathed a huge sigh of relief.


New hope


The fact is that even though Alzheimer's was discovered more than 100 years ago it is only in the last two decades that we have really come to know anything about it.


Lack of funding has a lot to do with it.


The US government spends roughly eight times as much on cancer research as is does researching Alzheimer's disease, and half what it spends on substance abuse.


Finally, though, there is some hope.


This week the Irish-American company Elan and the US firm Wyeth will jointly announce they are pressing ahead with the $300m (£151m) trial of a drug which could block the production of a protein called beta amyloid which many scientists believe causes Alzheimer's.


Present in all of us, too much beta amyloid can cause plaques to form in the brain, and those plaques feast on brain cells.


There is a lot at stake, not least financially. If a drug is discovered which prevents Alzheimer's half the population of the US alone could eventually end up taking it.


Need is great


Never has the need been greater: as the first baby boomers turn 60 the fear is the health care system could be overwhelmed by what some are predicting could be an epidemic of Alzheimer's disease.


It costs $50,000 a year just to keep Flossie in a nursing home.


Back in Missouri, Mike and Dianne are bidding her farewell: "There's that pretty smile, sleep tight OK?"


Flossie sits perfectly still - beyond hooded eyelids brain cells are dying.


As she reaches the hallway Dianne stifles a tear.


Hers is the heart-rending tragedy of the long goodbye.


THE LONG GOOD-BYE – PART 2:  The Second Instalment in a World News America Series On Alzheimer's Looks at Early Onset of The Disease.


Kris Bakowsk: 'I don't know if there will be a cure for me in my lifetime'


"If my son gets afflicted, I want there to be a cure for him."


The son in question is Kris Bakowski's only child Alan, who's about to be married and begin work at a Washington law firm.


Life is good for Alan, from almost every perspective.


But his 52-year-old mother Kris, diagnosed with early onset Alzheimer's disease six years ago, is frightened Alan may succumb to the terminal disease as well.


The younger the age at which the parent develops the disorder, scientists believe, the greater the risk to the children.


It is a startling but little known fact about the disease; one that has special resonance with Bakowski.

"I don't know if there will be a cure for me in my lifetime," she says. "But, I am working as hard as I can to help."


Searching for help


Bakowski spends the bulk of her time speaking out - at Alzheimer-focused conferences around the world, and to members of Congress on Capitol Hill.


What needs addressing most urgently, according to Bakowski, is the lack of an adequate diagnostic tool for detecting the disease, which in turn prevents some people from getting the help they need.


She discusses this, and her own story, on her blog, "Creating Memories".


Her diagnosis began with unusual behaviour, including memory loss that got increasingly worse.


It took six months of tests before it was determined she had Alzheimer's disease.


What followed was a mid-life nightmare.


She lost her job as a theatre director, several friends faded from her orbit and she went nearly four years without social security benefits.


Today, in her home of Athens, Georgia, Kris Bakowski has her job back - after a year of lawsuits - and her benefits.


But the real - and long - fight continues.


You can watch World News America's 'The Long Goodbye' Series on Alzheimer's on BBC America and BBC World News weeknights at 1900 ET/0000 BST (for viewers outside the UK only).


(Source:  /

Markers in Blood and Spinal Fluid, and a New Imaging Agent, Show Promise for Early Detection of Alzheimer's



With the continued aging of the population and the growing epidemic of Alzheimer's, early detection of the disease is crucial for risk assessment, testing new therapies, and eventual early intervention with better drugs, once they are developed. Four studies reported on 30 July at the Alzheimer's Association's 2008 International Conference on Alzheimer's Disease (ICAD 2008) in Chicago bring us closer to that goal of early detection by describing advances in biomarkers.


A biomarker is a substance or characteristic that can be objectively measured and evaluated as an indicator of normal body processes, disease processes, or the body's response(s) to a therapeutic intervention.


It is widely believed that Alzheimer's disease brain changes, including amyloid plaques and neurofibrillary tangles, begin many years before symptoms are evident or there is significant death of brain cells. It is critical to identify affected individuals while they are still cognitively normal so that future disease modifying therapies can preserve normal function. The testing and eventual use of such therapies requires identification of affected and "at risk" individuals in order to steer them to clinical trials, and to direct and monitor therapy.


"Discovery of measurable markers that track with the presence of Alzheimer's pathology and that predict the development of cognitive decline in people who are still cognitively normal, known as 'antecedent biomarkers,' are especially needed," said William Thies, PhD, vice president of Medical and Scientific Relations at the Alzheimer's Association. "It is greatly preferable that these markers be easy to obtain, such as in samples of blood or urine, or through readily available imaging technologies, such as MRI and PET."


Blood Test on White Blood Cells May Be Useful for Early Detection of Alzheimer's

Healthy brain cells do not go through the process of division and replication (known as the "cell cycle") that is common in other cells in the body. However, in Alzheimer's disease, brain cells have demonstrated an abnormal tendency to prepare to re-enter this cell cycle, which may increase their likelihood of dying or directly cause their death.


The equivalent cell cycle defect is found in lymphocytes of people with Alzheimer's. Lymphocytes are white blood cells in the immune system that can easily be collected for testing by a simple blood draw. Professor Thomas Arendt, Director of the Paul Flechsig Institute, University of Leipzig, Germany, thought that this suggested a vehicle for detecting Alzheimer's.


In a study performed in the U.S. by GW Medical, the licensor of Arendt's technology, Arendt and colleagues measured the expression of CD-69 (a protein involved in white blood cell growth and production) on multiple cell lines in people with probable Alzheimer's (n=32), healthy controls (n=30) and other dementias, chiefly Parkinson's disease dementia, (n=26).


Variations in levels of CD-69 enabled the researcher to clearly differentiate between Alzheimer's subjects and demented Parkinson's subjects. It was accurate 91 percent of the time when the diagnosis was Alzheimer's and 92 percent of the time when it was Parkinson's dementia. The assay correctly differentiated people with Alzheimer's from cognitively normal subjects 88 percent of the time when the diagnosis was Alzheimer's and 82 percent of the time when the person was cognitively normal.


In addition, Arendt found that the test results did not vary with dementia severity as measured by the Mini Mental State Exam.


"The lack of variation suggests that this test may be useful in the early stages of Alzheimer's," Arendt said. "A larger trial is underway with results expected by late summer 2008. If confirmed, it will give primary care physicians a better, more accurate and non-invasive test for Alzheimer's disease."


Spinal Fluid Marker Tracks Brain Amyloid, May Identify Alzheimer's Before Symptoms

Some researchers believe that flaws in processes governing production, accumulation, or disposal of amyloid protein in the brain are the primary cause of Alzheimer's. Aβ42 is a particularly "sticky" variety of amyloid protein fragment that is more likely to aggregate into small clusters and eventually into the plaques that are considered one hallmark of the Alzheimer brain.


Anne M. Fagan, PhD, of the Washington University School of Medicine, St. Louis, MO, and colleagues previously demonstrated in a small group (n=24) that a low level of Aβ42 in cerebrospinal fluid (CSF) is an effective marker for determining the presence of amyloid in the brain as assessed by PET scans using a marker called Pittsburgh Compound B (PIB).


In a new study presented at ICAD 2008, Fagan reported on a much larger cohort (n=132; age 45-88 years, mean 65.7). This group included individuals who were non-demented plus those with very mild or mild dementia. Consistent with the prior study, the researchers observed a striking inverse relation between presence of amyloid in the brain and levels of Aβ42 in CSF.


Overall, those people with high amounts of brain amyloid (as indicated by PET scan images showing positive PIB-binding) had low CSF Aβ42 (36/37, 97%). Those with low levels of brain amyloid (negative PIB-binding) had high CSF Aβ42 (80/95, 84%). This was true regardless of cognitive status, indicating excellent sensitivity of CSF Aβ42 for identifying the presence of brain amyloid, according to the researchers.


In addition, they observed that three non-demented, low CSF Aβ42, PIB-positive study participants have subsequently received an Alzheimer's diagnosis suggesting that positive PIB and low CSF Aβ42 may be useful as markers of "preclinical Alzheimer's" (that is, Alzheimer's prior to visible symptoms).

"We found that CSF Aβ42 is an excellent marker for identifying the presence of amyloid in the brain, regardless of the person's cognitive status," Fagan said. "Our analyses also suggest that a decline in CSF Aβ42 may effectively identify non-demented individuals who are in the preclinical stage of Alzheimer's, even before they are PIB positive."


Brain Enzyme May Improve Alzheimer's Risk Assessment and Early Detection

Researchers have previously found elevated β-secretase (BACE1) activity in the brains of patients with Alzheimer's compared to healthy individuals. BACE1 is one of two enzymes involved in the pathological processing of amyloid precursor protein (APP) and the production of toxic Aβ (beta amyloid, the main constituent of amyloid plaques in the brains of people with Alzheimer's).


Professor Harald Hampel, of Trinity College Dublin, Ireland and the University of Munich, Germany, Professor Yong Shen, of Sun Health Research Institute, USA, and colleagues investigated whether BACE1 assessed in cerebrospinal fluid (CSF) may be a feasible biomarker candidate for predicting Alzheimer's in people with mild cognitive impairment (MCI). MCI is a transition stage between the cognitive changes of normal aging and the more serious problems caused by Alzheimer's.


The research had two parts. In the first part, the scientists measured BACE1 levels in CSF in 80 people with Alzheimer's, 59 people with MCI, and 69 healthy elderly controls (HC) at two independent, international research centers. MCI subjects showed highly increased levels of BACE1 activity when compared to HC and people with Alzheimer's. BACE1 activity was significantly correlated with Aβ level. A subsequent validation study replicated these initial findings in a new and independent set of 41 people with Alzheimer's, 46 with amnestic MCI and elderly HC.


In the second part, 47 MCI subjects were clinically followed up over two years to assess the predictive value of BACE1 in combination with other biomarker candidates for predicting the conversion from MCI to Alzheimer's. The additional candidates were abnormal brain proteins total tau and phosphorylated tau measured in CSF, and baseline performance on a large neuropsychological testing battery. Fifteen (15) MCI subjects converted to Alzheimer's after a mean follow-up interval of 2.3 years. Analysis showed that BACE1 protein levels and ApoE genotype (a genetic risk factor for Alzheimer's) were the strongest predictors of conversion to Alzheimer's, after controlling for age and gender. The classification accuracy was 78%, the sensitivity was 80%, and the specificity was 77% for the combined model.


"These important findings pave the way for further rigorous assessment of BACE1 as an effective and accurate clinical diagnostic tool, which could significantly improve risk assessment and early detection of Alzheimer's," Hampel said. "We believe that BACE1 will be an excellent outcome biomarker to look at in ongoing clinical trials of anti-amyloid, disease modifying therapies. Furthermore, we are working on a blood-based diagnostic test for BACE1 as well."

Improved Amyloid Imaging Agents for PET in Development

A major recent advance in Alzheimer's is the ability to create images of amyloid in the brains of living people using positron emission tomography (PET) scanners. With PET, a radioactive compound, or tracer, is injected into the person to be scanned. The tracer attaches to a target substance in the body, in this case amyloid, which then "lights up" on the image captured by the scanner.


In research reported at ICAD 2008, Michael J. Pontecorvo, PhD, of Avid Radiopharmaceuticals, Philadelphia, PA, and colleagues reported the development of a novel 18F-labeled PET amyloid imaging agent, 18F-AV-45, that may eventually provide a practical approach for routine brain imaging for Alzheimer's


PET scanners are relatively common � they are available in most hospitals � yet one of the challenges to more widespread use of PET imaging in Alzheimer's is that the radioactivity of the first amyloid-imaging tracer, called 11C-PIB or Pittsburgh Compound B, is relatively short-lived. With this agent, based on radioactive carbon, half of the radioactivity is lost every 20 minutes. This means that it must be manufactured onsite, a process that requires a cyclotron (a type of particle accelerator), which is rarely found in community hospitals. This limitation has prompted a search for longer-lived tracers, such as 18F-labeled agents, based on radioactive fluorine, which would be suitable for regional production and wider community use.


In the study, three 18F-labeled compounds were evaluated in 42 cognitively healthy elderly volunteers and 39 individuals with Alzheimer's. Each participant received a single intravenous injection of one of the compounds followed by PET imaging.


People with Alzheimer's showed retention of all three tracers in brain areas expected to be high in amyloid. In contrast, cognitively healthy volunteers showed rapid removal of the tracers, with minimal retention in the brain. Two individuals diagnosed with Alzheimer's had a pattern of tracer uptake similar to healthy volunteers. Chart notes for both suggested unusual presentations � prominent Parkinsonism in one case and slowly progressive dementia in the other.


While the three compounds were similar in pattern and amount of tracer retention, they differed in how they were processed by the body in ways that favored one compound, 18F-AV-45. For example, 18F-AV-45 showed rapid uptake and steady levels were maintained in the brain between 50 and 90 minutes post injection. This allowed high quality images to be obtained from PET imaging beginning 50 minutes after 18F-AV-45 administration, with minimal inconvenience or delay for the patient or the imaging center, according to the researchers.


"18F-AV-45 is being used as a research tool today, but it has the potential to aid in the diagnosis and early detection of Alzheimer's in a community setting and may be a useful biomarker for the development and monitoring of novel amyloid reducing therapies," Pontecorvo said. "On the basis of the findings we reported today, Phase II trials with 18F-AV-45 have been initiated."



Lifestyle Factors Contribute to Lowering and Raising Risk of Alzheimer's Disease

·       Unmarried status in mid-life and heart disease factors may increase Alzheimer's risk

·       Repeatedly thinking about problems may reduce Alzheimer's risk



A new study suggests that those who are unmarried or not living with a partner in midlife could have an increased risk of developing Alzheimer's disease, according to research reported on 30 July at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008), in Chicago.


Additional research on Alzheimer risk factors presented at ICAD 2008 indicates that people who ruminate, or repeatedly think about their problems, may be less likely to develop the disease, while people with metabolic syndrome (a combination of cardiovascular health related symptoms) are at higher risk. Finally, a large meta-analysis of nine European risk factor surveys confirmed a well recognized group of Alzheimer risk factors, including memory complaint, severe head trauma, diabetes, stroke and low education.


"We may not be able to do anything about aging, genetics or family history, but research shows us that there are lifestyle decisions we all can make to keep our brains healthier as we age, and that also may lower our risk of developing Alzheimer's disease," said William Thies, PhD, Vice President of Medical and Scientific Relations for the Alzheimer's Association.


Unmarried Life: Paving the Way for Dementia?

Research suggests that maintaining regular social interaction can contribute to maintaining brain health as we age and possibly decrease one's risk of developing Alzheimer's. When people are married they are able to have close interaction on a regular basis. This may reduce the occurrence of dementia.


Krister Håkansson, BA, of Karolinska Institutet, KI Alzheimer Research Centre, Stockholm, Sweden and Växjö University, School of Social Sciences, Växjö, Sweden, conducted a first-of-its-kind evaluation of whether midlife marital status is related to late-life cognitive function. The study examined 1,449 individuals from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study in midlife and then again in 1998, an average of 21 years later.


At re-examination, 139 persons were diagnosed with some form of cognitive impairment: 82 with mild cognitive impairment (MCI) and 48 with Alzheimer's. Persons in the study who were living with a partner in midlife were significantly less likely to show cognitive impairment compared to all other categories (single, separated, divorced or widowed). Those in the study who were married or lived with a significant other in midlife had a 50% lower risk of having dementia in late-life compared to those who lived alone, even after adjustments for education, BMI, cholesterol, blood pressure, occupation, physical activity, smoking habits, depression, ApoE status, age at follow-up and gender.


The researcher observed that there were differences between groups of people who had been living alone for different reasons. The all-life singles had a doubled risk, whereas the ones who stayed divorced from midlife onwards had a tripled risk. The most dramatic risk increase was found for those widowed before midlife and who stayed widowed. Compared to those married at midlife and still so at late-life, they had more than a six-fold risk of developing Alzheimer's.


"Living in a couple relationship is normally one of the most intense forms of social and intellectual stimulation. If social and cognitive challenges can protect against dementia, so should living in a couple relation," said Håkansson. "This study points to the beneficial effects of a married life, consistent with the general hypothesis of social stimulation as a protective factor against dementia."


Tendency for Rumination in Midlife May Decrease Risk for Dementia Decades Later

According to Ramit Ravona-Springer, MD, of Sheba Medical Centre, Tel Hashomer, Ramat Gan, Israel and colleagues, "rumination" refers to the disposition for repetitive thinking over one's problems.

Tendency for rumination when confronting difficulties in family and work settings was assessed in about 9,000 participants in the IIHD study, a longitudinal investigation of the incidence and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Tendency for rumination was assessed as 1=always forget, 2=tend to forget, 3=tend to ruminate, 4=usually ruminate.


Dementia was assessed three decades later in 1,890 participants among 2,604 survivors of the original cohort. Mean age of the participants was 82 at the time of final assessment. 308 were diagnosed as demented, 175 as having mild cognitive impairment, and 1,407 had no cognitive impairment.


The prevalence rates of dementia (adjusted for age, area of birth, and socioeconomic status) were 21% for those who always forget difficulties in familial settings, 18% for those who tend to forget, 14% for those who tend to ruminate over difficulties, and 14% for those who usually ruminate. When rumination in response to difficulties at work was assessed, prevalence rates of dementia were 24% for those who always forget difficulties, 19% for those who tend to forget, 15% for those who tend to ruminate over difficulties, and 15% for those who usually ruminate.


A total score for rumination in both family and work settings was calculated, and subjects were divided into four groups according to this score. Relative to the group with the lowest total rumination score, dementia prevalence was 30 to 40 percent less in groups with higher scores.

"Your personality traits, specifically your psychological and cognitive style when confronting distress, may be associated with your risk for dementia," said Ravona-Springer. "However, exactly how this works still needs to be determined."


Metabolic Syndrome May Lead to Cognitive Decline

Metabolic syndrome (Met.S) is a group of heart disease risk factors that includes abdominal obesity, elevated blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. Those who have Met.S are at higher risk for developing diabetes, hypertension, and stroke, all of which increase the risk of developing dementia, including Alzheimer's disease.

Matheus Roriz-Cruz, MD, PhD, Federal University of Rio Grande do Sul State, Brazil and colleagues studied the effects of Met.S on the development of cognitive impairment in people who have not had a stroke. Researchers evaluated 422 healthy elderly men and women over age 60 in Brazil and used a battery of scales to assess cognition, depression, planning and activities of daily living. Met.S was present in 39.3% of participants.


Data from the study revealed that all neurofunctional scores were significantly lower for those with Met.S, and the difference increased with age. Older people with Met.S had an almost 35% higher level of cognitive compromise when compared to those without Met.S.


"Met.S was independently associated with lower cognitive, planning, neuromotor and functional scores, and with more depressive symptoms," said Roriz-Cruz. "The results from this study reinforce the importance of maintaining good physical health in order to reduce one's risk of experiencing cognitive decline, and possibly developing Alzheimer's disease."


Risk Factors for Progression to Dementia in General Population

In the general population, many risk factors and predictors for dementia have been identified. However, a combination of risk factors may give a more accurate prediction for dementia than each individual risk factor.


Sylvaine Artero, of INSERM, Montpellier, France; Pieter Jelle Visser, of the University of Maastricht, The Netherlands; and colleagues analysed a pooled database constructed from nine European surveys of dementia risk factors, including a total of 16,261 participants over age 55 without dementia. Potential risk factors were evaluated at baseline and incident dementia was assessed over a follow up period of up to 15 years. Risk factors included cardiovascular disorders, endocrine disorders, depression, head trauma, intoxicants (including alcohol, smoking and drugs), physical and intellectual activities, performance in activities of daily living, Apolipoprotein E genotype, cognitive complaint, and cognitive test performance.


In total, 1,530 subjects (9%) progressed towards dementia. In order, the most predictive variables were: impairment in executive function (planning), memory problems (as measured on tests), subjective complaints about memory/cognitive failure, Apolipoprotein E (ApoE) genotype, use of psychotropic medication, severe head trauma, diabetes, stroke, and problems with language. In addition, problems with activities of daily living, smoking, no drinking, no use of hypertensive drugs, low education, and female gender all independently predicted dementia at follow-up.


"Cases of dementia in the general population can be best identified by a combination of socio-demographic, clinical and cognitive factors," said Artero. "Developing a better understanding of the factors that increase risk for Alzheimer's will help us to create more effective methods to prevent people from developing the disease."


Research Studies Presented at The Alzheimer’s Association International Conference on Alzheimer’s Disease 2008 (July 26 – 31) Reported That "DIVERSE APPROACHES TO ALZHEIMER'S THERAPIES CONTINUE TO SHOW PROGRESS "

- Plus, taking anti-dementia drugs extends lifespan three years in Alzheimer's –


Results from clinical trials of three potential Alzheimer's therapies raise hope for new and better treatments of the disease, according to data reported on 30 July at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) in Chicago.


A related study showed that taking anti-dementia drugs appears to have a positive impact on extending lifespan in those with Alzheimer's.


These reports included:


·                Eighteen-month data from an open-label extension of a pivotal trial of Dimebon (Medivation) in mild to moderate Alzheimer's.

·                Nine-month data from an interim analysis of the first U.S. Phase II trial of intravenous immunoglobulin, or  IVIg (Baxter), in Alzheimer's.

·                Results of a Phase II study of a monoclonal antibody (LY2062430, Lilly) in mild to moderate Alzheimer's.

·                Research suggesting that persistent antidementia drug use increases survival in people with Alzheimer's.


"Therapies targeting amyloid in Alzheimer's disease must continue to be thoroughly tested," said William Thies, PhD, Alzheimer's Association Vice President for Medical and Scientific Relations. "At the same time, we know that Alzheimer's is a complex disease and that better treatments and preventions will likely also be complex, so we must investigate every promising drug target looking eventually towards the possibility of a multi-strategy approach."


18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer's

In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behaviour in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.


One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.


Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.


Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.


"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."


"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.


First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer's

IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.


Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Well Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.


Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.


In the total group, the researchers found statistically significant differences favouring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favouring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favoured IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.


When the results for each dose were analysed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.


Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioural disturbances in placebo-treated patients than those who received IVIg.


"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect."


Phase II Immunotherapy Trial with LY2062430 in Mild to Moderate Alzheimer's

Previous research has shown that antibodies that bind to beta amyloid can be given intravenously. By binding to beta amyloid and increasing the rate of its removal from the body, these antibody infusions may slow the progression of Alzheimer's.

Eric Siemers, MD, Medical Director of the Alzheimer's Disease Research Team at Eli Lilly and Company, and colleagues conducted a Phase II trial of a monoclonal antibody, known as LY2062430, that binds to the mid-domain of beta amyloid.


Fifty-two (52) people with mild to moderate Alzheimer's and 16 volunteer subjects were studied. Alzheimer's patients received 12 weekly infusions of placebo or antibody (100 mg every 4 weeks, 100 mg once per week, 400 mg every 4 weeks or 400 mg once per week). Volunteers received a single 100 mg dose of antibody. Safety assessments included brain imaging using magnetic resonance imaging (MRI) and examination of cerebrospinal fluid (CSF, a fluid normally present around the brain and spinal cord). In an optional sub-study, 24 Alzheimer's patients and 13 volunteers underwent a type of brain imaging known as SPECT using a tracer (known as IMPY) that measures the amount of amyloid plaque present in the brain. Measures of symptom severity were obtained in all AD patients using the Alzheimer's Disease Assessment Scale - Cognition (ADAS-cog).


The researchers found that following administration of the antibody, the amount of beta amyloid in blood increased substantially after the antibody bound to the beta amyloid protein. A small amount of the antibody enters the CSF, and in the Alzheimer's patients beta amyloid also increased in CSF, similarly bound to the antibody. For patients treated with 400 mg of the antibody, the amount of the type of beta amyloid primarily found in plaque (known as AB1-42) that appeared in the blood correlated with the amount of amyloid plaque in the brains based on IMPY scans (r=0.65, p=0.02). According to Siemers, this finding suggests that some of the beta amyloid protein present in plaque moves to blood after treatment with the antibody.


Certain other types of beta amyloid thought to be primarily or exclusively found in amyloid plaque are also increased in blood and CSF of study participants. The antibody produced no change in cognitive scores or in the total amount of amyloid plaque based on IMPY scans. Siemers said that this was expected in a study of this duration.


According to the researchers, brain imaging using MRI and CSF safety assessments showed no evidence of inflammation, bleeding or other side effects throughout the trial. No side effects were identified that appeared to be related to antibody treatment.


"We saw an increase in amyloid beta, which is thought to be bound to LY2062430, in both the blood and cerebrospinal fluid of study participants," Siemers said. "Additionally, after treatment we found a correlation between beta amyloid in blood and the amount of amyloid plaque in brain as determined by IMPY imaging, as well as an increase in blood and CSF in certain types of beta amyloid found in plaques. These biomarker data suggest that amyloid plaques in the brain may begin to 'dissolve' after 12 weeks of treatment with this antibody. We're now planning a Phase III clinical trial of this drug to be started in 2009."


Anti-dementia Drugs Contribute to Longer Life in People with Alzheimer's

Survival (life span) in people with Alzheimer's is recognized to be shorter than what is expected in cognitively normal seniors and is recognized to be influenced by several factors including age, disease severity, general debility, and gender. Approved anti-dementia drugs have been shown help with the symptoms of Alzheimer's but their influence on life span is not known.


At ICAD 2008, Susan Rountree, MD, of the Alzheimer's Disease and Memory Disorders Centre of Baylor College of Medicine in Houston, Texas, reported on a study of the persistent use of anti-dementia drugs and their influence on survival.


The researchers followed 641 people diagnosed with Alzheimer's at an academic medical clinic between 1989 and 2005. These individuals had been on drug therapy over the course of their Alzheimer's for variable amounts of time and the majority had used one or more of the commercially available anti-dementia drugs (donepezil, galantamine, rivastigmine, tacrine, or memantine).


Total years on medication was divided by the total years of disease symptoms to determine a persistency score for each individual. Participants were divided into four groups (1st, 2nd, 3rd, 4th quartiles) ranging from the lowest to highest persistency scores and the researchers compared life span among the groups after adjustment for a variety of factors generally recognized to influence survival. The 1st quartile took drug less than 33 percent of the time, 2nd quartile = 34-55 percent of the time, 3rd quartile = 56-70 percent of the time, and the 4th quartile = 71-99 percent of the time.


Over the entire course of the study, 12 percent of participants never took any anti-dementia drugs. Fifty-three (53) percent of the participants died.


The researchers found an inverse and statistically significant relationship between the overall risk of death and the persistency of drug use. Those in the lowest persistency group (1st quartile) were 2.4 times more likely to die than those in the highest persistency group (4th quartile). Those with intermediate drug exposure had increased risk of death of 2.2 times (2nd quartile) and 1.5 times (3rd quartile) compared to the most persistent users. More persistent therapy was associated with a longer median survival time; the median survival between the lowest quartile group and the most persistent users was 3.12 years.


"In our study, people with Alzheimer's who took anti-dementia drugs more persistently lived longer than those who took the medications for shorter time intervals," Rountree said. "In an earlier study involving this group, we reported that persistency of treatment was also associated with long term cognitive and functional benefits. Persistent drug therapy appears to help Alzheimer's patients live longer and the mechanism may be related to overall improvement of cognition and function resulting from current symptomatic therapies."