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.

Preliminary results from 2 studies presented here at the Alzheimer’s Association International Conference (AAIC) 2014 show that beta-amyloid detected in the eyes significantly correlated with the burden of beta-amyloid in the brain, allowing investigators to accurately identify individuals with AD.

In the first study, researchers at the Commonwealth Scientific and Industrial Research Organization (CSIRO), Australia’s national science agency, used curcumin fluorescence imaging to highlight beta-amyloid in the retina and correlated these results using Pittsburgh compound B (PiB) positron emission tomography (PET) imaging findings in the brain.

“Every single person who tested positive with high levels of plaque in the brain tested positive to the retinal test as well, so we had 100% sensitivity and no false negatives, which is a crucial component on a screen for Alzheimer’s disease because we don’t want to leave anyone behind when it comes to the early signs,” lead investigator Sean Frost said at a press briefing here.

The investigators note that although AD-related pathology in the brain is well documented, the disease has also been reported to affect the retina, a developmental outgrowth of the brain that is more accessible for imaging.

The primary substance in the Asian spice turmeric, curcumin has several properties that make it a good contrast medium ― it binds with high affinity to beta-amyloid, and it has fluorescent properties that enable amyloid plaques to be imaged in the retina. In addition, said Frost, it is safe.

Study participants included individuals with AD, individuals with mild cognitive impairment, and healthy control participants from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) study.

In addition to undergoing PiB PET imaging, participants made 2 visits for retinal fluorescence imaging. During the first visit, they drank a proprietary curcumin supplement. On the second visit, they underwent retinal amyloid imaging (RAI).

Preliminary data from the first 40 participants showed that amyloid levels detected in the retina were significantly correlated with brain amyloid levels, as shown by PiB PET imaging. In addition, RAI differentiated participants with AD from those without AD with 100% sensitivity and 80.6% specificity.

Furthermore, said Frost, longitudinal data showed an average increase of 3.5% in retinal amyloid during a 3.5-month period, suggesting that the technique may be used as a means of monitoring response to therapy.

If these early findings bear out, Frost said, this technology could be used as an initial screen for AD that could potentially be part of regular eye examinations.

“One day we hope there’s going to be better treatments available, and this will definitely provide a frontline screening tool to detect it in the early stages, before cognitive decline, and hopefully change the course of Alzheimer’s disease,” he said.

The full study is expected to be completed later this year.

On-the-Spot Results

In the second study, investigators from Cognoptix Inc, in Acton, Massachusetts, reported findings showing that a novel fluorescent ligand eye scanning (FLES) system that detects beta-amyloid in the lens of the eye also accurately detects amyloid burden and correlates with florbetapir PET brain imaging.

This phase 2 study included 20 individuals with probable mild to moderate AD and 20 healthy, age-matched control participants.

For the study, participants had a small molecule applied to the eye in the form of a sterile ophthalmic ointment. The compound is left to diffuse into the eye overnight; the next day, the eye is scanned with the laser and results are computed.

All 40 participants also underwent PET amyloid brain imaging.

According to Paul D. Hartung, president and CEO of Cognoptix Inc, who presented the findings, the study showed that the test was able to differentiate individuals with Alzheimer’s from healthy control participants with 85% sensitivity and 95% specificity (P < .001). In addition, amyloid levels in the lens significantly correlated with PET imaging results.

Hartung pointed out that at approximately $300, the test is about 10 times less expensive than PET imaging and much less invasive than cerebrospinal fluid testing.

In addition, he said, a single scan takes less than a second, and the instrument can compute a score, known as a fluorescence uptake value, in less than 5 minutes.

Furthermore, he said, the technology requires minimal training and has the potential to be used by general practitioners, nurses, and other healthcare practitioners in clinics and offices. It is also safe and could be administered on a regular basis to track disease progression and to monitor treatment.

“Early detection is critical. We are hoping the treatments that are being developed will be more effective if they are administered earlier, and we need something that can be made accessible to doctors everywhere,” he said.

With principal investigator Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, Arizona, Hartung said the investigators are currently conducting a pivotal phase 3, multicenter, US-based study to support US Food and Drug Administration approval of the FLES system as an aid in the diagnosis of probable AD.

Exciting Findings

Commenting on the studies for Medscape Medical News, David Knopman, MD, professor of neurology at the Mayo Clinic College of Medicine, consultant in neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the Alzheimer’s Association Medical and Scientific Advisory Council, who moderated a press conference on this topic, said he was “very impressed” by both papers and particularly the retina paper.

“I thought the data were very interesting, and if it is the case that the amyloid in the retina parallels the amyloid in the brain ― and that’s what they were showing ― that’s really an exciting finding.

“I think that brain amyloid imaging at this point has been of tremendous scientific value in allowing us to understand who is either at risk, or who actually has the pathology of Alzheimer’s disease in life, but it’s so expensive. At my institution, to do an Amyvid [Avid Radiopharmaceuticals, Inc] scan is somewhere between $5000 and $7000.

“The Center for Medicare and Medicaid Services doesn’t pay for amyloid imaging. We’re looking into that for research purposes, but if this actually could substitute for that, say, in clinical trials or under appropriate circumstances if there were therapies to identify people who would benefit from the therapies, that would be a tremendous advance.”

Unfortunately, said Dr. Knopman, at this point, the Alzheimer’s field lacks a powerful therapy to prevent the disease or stop it in its tracks.

“At this point, we understand that, but the kind of approaches described here are the kind of approaches we need to have in place when we have those effective therapies,” he said.

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.

Approval of this new indication for the 13.3 mg/24h dose rivastigmine patch means it can be used across all stages of disease, making it the only transdermal therapy that can be used across all stages of disease, the company notes in a statement. The patch is already approved for patients with mild to moderate dementia of the Alzheimer’s type and for patients with mild to moderate dementia associated with Parkinson’s disease.

The approval in severe AD was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer’s Type) study, a randomized, double-blind trial comparing the 13.3 mg/24h dose patch with the lower 4.6 mg/24h dose.

The higher-dose patch demonstrated statistically significant improvement in overall cognition and function in severe AD patients at week 24, as assessed by measures of cognition and daily function using the Severe Impairment Battery (SIB) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living–Severe Impairment Version (ADCS-ADL-SIV), respectively.

The most common adverse reactions included application site erythema, fall, insomnia, vomiting, diarrhea, weight loss, and nausea, and these were seen in a higher percentage of patients treated with the 13.3 mg/24h dose.

Full information is available at Exelon Patch Full Prescribing Information and Exelon Patch Patient Product Information.

The study shows that increased total white matter hyperintensities (WMHs) as seen on MRI independently predicted AD diagnosis, as did the brain amyloid tracer Pittsburgh compound B (PIB) measured by positron emission tomography (PET).

This finding suggests that although amyloidosis is necessary for a diagnosis of AD, it may not be sufficient to cause dementia and that WMH may represent another important pathogenetic factor that contributes to dementia.

“This study, along with a whole line of research that is coming out right now, is clearly highlighting the importance of vascular disease in Alzheimer’s disease,” said author Adam M. Brickman, PhD, assistant professor of neuropsychology at Columbia University, New York.

“In the past, we didn’t conceptualize AD as having a vascular component at all — we typically thought of it only as plaques and tangles — but now we’re showing, and other groups are showing, that these vascular lesions may be as important.”

The study was published online February 18 in JAMA Neurology.

ADNI Data

The researchers used data obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which was launched in 2003 by the National Institute on Aging, the Food and Drug Administration, pharmaceutical companies, and various other groups.

The goal of ADNI is to test whether serial MRI, PET, other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and AD.

From the ADNI database, the researchers downloaded data from 21 normal controls, 59 patients with MCI, and 20 patients with clinically defined AD. The 3 groups were similar in age, sex distribution, and modified Hachinski Ischemic Scale score.

The investigators also downloaded data from carbon 11–labeled PIB-PET scans. And they derived total WMH volumes for the participants from MRI.

Twenty-eight participants (68%) were classified as PIB positive, of whom 17 met clinical criteria for AD, and 13 participants were classified as PIB negative, of whom 3 met criteria for AD.

The mean total WMH volume was 5.71 cm³. Total WMH volume did not differ between PIB-positive and PIB-negative participants. However, there was a significant negative association between cortical PIB-uptake values and total WMH volume among all participants, including those with MCI.

The analysis demonstrated that higher WMH volume (P = .02) and PIB positivity (P = .049) were each independently associated with AD diagnosis. Age was not associated with the diagnosis.

As well, the analysis showed that patients with AD had greater WMH burden than normal controls who also were PIB positive.

WMH volume discriminated between persons with clinical AD and normal controls. Setting a cutoff at 1.25 cm³, total WMH volume yielded a sensitivity of AD classification of 83% and a specificity of 64%.

Of 59 participants with MCI, who were followed for about 2.5 years, 37% converted to AD. When comparing these patients with MCI according to their PIB positivity and high or low WMH volume, the researchers found that both of these factors were significant predictors of future conversion to AD.

Researchers don’t yet know how amyloid and WMHs are connected. “We showed a modest correlation between PIB positivity and WMH volume, suggesting that if you have a lot of WMHs, you also have a lot of amyloid in your brain, but that’s certainly not a definitive indication that they are mechanistically related,” said Dr. Brickman.

To get a better handle on the connection, the researchers are studying the pathologic basis of WMHs by investigating postmortem tissue with MRI and histologic techniques. “That might help us understand if the pathological basis of the WMHs is related to, [is] co-localized, or co-occurs in the same regions as the amyloid we see in AD,” said Dr. Brickman.

Tip of the Iceberg

But current MRI technology may not be sensitive enough to pick up all the pathologic features associated with WMH. “What we could be dealing with here is just sort of a tip-of-the-iceberg phenomenon,” said Dr. Brickman. “Everyone who has WMH could have these pathological features in their white matter, but we may not be detecting everyone who has those features with our current technology.”

In the future, though, MRI showing WMH could eventually become an important tool to help determine the presence of AD. “We have a syndrome of AD that looks like cognitive impairment with functional disability and I think there are various pathological features that contribute to that syndrome,” said Dr. Brickman. “In one person, it might be more of an amyloid and tangles story, and in another person, it might be more amyloid and vascular disease.”

Dr. Brickman stressed that AD is “a really heterogenous disease” and perhaps “not as simple as some of the theoretical models about the pathogenesis make it seem to be.”

In light of these results, it might become increasingly important to control risk factors for WMHs, said Dr. Brickman. These risk factors are essentially the same as those for stroke and include hypertension, diabetes, obesity, heart disease, and smoking.

“We know that all these risk factors, at least in the epidemiological literature, have been associated with the risk for AD, and here we’re showing that perhaps the mechanism through which they confer risk has to do with these small lesions we see on MRI scans,” said Dr. Brickman, adding that preventing these lesions is likely a “lifelong process.”

It’s unclear, though, whether controlling vascular risk factors and preventing the accumulation of WMHs would prevent AD, he said. “But I think there is a growing amount of evidence to suggest that control of vascular factors can at least reduce the risk, maybe delay the onset, and perhaps mitigate the symptoms of the disease itself.”

Open Area of Research

In an accompanying editorial, Karen M. Rodrigue, PhD, School of Behavioral and Brain Sciences, University of Texas at Dallas, observed that the contribution of vascular pathology to AD is an important and “open” area of current research.

The results of this study, said Dr. Rodrigue, indicate that among people with elevated brain amyloid levels, the WMH burden can discriminate between those with clinical AD and those who are cognitively normal.

“Additionally, both amyloid and WMH status combined to best predict who would convert to AD among those with MCI,” she writes.

Importantly, she pointed out that the study suggests that information about a patient’s WMH may help identify those who are at most risk for conversion to AD. “These findings have important clinical implications in light of the observation that 20% to 30% of cognitive healthy older adults show elevated amyloid levels.”

For a list of study sponsors, see the original article. The authors have disclosed no relevant financial relationships.

JAMA Neurol. Published online February 18, 2013. Abstract Editorial

The observations add to previous studies suggesting that “progressive exercise training markedly decreased diabetes associated neuropathic pain,” write Yu-Wen Chen, PhD, of China Medical University, Taichung, Taiwan, and colleagues. The link to Hsp72 offers a clue as to how exercise can prevent or slow the development of neuropathy—a major complication of diabetes.

Exercise Reduces Diabetic Nerve Pain in Rats
Neuropathic pain is a common and difficult-to-treat type of pain related to nerve damage—most commonly caused by diabetes. Affecting about half of patients with diabetes, diabetic neuropathy causes symptoms such as numbness, tingling, or pain in the arms and legs.

Dr Chen and colleagues examined the effects of exercise on neuropathy caused by chemically-induced diabetes in rats. For a few weeks after induction of diabetes, some animals were assigned to a progressive treadmill exercise program.

Within two weeks, the diabetic rats that did not exercise showed signs of diabetic neuropathy, based on observable pain behaviors. These included abnormal responses to temperature and pressure (thermal and tactile hypersensitivity)—both characteristic of neuropathic pain.

“In contrast, diabetic rats undergoing exercise demonstrated delayed progress of tactile and thermal hypersensitivity,” Dr Chen and colleagues write. The reduction in painful diabetic neuropathy was associated with lesser increases in blood glucose levels after induction of diabetes.

Previous studies have suggested that neuropathic pain may be related to expression of certain inflammation-promoting cytokines—such as tumor necrosis factor-alpha and interleukin-6—which might be reduced by exercise. In the new experiments, expression of TNF-alpha and IL-6 in nerve tissue were significantly increased after induction of diabetes, with no difference for exercising versus non-exercising animals.

Findings Suggest Role of Heat Shock Protein
However, diabetic rats assigned to exercise showed increased expression of Hsp72 in nerve tissues. Hsp 72 is one of a family of heat shock proteins that play essential roles in protecting against cellular damage caused by various types of stress (including heat stress). Previous experiments have shown protective effects of Hsp72 in other conditions, including neuropathy caused by mechanical nerve injury.

Exercise is commonly recommended for patients with various types of chronic pain, and is routinely prescribed as part of treatment to control diabetes. A growing body of evidence suggests that exercise may also have beneficial effects in reducing painful diabetic neuropathy.

The new study provides support for the concept that exercise can slow the progression of diabetic neuropathy. In the animal experiments, exercise had short-term effects on abnormal responses to pain and temperature, although long-term responses were unchanged.

The study also adds new evidence that exercise may protect against diabetic neuropathy by suppressing induced blood sugar levels while increasing expression of Hsp72 in nerve tissues. The results may present new opportunities for developing new, nondrug approaches that can “delay or protect against the development of diabetic peripheral nerve complications,” Dr Chen and coauthors conclude.

Read the article in Anesthesia & Analgesia

“This increase is due to an aging baby boom generation. It will place a huge burden on society, disabling more people who develop the disease, challenging their caregivers, and straining medical and social safety nets,” said co-author Jennifer Weuve, MPH, ScD, assistant professor of medicine, Rush Institute for Healthy Aging at Rush University Medical Center in Chicago. “Our study draws attention to an urgent need for more research, treatments and preventive strategies to reduce this epidemic.”

For the study, researchers analyzed information from 10,802 African-American and Caucasian people living in Chicago, ages 65 and older, between 1993 and 2011. Participants were interviewed and assessed for dementia every three years. Age, race and level of education were factored into the research.

The data were combined with US death rates, education and current and future population estimates from the US Census Bureau.

The study found that the total number of people with Alzheimer’s dementia in 2050 is projected to be 13.8 million, up from 4.7 million in 2010. About 7 million of those with the disease would be age 85 or older in 2050.

“Our detailed projections use the most up-to-date data, but they are similar to projections made years and decades ago. All of these projections anticipate a future with a dramatic increase in the number of people with Alzheimer’s and should compel us to prepare for it,” said Weuve.

Liesi Hebert, ScD, assistant professor, Rush University Medical Center, is lead author of the study.

The study was supported by the Alzheimer’s Association and the National Institute on Aging of the National Institutes of Health.

To learn more about Alzheimer’s disease, visit http://www.aan.com/patients.

And it’s not easy. Holes are drilled into the patient’s skull so tiny wires can be implanted into just the right spot.

A dramatic shift is beginning in the disappointing struggle to find something to slow the damage of this epidemic: The first US experiments with “brain pacemakers” for Alzheimer’s are getting under way. Scientists are looking beyond drugs to implants in the hunt for much-needed new treatments.

The research is in its infancy. Only a few dozen people with early-stage Alzheimer’s will be implanted in a handful of hospitals. No one knows if it might work, and if it does, how long the effects might last.

Kathy Sanford was among the first to sign up. The Ohio woman’s early-stage Alzheimer’s was gradually getting worse. She still lived independently, posting reminders to herself, but no longer could work. The usual medicines weren’t helping.

Then doctors at Ohio State University explained the hope – that constant electrical stimulation of brain circuits involved in memory and thinking might keep those neural networks active for longer, essentially bypassing some of dementia’s damage.

Ms Sanford decided it was worth a shot.

“The reason I’m doing it is, it’s really hard to not be able, sometimes, to remember,” Ms Sanford, 57, said from her home.

Her father is blunter.

“What’s our choice? To participate in a program or sit here and watch her slowly deteriorate?” asked Joe Jester, 78. He drives his daughter to follow-up testing, hoping to spot improvement.

A few months after the five-hour operation, the hair shaved for her brain surgery was growing back and Ms Sanford said she felt good, with an occasional tingling that she attributes to the electrodes. A battery-powered generator near her collarbone powers them, sending the tiny shocks up her neck and into her brain.

It’s too soon to know how she’ll fare; scientists will track her for two years.

“This is an ongoing evaluation right now that we are optimistic about,” is how Ohio State neurosurgeon Dr Ali Rezai cautiously puts it.

Today’s drugs only temporarily help some symptoms. Attempts to attack Alzheimer’s presumed cause, a brain-clogging gunk, so far haven’t panned out.

“We’re getting tired of not having other things work,” said Ohio State neurologist Dr Douglas Scharre.

The new approach is called deep brain stimulation, or DBS. While it won’t attack Alzheimer’s root cause either, “maybe we can make the brain work better,” he said.

Implanting electrodes into the brain isn’t new.

Between 85,000 and 100,000 people around the world have had DBS to block the tremors of Parkinson’s disease and other movement disorders. The continuous jolts quiet overactive nerve cells, with few side effects. Scientists also are testing whether stimulating other parts of the brain might help lift depression or curb appetite among the obese.

It was in one of those experiments that Canadian researchers back in 2003 stumbled onto the Alzheimer’s possibility. They switched on the electrical jolts in the brain of an obese man and unlocked a flood of old memories. Continuing his DBS also improved his ability to learn. He didn’t have dementia, but the researchers wondered if they could spur memory-making networks in someone who did.

But wait a minute.

Alzheimer’s doesn’t just steal memories, it eventually robs sufferers of the ability to do the simplest of tasks. How could stimulating a brain so damaged do any good?

A healthy brain is a connected brain. One circuit signals another to switch on and retrieve the memories needed to, say, drive a car or cook a meal.

At least early in the disease, Alzheimer’s kills only certain spots. But the disease’s hallmark gunky plaques act as a roadblock, stopping the “on” switch so that healthy circuits farther away are deactivated, explained Dr Andres Lozano, a neurosurgeon at Toronto Western Hospital whose research sparked the interest.

So the plan was to put the electrodes into hubs where brain pathways for memory, behaviour, concentration and other cognitive functions converge, to see if the jolts reactivate those silenced circuits, added Ohio State’s Dr Rezai.

“It’s like going through Grand Central Station and trying to affect all the trains going in and coming out,” he said.

Dr Lozano’s team found the first clue that it’s possible by implanting six Alzheimer’s patients in Canada. After at least 12 months of continuous stimulation, brain scans showed a sign of more activity in areas targeted by Alzheimer’s. Suddenly, the neurons there began using more glucose, the fuel for brain cells.

“It looked like a blackout before. We were able to turn the lights back on in those areas,” Dr Lozano said.

While most Alzheimer’s patients show clear declines in function every year, one Canadian man who has had the implants for four years hasn’t deteriorated, Dr Lozano said, although he cautioned that there’s no way to know whether that’s due to the DBS.

The evidence is preliminary and will take years of study to prove, but “this is an exciting novel approach,” said Dr Laurie Ryan of the National Institutes of Health’s aging division, which is funding a follow-up study.

Under way now:

-The Toronto researchers have teamed with four US medical centres – Johns Hopkins University, the University of Pennsylvania, University of Florida and Arizona’s Banner Health System – to try DBS in a part of the brain called the fornix, one of those memory hubs, in 40 patients. Half will have their electrodes turned on two weeks after the operation and the rest in a year, an attempt to spot any placebo effect from surgery.

-At Ohio State, Dr Rezai is implanting the electrodes into a different spot, the frontal lobes, that his own DBS work suggests could tap into cognition and behaviour pathways. That study will enrol 10 participants including Ms Sanford.

Surgery back in October was Ms Sanford’s first step. Then it was time to fine-tune how the electrodes fire. She took problem-solving tests while neurologist Dr Scharre adjusted the voltage and frequency and watched her reactions.

Ms Sanford was cheered to see her test scores climb a bit during those adjustments. She said she knows there are no guarantees, but “if we can beat some of this stuff, or at least get a leading edge on it, I’m in for the whole deal.”

From: AP

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

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

The researchers hope that this will be an effective solution at treating Alzheimer’s in and of itself, but if nothing else it should at least provide valuable information that could further other treatments as well. Johns Hopkins is currently accepting volunteers for the program, and hopefully those implants will give them—and all who follow—a fighting chance at hanging on to those precious memories.

Read more: ExtremeTech