Monthly Archives: May 2015

Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, with and without dementia, and its association with cognitive impairment.

The earliest recognizable pathological event in Alzheimer’s Disease (AD) is cerebral amyloid-beta aggregation (protein fragments that clump together to form plaque).This pathology may be present up to 20 years before the onset of dementia.

Therefore, estimates of the prevalence of amyloid pathology in persons without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

Led by Pieter Jelle Visser at VU University Medical Center in Amsterdam and Maastricht University, The Netherlands, these two studies compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from thousands of participants, and represent the largest data sets to date on how commonly amyloid builds up in people’s brains.

One meta-analysis looked at the prevalence of amyloid in cognitively normal people, and concluded that amyloid creeps into the brain 20 to 30 years before dementia can be diagnosed. This was particularly true for people who carry an ApoE4 allele; indeed, they developed amyloid at a younger age.

In the second study, the researchers compared amyloid prevalence among people clinically diagnosed with AD or other dementias, including dementia with Lewy bodies, frontotemporal dementia, and corticobasal syndrome. They found that the prevalence of brain amyloid in people diagnosed with most non-AD dementias was higher with increasing age. They concluded that older people may be likelier to have multiple pathologies, or to have been misdiagnosed. The data may help researchers set inclusion criteria for clinical trials, or make better diagnoses.

“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the researchers wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

However, the authors point out that follow-up studies need to be conducted since not all people with amyloid pathology develop dementia in their lifetime, and not all people with a clinical diagnosis of Alzheimer’s dementia have amyloid pathology.

“Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state,” they wrote. “Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”

The Innovative Medicines Initiative 2 (IMI 2) indicative topic text for Call 5 is now available, with heavy emphasis on Alzheimer’s Disease. The following topics are under consideration for inclusion in the call:

  • Patient perspective elicitation on benefits and risks of medicinal products from development through the entire life cycle, for integration into benefit risk assessments by regulators and health technology assessment bodies
  • Diabetic kidney disease biomarkers (DKD-BM)
  • Inflammation and Alzheimer’s disease (AD): modulating microglia function – focussing on TREM2 and CD33
  • Understanding the role of amyloid biomarkers in the current and future diagnosis and management of patients across the spectrum of cognitive impairment (from pre-dementia to dementia)
  • Evolving models of patient engagement and access for earlier identification of Alzheimer’s disease: phased expansion study
  • Apolipoprotein E (ApoE) biology to validated Alzheimer’s disease targets

Note: All information regarding future IMI Call topics is indicative and subject to change. Final information about future IMI Calls will be communicated after approval by the IMI Governing Board.

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction.

Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration.However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases.

This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.

A genetic study of over 173,000 individuals has confirmed that the TREM2 amino-acid-substitution mutation R47H increases the risk of Alzheimer disease in people of European descent.

Several studies have reported the TREM2 R47H mutation to be a risk factor for Alzheimer’s disease (AD), but the magnitude of this mutation’s role in AD and other neurodegenerative diseases has been far from clear.

“The effect size estimates varied widely across datasets,” says lead author of this study, Christina Lill University of Lübeck, Germany.

The results, published in the journal Alzheimer’s & Dementia, suggest the mutation contributes through tau dysfunction.

Two recent studies have investigated the direct links and associations between depression and Parkinson’s Disease

A longitudinal study from Sweden investigated the long-term risk of Parkinson disease (PD) after depression and evaluated potential confounding by shared susceptibility to the two diagnoses.

Published in the journal Neurology, this study demonstrated a time-dependent effect, dose-response pattern for recurrent depression, and lack of evidence for co-aggregation among siblings which together indicate a direct association between depression and subsequent PD. Given that the association was significant for a follow-up period of more than two decades, depression may be a very early pro-dromal symptom of PD, or a causal risk factor.

The effects of anti-depressive treatments for Parkinson’s Disease were also recently reviewed in the journal Parkinsonism & Related Disorders.  The associated meta-analysis in the study demonstrates that pharmacologic treatment with antidepressant medications, specifically the selective serotonin reuptake inhibitors (SSRIs), and behavioral interventions (CBT) significantly improved depression among Parkinson’s disease patients.

The authors examined trials assessing treatment for depression in Parkinson’s disease (dPD) and found that:

  • SSRIs demonstrate significant improvement in depressive symptoms.
  • Cognitive behavioral therapy (CBT) shows a substantial effect in dPD treatment.
  • Evidence of efficacy of both SSRIs and CBT is provided, at least on the short term.

Cohort Study:  Depression and subsequent risk of Parkinson disease – A nationwide cohort study. Gustaffssonn et al., Neurology.  Published online before print May 20, 2015, doi: 10.1212/WNL.0000000000001684

Antidepressive treatments for Parkinson’s disease: A systematic review and meta-analysis
Emily Bomasang-Layno, et al., Parkinsonism & Related Disorders, Available online 16 May 2015

Three former top researchers at Genentech (now part of Roche Holding), have raised $217 million in venture capital to start a new company, Denali Therapeutics, focused on treating and curing neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s.

The news is sign of a financial turnaround for research efforts against these brain diseases that have been tough to beat.

NeuroPerspective, a newsletter that tracks neurological treatments, says in the past five years the number of drugs being developed by large drug makers for brain and nervous system disorders fell 50% to 129 – but that last year, investors poured $3.3 billion into the field, more than in any of the last ten years.

The raise for Denali is a series A, the very first round of getting funding for a new company. It is the largest such round in biotech history.

Researchers at the Luxembourg Centre for Systems Biomedicine (LCSB), of the University of Luxembourg, have successfully measured metabolic profiles, or the metabolomes, of different brain regions, and their findings could help better understand neurodegenerative diseases.

The metabolome represents all or at least a large part of the metabolites in a given tissue, and thus, it gives a snapshot of its physiology.

“Our results, obtained in the mouse, are promising”, says Manuel Buttini: “They open up new opportunities to better understand neurodegenerative diseases, such as Parkinson’s, and could offer new ways to intervene therapeutically. In addition, with the help of metabolic profiles, such as those we have measured, the efficacy of novel therapeutic interventions could be tested more efficiently than with more common approaches.” The researchers have just published their results in the American Journal of Pathology.

Neurodegenerative processes, such as those occurring in Parkinson’s disease, are characterized by pathological alterations of the brain cells: these cells lose their structure and function, a process that is accompanied by changes in their metabolism. Until now, most scientists have always focused on just one or a few aspects of the disease to better describe and understand the underlying mechanisms. By analysing the whole metabolome however, LCSB researchers have realized a more global approach: they now can analyse hundreds of biomolecules, produced by nerve cells in upper, middle, and lower brain regions of the mouse. In the process, they not only look at healthy brains, but also at brains in which neurodegeneration occurs.

Study demonstrates that free-water provides a potential non-invasive progression marker of the substantia nigra region in the brain.

Parkinson’s disease is a CNS disorder that results from the loss of cells in various parts of the brain, including a region called the substantia nigra. The substantia nigra cells produce dopamine, a chemical messenger responsible for transmitting signals within the brain that allow for coordination of movement.

With no objective test or biomarker for Parkinson’s, there is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson’s disease. This study’s authors had previously found elevated free-water levels in the substantia nigra for patients with Parkinson’s disease compared with controls in single-site and multi-site cohorts.

In this study, published in the journal “Brain”, they tested the hypotheses that free-water levels in the substantia nigra of Parkinson’s disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year.
The researchers conducted a longitudinal study in controls (n = 19) and patients with Parkinson’s disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra.

The results found that free water levels increases with progression of Parkinson’s disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year, thus demonstrating that free-water provides a potential non-invasive progression marker of the substantia nigra.

Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease
Edward Ofori ,et al.,  DOI:

Over the past few years, the OECD has conducted work in a number of areas related to innovation in biomedical research and health innovation for healthy ageing.

Entitled “Enhancing Translational Research and Clinical Development for Alzheimer’s Disease and other Dementias”, this report is the main output from a Nov 2014 OECD workshop aimed to provide an international forum for all stakeholders to drive forward a change in the global paradigm in biomedical research and health innovation for Alzheimer’s disease and other dementias.

Discussions at the workshop have shown that progress on key issues is being made, thanks to a willingness of stakeholders to join forces and work together towards a future cure.

In line with recommendations of the G8 Dementia Summit Declaration to strengthen collaboration for innovation and cross-sector partnerships this report considers the challenges and options to promote and accelerate research in dementia and its transformation into innovative therapies and diagnostics.

Scientists at Mayo Clinic, Jacksonville, Florida, USA have created a novel mouse that exhibits the symptoms and neurodegeneration associated with the most common genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both of which are caused by a mutation in the a gene called C9ORF72. The study was published in the journal Science.

ALS destroys nerves that control essential movements, including speaking, walking, breathing and swallowing. After Alzheimer’s disease, FTD is the most common form of early onset dementia. It is characterized by changes in personality, behavior and language due to loss of neurons in the brain’s frontal and temporal lobes. Patients with mutations in the chromosome 9 open reading frame 72 (C9ORF72) gene have all or some symptoms associated with both disorders.

“Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with theC9ORF72 mutation,” said the study’s lead author, Leonard Petrucelli, Ph.D., chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and a senior author of the study. “These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments.”

To create the model, Ms. Jeannie Chew, a Mayo Graduate School student and member of Dr. Petrucelli’s team, injected the brains of newborn mice with a disease-causing version of the C9ORF72 gene. As the mice aged, they became hyperactive, anxious, and antisocial, in addition to having problems with movement that mirrored patient symptoms. The brains of the mice were smaller than normal and had fewer neurons in areas that controlled the affected behaviors. The scientists also found that the mouse brains had key hallmarks of the disorders, including toxic clusters of ribonucleic acids (RNA) and TDP-43, a protein that has long been known to go awry in the majority of ALS and FTD cases.

“Finding TDP-43 in these mice was unexpected” Dr. Petrucelli said. “We don’t yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities, but with our new animal model, we now have a way to find out.” Dr. Petrucelli and his team think these results are an important step in the development of therapies for these forms of ALS and FTD and other neurodegenerative disorders.

Chew et al. “C9ORF72 Repeat Expansions in Mice Cause TDP-43 Pathology, Neuronal Loss and Behavioral Deficits,” Science, May 14, 2015. DOI: 10.1126/science.aaa9344