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New findings published in Archives of Neurology indicate that the progression of Alzheimer’s pathology to a clinically diagnosable state relies on both elevated p-tau protein levels and amyloid plaques. The authors suggest that without the presence of hyperphosphorylated tau (p-tau), the impact of amyloid-β (Aβ) on cognitive decline in healthy elderly individuals is negligible.

With 10–20% of Americans aged 65 years or older experiencing mild cognitive impairment, efforts to delay or prevent the progression to full blown Alzheimer’s disease (AD) are extremely pressing. The finding of p-tau’s involvement in neurodegeneration suggests that it could act as a preclinical AD biomarker. In addition, these findings also underscore the potential of p-tau as a novel target for treatment in cognitively impaired patients.

“I think this is the biggest contribution of our work,” highlights Rahul Desikan, from the University of California, San Diego (CA, USA) and first author of the study, who continues, “A number of planned clinical trials – and the majority of AD studies – focus predominantly on Aβ. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove Aβ. Older, nondemented individuals who have elevated Aβ levels, but normal p-tau levels, may not progress to AD, while older individuals with elevated levels of both will likely develop the disease.”

The team enrolled healthy, nondemented elderly participants from the Alzheimer’s Disease Neuroimaging Initiative, a multisite longitudinal study with the intention of measuring the progression of mild cognitive impairment and early-stage AD. The researchers analyzed the participants’ cerebrospinal fluid samples. The presence of Aβ alone was not correlated with clinical decline; however, the combination of p-tau and Aβ was significantly associated with cognitive decline over the 3-year study.

Although the underlying mechanisms are not fully understood, it is thought that p-tau exacerbates the toxic effects of Aβ aggregations on neuronal integrity. High levels of the protein are strongly associated with increased neurofibrillary tangles in neurons: a hallmark of AD.

“It may be that Aβ initiates the AD cascade,” explained Desikan. “But once started, the neurodegenerative mechanism may become independent of Aβ, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-Aβ compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or AD.”

More research is needed, as cerebrospinal fluid biomarkers provide only an indirect assessment of AD pathology; the dynamics of neurodegeneration need to be witnessed in human cells. The team conclude that this study highlights the complex interaction of multiple pathologies at play in the progression from preclinical to clinical AD and suggests that early intervention may be possible to prevent the onset of symptoms.

– Written by Sarah Freeston

Source: Desikan RS, McEvoy LK, Thompson WK et al. Amyloid-β-associated clinical decline occurs only in the presence of elevated p-tau. Arch. Neurol. doi:10.1001/archneurol.2011.3354 (2012) (Epub ahead of print).

The rate of progression of dementia may be predicted using a new technique for analyzing brain imaging, a recent study suggests. The study has also provided further evidence that implies that degenerative brain diseases spread throughout the brain in a similar manner to that of prion diseases.

The study, which was published in Neuron, used MRI to map the neuronal pathways connecting different areas of the brain. A predictive model of dementia was created using 14 images of healthy brains. The pathways along which degeneration was predicted to spread closely matched actual MRI images of brain degeneration in 18 Alzheimer’s patients and 18 frontotemporal dementia patients.

“The results need to be replicated, but they suggest that, by using this approach, we can predict the location and course of future brain atrophy in Alzheimer’s, frontotemporal dementia and other degenerative brain diseases, based on just one MRI taken at the outset of the disease,” explained lead author Michael Weiner, Center for Imaging of Neurodegenerative Diseases (US Department of Veterans Affairs, Washington, DC, USA). “This would be extremely useful in planning treatment, and in helping patients and families know what to expect as dementia progresses.”

Currently, it is a popular concept that brain damage in neurodegenerative disease occurs in a prion-like manner. These results support this idea.

“The idea of a prion-like model of progression in dementias, which many scientists are beginning to support, is that the misfolded protein in one neuron will infect a neighboring brain cell, causing proteins in that cell to misfold in turn, and that the spread of these misfolded proteins flows along certain networks in the brain,” explained Weiner. “For instance, in Alzheimer’s disease, there is a spread of amyloid protein along the memory network. This paper reinforces the idea that the damage occurs progressively along that network and others.”

Although it should be made clear that Alzheimer’s and frontotemporal dementia are not infectious diseases, Weiner said “it may be that a little seed of the disease begins in one neuron in the brain and spreads in a similar way – so it’s infectious within the brain, from one neuron to the next.”

– Written by Laura McGuinness

Source: Raj A, Kuceyeski A, Weiner M. A network diffusion model of disease progression in dementia. Neuron 73(6) 1204–1215 (2012).

University of California, San Diego researchers (CA, USA) have provided a sequential molecular explanation for α-synuclein (α-syn) oligomerization; the study supports the role of pore-like structures in neuronal membranes in the pathogenesis of Parkinson’s disease (PD).

PD and dementia with Lewy bodies are commonly associated with aging and are characterized by a progressive accumulation of α-syn in the CNS. However, the underlying mechanisms leading to and resulting from this protein aggregation have not yet been elucidated.

The study, published in FEBS Journal, describes how α-syn monomers rapidly penetrate cell membranes, become coiled and aggregate into ring-like structures that are thought to be responsible for neuronal toxicity in PD. It is thought that many ring structures would be necessary to kill resilient neurons; however, at some point, the assault proves too great and neuronal repair cannot compete. Thus, the symptoms of PD gradually worsen.

“We think we can create drugs to give us an anti-Parkinson’s effect by slowing the formation and growth of these ring structures,” explains Igor Tsigelny, lead author of the study.

The A53T mutation is commonly associated with familial PD. Through computer modeling and cell-based studies, the team investigated the membrane-based oligomerization process, which occurred more rapidly for the A53T mutant α-syn compared with wild-type α-syn. Following 9 ns of stimulation, oligomer penetration resulted in a pore-like hole in the membrane. Mutant α-syn demonstrated a greater tendency to accumulate in neuronal membranes, thus resulting in greater permeability.

These results controversially support a once-marginalized theory for PD and conflict with the belief that insoluble intracellular fibrils, or amyloids, are the underlying cause of PD. “The most dangerous assault on the neurons of PD patients appears to be the relatively small α-syn ring structures themselves,” explains Tsigelny, who continues, “It was once heretical to suggest that these ring structures, rather than long fibrils found in neurons of people having PD, were responsible for the symptoms of the disease; however, the ring theory is becoming more and more accepted for this neurodegenerative disease and others such as Alzheimer’s disease. Our results support this shift in thinking.” This discovery has already inspired a hunt for potential drug candidates with the ability to block ring formation. The hope is that molecules that induce different conformations of α-syn proteins, that are less likely to aggregate, could reduce the symptoms of PD.

– Written by Sarah Freeston

Source: Tsigelny IF, Sharikov Y, Wrasidlo W et al. Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J. 279(6), 1000–1013 (2012).

Novartis are expected to present new data in support of Gilenya^®’s (fingolimod) efficacy and safety profile at the 64th Annual Meeting of the American Academy of Neurology.

Multiple sclerosis (MS) is estimated to affect approximately 2.1 million sufferers worldwide, so more advanced treatment options are necessary.

Gilenya is the first drug in a new class of sphingosine-1-phosphate receptor modulating compounds developed for the treatment of relapsing MS. The oral therapy has proved to be efficacious compared with other commonly prescribed treatments, such as IFN-β.

In a comparative trial with MS patients, Gilenya achieved a 52% relative reduction of the yearly relapse rate and a 40% reduction in the rate of brain atrophy at 1-year follow-up. A recent Phase III extension study (FREEDOMS) has demonstrated the long-term efficacy of the drug. The double-blind 2-year core study involved 1033 patients. Patients who initially received placebo in the core study, but were given Gilenya during the extension, experienced significant clinical improvements and positive MRI measures. The annual relapse rate was reduced from 0.29 to 0.13 in patients who switched to Gilenya treatment. A greater proportion of participants (59%) remained relapse-free if they had taken the drug continuously.

Ludwig Kappos from the University of Basel (Basel, Switzerland) explained, “This extension study confirms the efficacy shown in the published Phase III studies and supports positive long-term impact of continuous treatment. The favorable longer-term safety profile is consistent with results from the Phase III studies. These observations in a large group of patients, now for 4 and more years, confirm that fingolimod is a valuable treatment option for patients with relapsing-remitting MS.”

The safety profile was consistent with earlier trials. The most common adverse events were nasopharyngitis, diarrhea and respiratory tract infections. The EMA’s Committee for Medicinal Products for Human Use has recently confirmed a positive benefit–risk profile for the once-a-day orally administered drug.

In addition, new data from a Phase II extension study demonstrate that, following the 7-year follow-up, 122 patients treated with Gilenya sustained low MRI and clinical disease activity. The annual relapse rate for those who had taken the drug continuously equated to one relapse every 6 years. Furthermore, at study end, half of this group did not relapse during the long-term study.

With a manageable safety profile and evidence that Gilenya is well-tolerated in the long-term, researchers are optimistic that this drug will be successful as a treatment option for MS patients.

– Written by Sarah Freeston

Source: Press release: Novartis confirms positive benefit-risk profile of Gilenya® following CHMP review and label update recommendation: www.novartis.com/newsroom/media-releases/en/2012/1604415.shtml

Researchers from Brigham and Women’s Hospital (MA, USA) and Harvard Medical School (MA, USA) have prospectively evaluated whether rates of cognitive decline can be reduced in elderly women with a greater long-term intake of berries.

With an increasingly aging population, researchers are keen to outline simple lifestyle modifications that can slow such debilitating neuronal degeneration. “As the US population ages, understanding the health issues facing this group becomes increasingly important. Our study examined whether a greater intake of berries could slow rates of cognitive decline,” explains Elizabeth Devore, lead author of the study.

“Previously, only animal studies and very small human studies had examined berry intake in relation to memory decline, so this study adds substantially to our knowledge of this topic,” explains Devore in correspondence with Neurodegenerative Disease Management.

The team began their investigation back in 1980, when a food frequency questionnaire was administered to the Nurses’ Health Study participants at 4-year intervals.

Between 1995 and 2001, the researchers measured cognitive function in 16,010 participants who were aged over 70 years. The participants were then followed-up twice, at 2-year intervals.

To ascertain long-term effects, dietary variables from 1980 through to the initial cognitive interview were averaged. Using mixed linear regression, mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes were estimated. Berries contain high levels of flavonoids, especially anthocyanidins; flavonoids are anti-inflammatory substances thought to counteract the negative impact of stress on cognition.

The researchers found that greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline; cognitive aging was delayed by approximately 2.5 years.

“The most surprising finding was that the amount of berries necessary for memory benefits appears to be relatively modest: one serving per week for blueberries (one serving = a half cup), and two servings per week for strawberries. It seems like a simple dietary intervention that many people could easily incorporate into their diet,” clarified Devore for Neurodegenerative Disease Management.

Greater intakes of anthocyanidins and total flavonoids were demonstrated to have a similar beneficial effect. “We provide the first epidemiologic evidence that berries may slow progression of cognitive decline in elderly women. Our findings have significant public health implications as increasing berry intake is a fairly simple dietary modification to test cognition protection in older adults.”

“Increasing berry intake can be recommended to adults of all ages, especially since higher intakes of fruits and vegetables have other health benefits as well,” concludes Devore.

– Written by Sarah Freeston

Source: Devore EE, Kang JH, Breteler MMB, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann. Neurol. doi:10.1002/ana.23594 (2012) (Epub ahead of print).