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

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

The mutation, in an immunoregulatory gene known as TREM2, was more common in Alzheimer’s disease patients than in the general 85-and-older population in Iceland with an odds ratio of 2.91 (95% CI 2.09 to 4.09, P=3.42×10^-10), reported Kari Stefansson, MD, PhD, of deCode Genetics in Reykjavik, Iceland, and colleagues.

Because of the gene’s function within the central nervous system, the mutation “may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes,” the researchers wrote online in the New England Journal of Medicine.

Such processes have been implicated in Alzheimer’s disease previously, they noted. In fact, the so-called amyloid theory of the disease holds that brain inflammation is the “downstream effect” of the accumulation of beta-amyloid protein plaques, Stefansson and colleagues wrote.

On the other hand, the TREM2 mutation’s rarity, and the fact that many carriers in the study remained free of Alzheimer’s disease into extreme old age, suggested that it is neither necessary nor sufficient to trigger the disease.

In the study, Stefansson and colleagues first analyzed genome sequences from 2,261 Icelanders to identify variants considered likely to produce gain- or loss-of-function mutations in expressed proteins.

They then compared frequencies of such variants in 3,550 individuals with Alzheimer’s disease versus 110,050 individuals from the general Icelandic population. Included in the latter group were 8,888 who had reached the age of 85 without a diagnosis of Alzheimer’s disease and 1,236 who were that old and showed no sign of cognitive impairment.

A mutation in TREM2 causing an amino acid substitution at position 47 was the only one significantly associated with Alzheimer’s disease in the analysis. Compared with the sample drawn from the all-ages general population, the odds ratio was 2.26 95% CI 1.71 to 2.98) for increased frequency of the mutation in Alzheimer’s disease patients.

And, compared with the 1,236 controls older than 85 with no cognitive impairment, the odds ratio in patients was 4.66 (95% CI 2.38 to 9.14).

Nevertheless, the mutation was present in all three control groups at low frequencies, ranging from 0.62% in the general population sample to 0.31% in the cognitively intact older controls.

Older control members carrying the mutation — even those without Alzheimer’s disease — had poorer cognitive performance according to test results obtained periodically in Icelandic nursing home residents.

Mean scores in 3,699 noncarriers trended slowly upward by age, indicating progressively poorer cognitive function, from about 2.2 at age 81 to 2.7 at age 99.

The upward slope was noticeably steeper in 53 mutation carriers, increasing from a mean of about 2.3 at age 81 to 4 at age 97 (P=0.003 for trend).

Stefansson and colleagues also sought to replicate the frequency comparison in Alzheimer’s disease patients versus controls in other cohorts. They were able to test the frequency of the TREM2 mutation in groups of patients and controls assembled in the U.S., Germany, the Netherlands, and Norway — a total of 2,037 patients and 9,727 controls.

The mutation was less common in the control groups in those cohorts, ranging in frequency from 0.12% to 0.19%. But the approximately threefold increase in frequency in Alzheimer’s disease patients was preserved in pooled data from all four groups (OR 2.83, 95% CI 1.45 to 5.40, P=0.002).

On the other hand, among the individual cohorts, the association was significant in only one, from Munich (OR 3.15, 95% CI 1.06 to 10.40, P=0.04).

In an accompanying editorial, two other researchers commented that the study was important for its clear implication of inflammatory processes in at least a subset of Alzheimer’s disease cases.

The findings “may generate new insights into the pathogenesis of late-onset Alzheimer’s disease,” wrote Harald Neumann, MD, of the University of Bonn in Germany, and Mark J. Daly, MD, of Massachusetts General Hospital in Boston.

They also pointed out that the risk of Alzheimer’s disease associated with the TREM2 variant was in the same range as for the much more common APOE epsilon 4 variant.

Severe loss of function in TREM2 from homozygous mutation is already a recognized human disorder known as Nasu-Hakola disease, Neumann and Daly added. In this condition, a number of organ systems are affected, with severe dementia a late-stage symptom. Most patients die by age 50.

Previous research has indicated that heterozygous carriers of the Nasu-Hakola mutation are at increased risk for late-onset Alzheimer’s disease.