Researchers find link between concussions and Alzheimer’s disease

Boston University School of Medicine

New research has found concussions accelerate Alzheimer’s disease–related brain atrophy and cognitive decline in people who are at genetic risk for the condition. The findings, which appeared in the journal Brain, show promise for detecting the influence of concussion on neurodegeneration.

Moderate–to–severe traumatic brain injury is one of the strongest environmental risk factors for developing neurodegenerative diseases such as late–onset Alzheimer’s disease, although it is unclear whether mild traumatic brain injury or concussion also increases this risk.

BUSM researchers studied 160 Iraq and Afghanistan war veterans, some who had suffered one or more concussions and some who had never had a concussion. Using MRI imaging, the thickness of their cerebral cortex was measured in seven regions that are the first to show atrophy in Alzheimer’s disease, as well as seven control regions.

“We found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer’s disease,” explained corresponding author Jasmeet Hayes, PhD, assistant professor of psychiatry at BUSM and research psychologist at the National Center for PTSD, VA Boston Healthcare System. “Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer’s disease relevant areas.”

Of particular note was that these brain abnormalities were found in a relatively young group, with the average age being 32 years old. “These findings show promise for detecting the influence of concussion on neurodegeneration early in one’s lifetime, thus it is important to document the occurrence and subsequent symptoms of a concussion, even if the person reports only having their “bell rung” and is able to shake it off fairly quickly, given that when combined with factors such as genetics, the concussion may produce negative long–term health consequences,” said Hayes.

The researchers hope that others can build upon these findings to find the precise concussion–related mechanisms that accelerate the onset of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy, Parkinson’s and others. “Treatments may then one day be developed to target those mechanisms and delay the onset of neurodegenerative pathology,” she added.

A small phase 1 pilot study showed that some patients with AD who received constant stimulation to the fornix — the principle outflow tract from the hippocampus — had increased hippocampal volume after 1 year.

There was also some evidence that this increased hippocampal volume correlated with cognitive benefit.

These results, published online in Brain Stimulation, suggest that fornix stimulation affects the structure of the brain and, if replicated, would be promising for AD treatment.

“In Alzheimer’s disease, the brain, in particular the hippocampus, melts away; as you lose your hippocampus, you lose your memory, and so far, there is nothing that can stop or slow down this process,” said study author Andres Lozano, MD, a neurosurgeon at Toronto Western Hospital and professor and chair, neurosurgery, University of Toronto, Ontario, Canada.

“If we are able to apply electrical stimulation, and if indeed we’re able in some cases to slow down or even reverse the process, it would be a very exciting finding.”

A second, larger study, a double-blind, randomized trial in 42 patients, is about to wrap up and should soon shed more light on the effectiveness of DBS in AD, the researchers say.

Circuit of Papez

Characterized by atrophy in the hippocampus as well as other brain structures, AD involves amyloid and tau deposition, formation of neurofibrillary tangles, and cerebral hypometabolism, the authors note. These processes result in dysfunction in several neural circuits, including the memory circuit of Papez.

DBS has already been proven effective for movement disorders, such as Parkinson’s disease, tremor, and dystonia. It’s also being used experimentally to treat patients with intractable psychiatric conditions, including major depression, obsessive-compulsive disorder, and anorexia nervosa.

Although the mechanism of action is uncertain, experts believe it likely involves modulated activity within dysfunctional neural circuits. But the prevailing thought has been that DBS is unable to influence progressive neurodegenerative processes acting on these circuits.

The current study included six patients with AD who participated in a phase 1 clinical trial showing that the DBS procedure was safe and could alter brain metabolism. These patients with AD were the first in the world to receive DBS, according to Dr Lozano.

The patients — four men and two women — were relatively young (aged 51, 69, 58, 62, 60, and 64 years) and had received the diagnosis of probable AD within the previous 2 years. They had a spectrum of dementia from mild to moderate and severe.

After electrodes were implanted, these patients received constant mild stimulation of the fornix. From structural MRI scans, researchers measured the volume of the hippocampus, fornix, and mammillary bodies — critical components of the Papez circuit — at baseline and after 1 year of continuous stimulation. They also looked for evidence of brain-wide structural changes.

At the end of the study period, two of the six patients (patients 1 and 4) showed a striking increase in right and left hippocampal volume. The mean (average of right and left) hippocampal enlargement was 5.6% in patient 1 and 8.2% in patient 4.

Caught by Surprise

“Not only did the hippocampus not shrink in these patients but the thing that caught us completely by surprise was that it actually grew and it grew by a large amount,” said Dr Lozano.

He noted that the baseline Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score for these two patients (18.67 for patient 1 and 11.67 for patient 4) indicated relatively mild AD.

Hippocampal volume did not increase in the other four patients, but their baseline ADAS-Cog scores were higher. “They were too far along and the circuit too destroyed or damaged that there was no one home to stimulate,” commented Dr Lozano.

“We think there may be a point of no return where damage is so extensive that you can’t recuperate function. Our feeling is that the earlier you go in, the more likely there will be something to rescue and something to work with.”

The researchers compared these hippocampal volume changes to a control group of 25 persons matched for age, sex, and neurocognitive severity who did not receive DBS. MRI data at baseline and at 12 months for these controls were available from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

No hippocampal growth occurred in any of these 25 controls. “So we think this does not occur spontaneously in Alzheimer’s disease, that it has occurred as a consequence of the brain stimulation in this case,” commented Dr Lozano.

Circuit Training

He believes that the stimulation is reactivating the memory circuit that is atrophying in AD. “It’s almost like circuit training, putting the circuit on a treadmill and making it work, and in so doing so, we think that the circuit can be maintained.”

Studies show that rodents receiving DBS actually generate more neurons, he added. “If this were to occur in humans, maybe we would have a way of repairing these damaged circuits. That’s important because you would go from a purely symptomatic treatment to actually treating the root cause and modifying the course of the illness.”

The hippocampal volume increases in the two patients appeared to correspond to cognitive outcome. Patient 4’s ADAS-Cog score improved from 11.67 at baseline to 7.33 at 1 year. Patient 1 did not have an improved ADAS-Cog score but showed the least deterioration among the other patients.

“Those whose hippocampus grew either got better cognitive function or stabilized whereas in those where it shrunk, cognitive function continued to deteriorate as expected in a progressive disease like Alzheimer’s disease,” said Dr Lozano.

The study also found evidence that fornix stimulation was associated with clusters of local volume expansion in temporoparietal regions of the brain that, although far from the Papez circuit, are known to be atrophic in AD.

The study did not find enlargement of the fornix or mammillary bodies. However, patients 1 and 4 showed the slowest atrophy rate in both of these structures, possibly suggesting a circuit-wide structural effect of fornix DBS.

Patient 4, who opted to continue to receive DBS, was reimaged at 3 years. After the 4-point improvement at year 1, this male patient got worse again (ADAS-Cog score of 15.33). But Dr Lozano pointed out that the average per year drop in this score in patients with AD is 7 points.

“So we would expect him to go from 11 to 18 to 25. That’s not what happened; he went from 11 to 7 to 15. We think that is possibly significant; it’s different than the expected natural course.”

Glucose Metabolism

Researchers also measured hippocampal glucose metabolism using positron emission tomography (PET) with a radio tracer. They did this preoperatively and in the “on” stimulation condition following 12 months of continuous DBS.

They found increased glucose metabolism — indicating the brain is using fuel — but it’s not clear how this is connected to increased hippocampal volume, said Dr Lozano. “We think the two are linked, but we don’t know which one comes first or whether one leads to the other or they’re independent.”

According to Dr Lozano, noninvasive stimulation methods, such as transcranial magnetic stimulation, would not produce the same results. For one thing, DBS provides targeted and precise stimulation “24/7,” which wouldn’t be possible with other modalities. In addition, the fornix is located at the center of the brain, which would be difficult to reach externally.

Would a stronger stimulus produce even better results? Possibly, he said, but when researchers at one point turned up the stimulation to a very high level, it produced unwanted vivid memories in some patients. The current settings were arrived at through patient input.

Information on the two patients whose hippocampus got bigger and whose illness stabilized has informed the next year-long study. The multicenter, randomized, blinded study included only patients with milder AD. Half of the 42 enrolled patients received DBS and the other half a sham treatment (electrodes were implanted but not turned on).

Cutting Edge

Medscape Medical News invited Howard Chertkow, MD, professor, neurology, McGill University, and director, aging and Alzheimer’s research axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada, as well as scientific director, Canadian Consortium on Neurodegeneration in Aging, to comment on this new study.

Dr Chertkow applauded Dr Lozano, whom he called a “very respected” world expert in neuromodulation in DBS. The new research, he said, is “cutting edge” and the study findings “certainly novel.”

Because there are limited effective treatments for AD, which affects almost 36 million people worldwide, and its cause is not yet confirmed, “any new treatment, any new lead, certainly has to be pursued,” he said.

The suggestion that stimulating the memory network can improve memory and is accompanied by changes on MRI and PET “is very exciting” and indicates that the results “are not just serendipitous,” added Dr Chertkow.

Another encouraging aspect of the study for Dr Chertkow is that it provides “the first clear evidence in humans” that stimulation might produce neurogenesis. “If we can create new connections in the hippocampus, maybe we can do so in a whole range of other brain disease, even beyond Alzheimer’s disease.”

But Dr Chertkow pointed out what he sees as negative aspects of the DBS approach used in the study. For example, the stimulation targets memory and so the best result is improved memory, but AD also involves changes in personality, emotions, and other cognitive functions, such as planning and language.

“There are other brain networks involved and it doesn’t seem logical that if you impact on one network that you are going to necessarily improve things in other networks.”

AD is a degenerative disease characterized by deposition of toxic proteins, such as amyloid and tau. “It’s doubtful that this treatment is going to stall or attenuate or stop this process,” said Dr Chertkow. “While it might improve symptoms, it’s not really attacking the disease itself.”

Other disadvantages to DBS in AD are that it’s invasive and costly and so “will always have limited applicability,” said Dr Chertkow.

“This is not going to be the answer for Alzheimer’s disease and memory loss with aging around the world, but it may have a role.”

Dr Lozano received support from the Surgeon Scientist Program, Department of Surgery, University of Toronto, and Neurosurgical Research and Education Foundation of the American Association of Neurological Surgeons. He is a Canada Research Chair in Neuroscience and is supported by the R.R. Tasker Chair in Functional Neurosurgery. Additional support was provided by the Dana Foundation and Krembil Neuroscience Discovery Fund. Dr Lozano is a consultant to Medtronic, St. Jude, and Boston Scientific; serves on the scientific advisory board of Ceregene, Codman, Neurophage, Aleva, and Alcyone Life Sciences; is cofounder of Functional Neuromodulation Inc; and holds intellectual property in the field of deep brain stimulation. Dr Chertkow has disclosed no relevant financial relationships.

Brain Stim. Published online December 3, 2014.

MRI scans carried out in 60 normally developing children, age 2 to 25 months, who carried the APOE epsilon-4 allele, showed smaller volumes of gray matter and and lower white matter myelin water fraction (MWF) compared with 102 children in the same age range whose APOE genes only include the epsilon-2 and/or epsilon-3 alleles, according to Sean C. L. Deoni, PhD, of Brown University in Providence, R.I., and colleagues.

“While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the major genetic risk factor for late-onset Alzheimer’s disease,” the researchers wrote online in JAMA Neurology.

Because MWF is a measure of myelination, the finding of reduced MWF may suggest that nerve fibers in APOE4 carriers have less of the protective myelin coating and are therefore more vulnerable to neurodegenerative pathologies. APOE genotype has previously been linked to differences in beta-amyloid protein processing, with the epsilon-4 allele associated with greater production of a form prone to fibril and plaque formation.

Deoni and colleagues indicated that their working hypothesis was that APOE4 carriers “have neurodevelopmental alterations that provide a foothold for the neuropathological changes associated with the subsequent course of Alzheimer’s disease.”

In an accompanying editorial, two researchers from Massachusetts General Hospital in Boston, John Growdon, MD, and Bradley Hyman, MD, PhD, noted several methodological concerns about the study.

Nevertheless, they indicated, the study results “raise intriguing questions about the kind of substrate in the developing nervous system that might predispose to AD neuropathological changes and neurodegeneration much later in life.”

Other experts contacted by MedPage Today agreed that the study was interesting, but the implications for Alzheimer’s disease risk prediction and prevention remained uncertain.

Zaven Khachaturian, PhD, editor-in-chief of Alzheimer’s and Dementia, commented that the findings — even if true — may not have any clinical relevance.

“My concern is that a mere validation study to confirm this observed ‘association’ in a larger study will only perpetuate the prevailing models/ideas/assumptions about Alzheimer’s disease pathophysiology, which thus far have not been productive in generating any effective interventions — as demonstrated by the repeated failure of several clinical trials based on these ideas,” he wrote in an email.

Although the role of apolipoprotein E, the product of APOE expression, in Alzheimer’s disease is typically couched in terms of its impact on beta-amyloid trafficking, Khachaturian noted that its main function is in cholesterol transport, “which suggests a far more broad set of possibilities regarding neural functions/functionality such as synaptic turnover/repair,” he said. Also, the APOE4 genotype is not causative of Alzheimer’s disease, but only a risk factor, he said.

He also pointed out that the study, conducted only in very young children, does not address whether the differences persist through later childhood and beyond. And, even if they do, other studies have indicated that differences in brain structure do not correlate well with cognitive function.

“The link between image changes and clinical pathology is tenuous,” Khachaturian said.

F. Sessions Cole, MD, director of the newborn medicine division and chief medical officer at St. Louis Children’s Hospital, told MedPage Today that a long-term follow-up study would be the best way to answer some of these questions.

Such a study, following APOE4 carriers and noncarriers over time, could “define the metabolic profiles of affected and unaffected brain regions as well as risk factors that modify development of Alzheimer disease.”

But that would take decades, Cole said. He agreed with Khachaturian about the limited correlation between the APOE4 genotype and Alzheimer’s disease — an important point if one were to develop a preventive treatment to be given during childhood to APOE4 carriers.

“As of today, I think that it would be unethical, based on this study, to initiate a potentially brain-modifying therapy in possibly affected children,” he said.

The 162 infants and toddlers recruited for the study underwent imaging while they slept. Analysis of gray matter volume was limited to 59 of the children — many of the others woke up before the scanning was completed, and Deoni and colleagues decided to exclude children younger than 6 months after discovering that the automated image-processing algorithm did not work reliably in them.

For the MWF measurements, the researchers found that APOE4 carriers in the entire cohort had lower values than the control children in posterior white matter areas, “including the optic radiations, corticospinal tracts, and splenium of the corpus callosum,” they wrote. Carriers also had greater MWF in the frontal white matter, especially the corona radiata, genu of the corpus callosum, and orbitofrontal cortex.

These patterns were also true when the analysis was limited to participants age 2 to 6 months.

Reductions in gray matter volume were concentrated in the bilateral precuneus, posterior and middle cingulate, and occipitotemporal and left lateral temporal regions. Increased gray matter volume in carriers versus noncarriers was seen in medial and lateral frontal regions.

Comparison of older versus younger participants demonstrated “an attenuated relationship” between MWF and age in posterior white matter regions in APOE4 carriers, whereas the relationship was strengthened in later-developing frontal areas of white matter.

But while these associations met standard criteria for statistical significance, Growdon and Hyman pointed out that they represented a small proportion of the number of potential associations examined in the study. “Most results do not hold up to multiple comparison testing, making this more of a hypothesis-generating data set than a confirmed set of observations,” they wrote in the editorial.

Also, the editorialists pointed out that the regions of interest selected for the study were chosen on the basis of “prior experience in Alzheimer’s disease, so a certain circularity in logic is inevitable.”

If you treat the elderly, or any member of the growing number of families devastated by Alzheimer’s disease, you may be asked some version of that question, as posed by CBS News, in the coming weeks. You can thank media coverage of a study in the Oct. 15 issue of the Journal of Neurological Sciences titled “A Brief Olfactory Test for Alzheimer’s Disease.”

Here’s that brief olfactory test, as the CBS headline suggests: “A container of 14 g of peanut butter was opened, held medially at the bottom of a 30 cm ruler, and moved up 1 cm at a time during the participants’ exhale. Upon odor detection, the distance between the subject’s nostril and container was measured.”

(If this sounds a bit strange to those who haven’t kept up with the Alzheimer’s literature, there have been a number of studies showing that the olfactory lobe is affected by the devastating neurological disorder.)

Reading CBS News’s headline, “Cheap Alzheimer’s Test Made From Peanut Butter and Ruler, Researchers Report,” reminded me of the old adage “Fast, good, or cheap: Pick two.”

A couple things made me wonder just how much of an advance this was:

• The study was small, fewer than 100 people all together, divided into four groups ranging from probable Alzheimer’s to healthy controls.
• The journal — which is not exactly a core clinical title — is ranked in the bottom third of neuroscience journals by Thomson Scientific’s impact factor, 162 out of 252. Wouldn’t the researchers have tried for a more prestigious, and clinical, journal first?

So we asked a range of Alzheimer’s researchers what they thought. Here’s a sampling:

Richard Caselli, MD, of the Mayo Clinic, Scottsdale: “I don’t think anyone will feel comfortable diagnosing AD on the basis of a smell test.”

Samuel Gandy, of Mount Sinai School of Medicine: “Smell tests for dementia screening have been proposed for years, but the lack of specificity has repeatedly undone the early claims. Ditto for eye tests. This might be the exception, but I would urge caution pending independent replication on larger numbers and diversities of subjects.”

George Bartzokis, MD, UCLA: “Do not dismiss the study. What is new here is simply what they used to test it out — peanut butter. The principal problem with smell tests is that they are nonspecific and therefore only one small piece of the diagnostic puzzle. Not only can you have some congestion in your nasal cavities that can reduce your smell on a temporary basis but a past head trauma, severe past sinus infections, etc. can do so on a permanent basis. Individuals may not even remember these past events or be aware of current sinus problems that could interfere with their ability to smell.”

To be fair, the authors of the study, including well-known Alzheimer’s researcher Kenneth Heilman, MD, also note caveats, including “that it cannot be reliably used in patients with comorbid dementias or that have a history of any other common cause of olfactory loss besides aging.”

So, not yet an Alzheimer’s test in a Jif, as a colleague’s husband quipped. (In case you’re wondering, the NIH, not the National Peanut Board, funded the study.)

While I’m on the subject of Alzheimer’s, find some time to read the gripping accounts of living with the disease that physician David Hilfiker, MD, is sharing with the world on his blog, “Watching The Lights Go Out.” It’s been a must-read of mine for months.

The study was published in the Journal of the Neurological Sciences.

More and more research has raised concern over the dangers of concussions – one of the most common forms of head trauma – as many sufferers go on to experience persistent neurological symptoms throughout their lives.

Now, scientists have discovered a clue as to why mild traumatic brain injuries (MTBI) can have such long-lasting health consequences.

In a study published in the journal Radiology, researchers found that white matter damage in the brains of people who had experienced concussions closely resembled the type of white matter damage found in patients with Alzheimer’s disease.  These findings suggest that concussions set off a chain of neurological events that can cause long-term damage to the brain.

“It’s not the hitting your head that’s the problem.  It’s everything else that happens after that,” said lead study author Dr. Saeed Fakhran, assistant professor of radiology in the Division of Neuroradiology at the University of Pittsburgh School of Medicine.

Concussions affect more than 1.7 million people in the United States annually – and around 15 percent of those people suffer lasting neurological symptoms.

Typically, when people experience concussions, CT and MRI scans of their brains look normal and doctors have remained largely in the dark regarding the best ways to treat these types of injuries, according to Fakhran.

Fakhran and his colleagues decided to take a closer look at the impact concussions were having on the brain. Researchers gathered data from 64 MTBI patients, with a mean age of 17, and 15 control patients. Thirty-nine percent of the MTBI patients had suffered a prior concussion and two-thirds of the patients had suffered a concussion as a result of a sports-related injury.

“We used something called diffusion tensor imaging, which is a subset of MRI looking at just the white matter,” Fakhran said. “It looks at areas where your white matter is injured.”

Due to the white matter injuries seen on the patients’ scans, researchers were able to hypothesize that when a person hits his or her head, it sets off a chain of events in the brain that can potentially lead to long-lasting neurological damage.

“Most people will tell you if you hit your head, you get a concussion, and the damage comes from the act of hitting your head,” Fakhran said. “(But) maybe the hitting your head is lighting the fuse and the damage  comes from a neurodegenerative cascade (afterwards).”

If doctors can figure out how to stop the chain of damage that occurs in the brain after a concussion, Fakhran said they may be able to mitigate some of the side effects associated with the injury.

“If you look through medical record of kids with concussions, some of them have horrible consequences…Their school work falls off a cliff…It’s really scary to think about,” Fakhran said.

One of the most disabling side effects of concussions is sleep-wake disturbances, which disrupt sleep and can seriously decrease quality of life in patients, leading to memory problems and even social dysfunction.

“Imagine not sleeping all night and having to go to work and sit at work all day.  You’re not able to concentrate, your grades at school will fall. If you can’t sleep, you can’t function,” Fakhran said.

A subset of the patients in Fakhran’s study suffered from sleep-wake disturbances – which researchers were able to link to abnormalities in the hippocampus area of the brain. Fakhran pointed out that one of the earliest signs of Alzheimer’s disease is sleep-wake disturbances.

Though more research is needed, the scientists hope that by pinpointing the areas of the brain in which various concussion symptoms originate, they will be able to find a way to stop those symptoms before they progress and cause long-term neurological problems.

“Hitting your head is lighting the fuse. If you lit the fuse and I blow it out, you just have a bruise, no damage done. But if you don’t, then it gets down to the bottom and explodes. To me the explosion is Alzheimer’s,” Fakhran said.

MRI-predicted values for total tau and β-amyloid ratio (tt/Aβ) in gray matter correctly pinpointed the diagnosis in 75% of patients with genetically or neuropathologically confirmed diagnoses, according to Corey McMillan, PhD, of the University of Pennsylvania in Philadelphia, and colleagues. Predicted values also had good correlation with actual tt/Aβ measured in cerebrospinal fluid (CSF), they said.

The findings are consistent with previous in vivo and autopsy studies of CSF tt/Aβ, the group reported in the Jan. 8 issue of Neurology.

“Specifically, MRI-predicted and actual CSF tt/Aβ values are highly correlated, predicted tt/Aβ accurately defines the anatomic distribution in Alzheimer’s disease and frontotemporal lobar degeneration (FTLD), and predicted tt/Aβ values are reasonably accurate for classifying individual patients as having Alzheimer’s disease or FTLD pathology,” they wrote.

“This study establishes empirical evidence that an MRI-based technique can predict a single, biologically valid level of CSF tt/Aβ. This may contribute to diagnosis and treatment trials of neurodegenerative conditions by screening for individuals requiring a more invasive diagnostic lumbar puncture,” they added.

Measurement of tt/Aβ in CSF has demonstrated diagnostic accuracy for distinguishing between Alzheimer’s disease and FTLD. However, the measurement requires lumbar puncture, which is invasive and problematic in situations that require repeated measurements, such as a clinical trial. An accurate, non-invasive alternative is needed, the authors noted.

Volumetric MRI has shown potential as an alternative to assessment of CSF tt/Aβ because of its ability to capture neuroanatomical features that distinguish Alzheimer’s disease from FTLD.

The authors performed a prospective study to compare MRI-predicted versus actual CSF tt/Aβ in 185 patients with clinically diagnosed neurodegenerative disease. All patients underwent lumbar puncture, and CSF tt/Aβ showed a profile consistent with Alzheimer disease in 88 cases and other conditions in the remaining 97 patients.

The patients underwent volumetric MRI an average of 5 months after lumbar puncture.

The authors estimated MRI-predicted CSF tt/Aβ on the basis of the extent of gray matter atrophy. Comparison of predicted and actual CSF tt/Aβ showed significant correlation between the two measures (P<0.0001).

Next, investigators examined neuroanatomic features of the patients’ gray matter to develop profiles associated with measured CSF tt/Aβ. Lower actual values for CSF tt/Aβ, indicative of FTLD, were associated with reduced gray matter density in the ventromedial prefrontal cortex, orbital frontal cortex, insula, thalamus, and anterior temporal cortex.

Higher CSF tt/Aβ values, associated with Alzheimer’s disease, were associated with reduced gray matter density in posterior regions, including superior parietal cortex, precuneus, and occipital association cortex.

“A regression revealed a very similar distribution of reduced gray matter density associated with tt/Aβ levels predicted by MRI,” the authors wrote. “Lower predicted tt/Aβ values, consistent with FTLD, were related to reduced gray matter density in frontal regions … by comparison, higher predicted tt/Aβ values, consistent with Alzheimer’s disease, were related to reduced density in posterior gray matter regions.”

The investigators compared the predicted and actual tt/Aβ in a subset of 32 patients with known pathology (21 with FTLD, 11 with Alzheimer’s), as determined by genetic mutations or detailed neuropathologic studies. Using a cutoff of -1.38 for actual tt/Aβ resulted in 91% sensitivity and 81% specificity for Alzheimer’s disease and overall classification accuracy of 84%.

The authors reported that 17 patients were correctly identified as having FTLD, and 10 patients with Alzheimer’s disease were classified correctly on the basis of actual tt/Aβ.

Using the same cutoff value, investigators repeated the calculations for MRI and found 75% overall accuracy for classification of the patients: 17 of 21 patients with FTLD and seven of 11 with Alzheimer’s disease.

McMillan’s group cautioned that the trajectory of disease may be a limiting factor for MRI-based CSF screening.

“While we demonstrate that the distribution of gray matter atrophy in Alzheimer’s disease and FTLD is highly related to a distinct range of CSF tt/Aβ values, these biological changes may occur at different stages in the disease course,” they said.

The authors of an accompanying editorial praised the work as another step forward in defining MRI’s role in pathologic diagnosis.

“The results of McMillan et al are impressive,” wrote Christian Habeck, PhD, of Columbia University in New York City and Jennifer Whitwell, PhD, of the Mayo Clinic in Rochester, Minn. “The clinical diagnoses of the patients with Alzheimer’s disease and FTLD overlapped substantially, demonstrating utility for predicting pathology in clinically atypical patients in which diagnosis is the most challenging.”

By Charles Bankhead, Staff Writer, MedPage Today

A team of scientists under the guidance of the University of Bonn and University of Massachusetts (USA) and with the participation of the German Center for Neurodegenerative Diseases have discovered a new signaling pathway in mice which is involved in the development of chronic inflammation which causes nerve cells in the brain to malfunction and die off. The results are now being published in the renowned scientific journal “Nature”.

Alzheimer’s disease gradually leads to the destruction of nerve cells and thus to significant losses in memory formation and recall. “Many years before the initial symptoms occur, so-called plaques, which consist of incorrectly folded beta-amyloid peptides, form in the brain of affected persons,” says lead author Prof. Dr. Michael T. Heneka, director of the Clinical Neurosciences study group at the Neurology Clinic of the University of Bonn and researcher at the German Center for Neurodegenerative Diseases (DZNE). In addition, there are abnormal tau protein deposits in the brain cells of the patients. “As a result of a signal cascade, there is a chronic inflammatory reaction and the progressive loss of nerve cells,” reports Prof. Dr. Eicke Latz from the Institute of Innate Immunity of the Bonn University Hospital, who also performs research for the DZNE and the University of Massachusetts Medical School (USA).

Caspase-1 is increased in the brains of Alzheimer’s patients

The scientists from the University of Bonn and the DZNE, in a successful alliance of neurologists and immunologists together with their colleagues from the Caesar Research Center and the Technical University of Braunschweig, have discovered a new signaling pathway which is involved in the development of chronic inflammation of the brain cells. Caspase-1 plays a key role and it is jointly responsible for the activation of the inflammatory reaction. The researchers detected substantially increased amounts of caspase-1 in the brains of Alzheimer’s patients in comparison to healthy persons. These increased levels were associated with chronic inflammatory reactions of the immune cells in the brain. The scientists also observed these findings in genetically modified mice who represent a well established model of Alzheimer’s disease.

Silent genes prevent inflammation and memory loss

The gene NLRP3 is also crucially involved in the inflammatory signaling pathways which lead to the degneration and loss of brain cells. The scientists therefore deactivated the NLRP3 gene as well as caspase-1 in the Alzheimer’s mice. As a result, there was no inflammation in the brains of these animals and they did not develop any memory loss. In addition, there was shown to be far less beta-amyloid peptide deposited in the brain cells of the genetically silent mice. It is evident that the non-inflamed cells were able to dispose of the deposited plaques much better as “metabolic waste.” If the genes for caspase-1 and NLRP3 are muted, the nerve cells and memory are evidently protected from the typical Alzheimer’s processes.

Possible starting point for new therapies

These results indicate a starting point which could possibly aid in the development of new forms of therapy for the treatment of early-stage Alzheimer’s disease. “We are still in the basic research stage and thus therapeutic success cannot be foreseen at this time point ,” says Prof. Heneka. “There is still a long way to go until the first clinical studies.”

Read more: Inflammation as a New Therapeutic Approach For Alzheimer’s Disease | Medindia http://www.medindia.net/news/inflammation-as-a-new-therapeutic-approach-for-alzheimers-disease-111868-1.htm#ixzz2GJpoDIZm

A second phase 3 trial investigating bapineuzumab IV in patients with mild to moderate Alzheimer’s disease (AD) has been stopped, essentially spelling the end of the program to investigate this agent in patients with this type of dementia.

The 18-month, randomized, double-blind, multicenter studies were examining the efficacy and safety of bapineuzumab, a monoclonal antibody that targets beta-amyloid (Aß), in patients who carry the apolipoprotein E epsilon 4 (ApoE4) genotype and in those who do not.

The study involving ApoE4 carriers (Study 302) failed to meet co-primary clinical endpoints of change in cognitive and functional performance compared with placebo; topline results were released July 23.

The phase 3 trial of those without the ApoE4 genotype included some 1300 patients, and the study of carriers included about 1100 subjects. The co-primary clinical endpoints for both studies were the change in the AD Assessment Scale–Cognitive Subscale (ADAS-Cog) and in the Disability Assessment for Dementia (DAD).

These studies were led by Janssen Alzheimer Immunotherapy R&D LLC (Janssen AI), a partner with Pfizer Inc in the Alzheimer’s Immunotherapy Program (AIP). Based on results of these trials, the Janssen AI and Pfizer Joint Steering Committee for the AIP “has decided to discontinue all other bapineuzumab IV studies in patients with mild-to-moderate Alzheimer’s disease,” the statement said.

These clinical findings and the decision to discontinue the other trials have, “been shared with regulatory authorities and study investigators.” No new safety signals were seen in these trials, the statement notes.

Pfizer was conducting 2 additional phase 3 trials, primarily outside of North America, that also enrolled patients with mild to moderate AD with and without the ApoE4 risk allele. The statement notes that all patients in the discontinued studies will undergo a follow-up evaluation, and final data analyses will be conducted.

Data from both phase 3 trials are expected to be presented in September at the European Federation of Neurological Societies (EFNS) meeting in Stockholm.

Not Surprising

The decision to pull the plug on this research came as no surprise to some experts in the field, some of whom maintain that the intervention was introduced too late in the disease process to make a difference.

Sam Gandy, MD, PhD, director of the Mount Sinai Center for Cognitive Health, Mount Sinai chair in Alzheimer’s disease research, and professor of neurology and psychiatry at Mount Sinai School of Medicine in New York City, is one of these. He told Medscape Medical News that he was not surprised by the news that the trials were being disbanded; however, he was not discouraged by it.

He pointed to one potential new strategy for addressing AD — lowering amyloid-beta. This development arises from the recent discovery by a team of researchers in Iceland of an amyloid precursor protein (APP) mutation that may protect against AD. He noted mounting evidence of the importance of physical exercise and social engagement in preserving cognition — and even reversing the effects of ApoE4 in the case of social engagement.

Understanding how these interventions affect the brain at the molecular level is an important new research direction, said Dr. Gandy.

More Optimistic

Dr. Gandy says he feels “more optimistic than ever” that scientists eventually will find a way to lower amyloid-beta to preserve cognition throughout one’s entire life. “I think that controlling one’s amyloid-beta is likely to be a lifelong endeavor, just like controlling one’s cholesterol.”

Reisa Sperling, MD, professor of neurology at Harvard Medical School, and director of the Center for Alzheimer Research and Treatment, at Brigham and Women’s Hospital, in Boston, Massachusetts, was lead investigator in the study involving ApoE4 carriers and served as a member of the steering committee for the study of noncarriers.

When topline results of the study in ApoE carriers were released in July, Dr. Sperling told Medscape Medical News that the lack of clinical efficacy perhaps was not surprising, “given the significant pathology by this stage of the disease in this genetic risk group.”

She said she hoped to see “at least a signal” of clinical effect in the noncarrier study, but “ultimately, I suspect we will have to treat Alzheimer’s disease at least 5 to 10 years earlier in the disease process to really affect the clinical course.”

Brendon Boot, MD, a neurologist at the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, pointed out that results of these trials will be disappointing for patients living with AD and their families. However, he said that he and others in the field believe that there is still hope for successful treatment of the disease.

“It may be that these treatments are biologically active, but that we need to begin treatment earlier — possibly even before cognitive symptoms begin,” he told Medscape Medical News.

A large consortium of academic units is working on such a plan “as we speak,” said Dr. Boot.

In the press release, Steven J. Romano, MD, senior vice president and head of the Medicines Development Group, in the Global Primary Care Business Unit at Pfizer Inc, said that he and others are “obviously very disappointed” in the outcome of the research.

“We are also saddened by the lost opportunity to provide a meaningful advance for patients afflicted with mild to moderate Alzheimer’s disease and their caregivers,” he said. “Yet these data and the subgroup and biomarker analyses under way will further inform our understanding of this complex disease and advance research in this field.”

Women with the highest levels of ceramides had a 10-fold higher risk of developing Alzheimer’s compared with those with the lowest levels, said Michelle M. Mielke, PhD, from the Mayo Clinic, Rochester, Minnesota.

“The study is small — that’s a limitation, and it was a preliminary study. However, given the small sample size, to have hazard ratios that are near 10 was quite striking and we didn’t expect to see that at all,” Dr. Mielke told Medscape Medical News.

“Pretty much any marker is not going to be associated with a 10-fold risk, so yes, this does need to be replicated in another study, but it suggests to us that plasma or blood ceramide levels are associated with an increased risk of Alzheimer’s disease,” she said.

Results of the preliminary study were published online July 18 in Neurology.

High Ceramide Levels

Previous studies have found links between high serum ceramide levels and memory impairment and hippocampal volume loss. In this study, Dr. Mielke and her group wanted to see whether blood levels of ceramides and sphingomyelins would be associated with increased risk of Alzheimer’s disease (AD).

Researchers used participants who were enrolled in the Women’s Health and Aging Study II, a longitudinal, population-based study of healthy women 70 to 80 years of age, living in Baltimore, Maryland. None had dementia at baseline.

Participants were followed for up to 6 visits over 9 years. Their blood was collected at baseline and at each subsequent visit.

Of 99 women, 27 (27.3%) developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable Alzheimer’s disease.

The study found that higher baseline serum ceramides were associated with increased risk of Alzheimer’s disease. Higher levels of sphingomyelins were not linked to increased Alzheimer’s disease risk.

However, women in the middle tertile of serum ceramide levels had the highest risk for Alzheimer’s versus those in the lowest tertile, with an intermediate increased risk seen among those in the highest tertile.

“We think that this might indicate a threshold effect for the ceramides, so it may be that instead of high levels being a risk factor, low levels are protective. We haven’t quite figured that out, and further studies are needed to better determine this threshold effect,” Dr. Mielke said.

She added that she and her group currently have a study of more than 1000 people with some 4500 blood samples ongoing.

“We are just starting to get the data in,” she noted. “The thing with these lipids is that the assay methods are a bit more difficult than they are for some of the more common lipids, and so we are working on trying to develop more of a high throughput method, and one that can be used reliably across laboratories. That is one of the reasons why these tests haven’t been done in bigger population-based studies, and we are just starting to get into that route right now.”

The next goal is to examine what normal ceramide levels are and what factors affect them, she added.

Findings Noteworthy

Writing in an accompanying editorial, Valory Pavlik, PhD, of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine, Houston, Texas, called the study findings “noteworthy.”

Identification of an accurate biomarker to predict Alzheimer’s disease, “which can be obtained with a minimum of cost and inconvenience to the individual, would greatly facilitate the transition of AD therapeutics research from the traditional model focused on treating established disease to a model focused on preventing or delaying disease onset,” Dr. Pavlik writes.

The study was funded by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the Johns Hopkins Older Americans Independence Center. Drs. Mielke and Pavlik have disclosed no relevant financial relationships. (Fran Lowry)

Bapineuzumab is an investigational monoclonal antibody that targets amyloid-ß (Aß) under development by the Alzheimer’s Immunotherapy Program (AIP), a partnership between Janssen Alzheimer Immunotherapy R&D LLC (Janssen AI) and Pfizer Inc.

“These clinical findings have been shared with regulatory authorities and study investigators so that participants in the ongoing clinical program can be informed,” a statement from the companies notes. “Because in this study, clinical efficacy was not demonstrated in ApoE4 carriers, the Janssen AI and Pfizer Joint Steering Committee for the AIP has decided that participants from this study who enrolled in a follow-on extension study will no longer receive doses of bapineuzumab. However, these patients will have a follow-up evaluation.”

The findings would appear to mirror phase 2 study results with bapineuzumab that had missed the same primary endpoints but showed a suggestion of benefit only in ApoE4 noncarriers.

“The lack of clinical efficacy in the ApoE4 carriers at the stage of dementia is very disappointing, but perhaps not surprising, given the significant pathology by this stage of the disease in this genetic risk group,” Reisa Sperling, MD, professor of neurology at Harvard Medical School, and director, Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, in Boston, Massachusetts, told Medscape Medical News. Dr. Sperling was lead investigator on the study.

She said they hope to see “at least a signal” of clinical effect in the noncarrier study, on which she is also a member of the steering committee, “but ultimately, I suspect we will have to treat Alzheimer’s disease at least 5 to 10 years earlier in the disease process to really affect the clinical course.”

Dr. Sperling pointed out that it will be important to investigate biomarker data from the trial, including positron emission tomography (PET) imaging and cerebrospinal fluid markers, to better understand the biological effects of treatment in both carriers and noncarriers. “We plan to present these data in early September,” she noted.

Topline results of a second trial, Study 301 in noncarriers, are expected later this summer, the Pfizer statement notes, adding that both Study 302 and Study 301 have been accepted as late breakers for presentation at the upcoming European Federation of Neurological Societies meeting in Stockholm, Sweden, in September. The AIP plans to expedite completion of the interim analysis of Study 3001 in ApoE4 carriers based on results of the current study.

This phase 3 trial, called Study 302, is one of 4 studies examining the efficacy of bapineuzumab in AD. Janssen AI is leading Study 302 in ApoE4 carriers, as well as Study 301 in noncarriers, with AD. Pfizer is conducting 2 additional phase 3 trials, primarily outside of North America, also enrolling patients with mild to moderate AD who are ApoE4 noncarriers (Study 3000) and carriers (Study 3001).

“Based on a comprehensive review of the data by the independent safety monitoring committee, all the other ongoing Janssen AI and Pfizer bapineuzumab studies are continuing as planned and without modifications,” the statement notes.

Study 302 included 1100 patients with the ApoE4 risk allele. The co-primary endpoints were change in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and in the Disability Assessment for Dementia (DAD). No data were released at this time, but the treatment did not meet either endpoint.

The most common adverse events that occurred with higher frequency with treatment than with placebo at an incidence of at least 1% were amyloid-related imaging abnormalities suggestive of edema or effusion (ARIA-E) on magnetic resonance imaging — an effect that has been a concern with bapineuzumab in the past — and dehydration.

Aß Hypothesis

Passive or active immunotherapy against Aß is one of the major strategies being evaluated as a disease-modifying therapy for AD, and several other companies have immunotherapies in phase 2 and 3 investigation. The hope is to bind and clear amyloid from the brain, but the question has begun to arise of whether Aß is the real culprit in the disease process.

To date, amyloid-clearing therapies have not been able to stop cognitive or functional decline associated with the disease, despite evidence that they are successfully clearing amyloid. Many speculate that treatment is coming too late in the process, once cognitive and functional symptoms appear.

Earlier detection of Aß deposition using PET tracer agents that have recently been approved or that are in late stages of development may provide an opportunity to remove amyloid before symptoms appear, researchers suggest.

Dr. Sperling was head of the writing committee that recently published a new guideline proposing diagnostic criteria for a preclinical stage of Alzheimer’s disease. They are considering the possibility of using bapineuzumab in a large prevention trial that is now being planned in those with early, preclinical disease, Dr. Sperling noted.

Progress ‘Incremental’

In a statement, the Alzheimer’s Association noted that the results are disappointing, but not surprising.

“While we have high hopes for every Alzheimer’s and dementia therapy trial, history shows that progress is incremental and we will have setbacks along the way. These setbacks also provide critical information to the research community for application in future studies,” the statement notes. “The Alzheimer’s Association is not surprised by these newly announced results based on reports from earlier studies in carriers of the ApoE4 Alzheimer’s risk gene.

“While not the overall positive results we would all hope for, a positive finding is that the side effects profile appears to be manageable based on the data currently released,” the Association statement adds. “This gives us hope for the potential usability of drugs of this type (immunotherapies that target a protein called beta amyloid in the brain) in future studies.”

Trials of several Alzheimer’s drugs with varied mechanisms of action have shown differing results in carriers versus noncarriers, they add, and “this may also be the case with bapineuzumab. We learn more about Alzheimer’s disease from every study, and results from additional phase 3 studies of this drug, in an additional population of people who carry the ApoE4 gene as well as people who do not carry the gene, are expected soon.”

The Association “remains unwaveringly committed to finding better therapies and prevention for Alzheimer’s disease and related disorders as well as providing 24/7 support for people and families facing Alzheimer’s disease today.

“We are eager for the launch of upcoming Alzheimer’s disease prevention trials, which were featured at the just-concluded Alzheimer’s Association International Conference (AAIC), and also about how the field will benefit from projects such as the worldwide Alzheimer Disease Neuroimaging Initiative, which now includes whole genome sequencing for all participants, and the International Genomics of Alzheimer’s Project,” the statement concludes. (Susan Jeffrey)