Ziogas and Koliatsos identify pathway regulating axonal damage in traumatic brain injury

April 17th, 2018

Traumatic brain injury (TBI) results in significant injury to axons, which carry electrical activity in the brain. Ziogas and Koliatsos recently reported in The Journal of Neuroscience that the “SARM1” pathway can regulate this process. When they blocked SARM1 using genetic or pharmacological strategies, they observed a significant reduction in the number of axonal lesions early after injury. The study took advantage of CLARITY analysis to image the brainstem at single-axon resolution.

The Verhoeff-Zimmerman Society Meets In Baltimore

April 6th, 2018

The Verhoeff-Zimmerman Society (VZS) is holding it 2018 annual meeting in Baltimore at the Marriott Waterfront Hotel from April 5-7, hosted by Drs. Eberhart and Rodriguez of the ophthalmic pathology/neuropathology division. VZS members and guests will present 42 cases with interesting pathology involving the eye. Dr. Steffen Heegard attended as the representative of the European Ophthalmic Pathology Society.  Shown is Dr. David Wilson discussing retinal findings in Neuronal Ceroid Lipofuscinosis.

Regulation Of DNA Repeat Translation In Neurodegenerative Disease By Stress And eIF2alpha

January 10th, 2018

Pathology department and Brain Science Institute researcher Shuying Sun and her group have uncovered a mechanism by which genetic alterations common in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and some dementias may promote loss of neurons. They focus on how aberrant proteins are produced in disease, and their findings suggest a possible new point of therapeutic intervention. Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both ALS and frontotemporal dementia (FTD). Unconventional translation of the repeat-containing RNA produces multiple toxic poly-dipeptides, which contribute to neurodegeneration. The new study demonstrates that the repeat translation is upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response. Compounds inhibiting phospho-eIF2α-signaling pathways were shown to suppress translation of the repeats. Since the poly-dipeptides can themselves induce stress, this could trigger a feedforward loop with initial repeat-mediated toxicity enhancing the repeat translation and subsequent production of additional poly-dipeptides, thereby driving relentless disease progression. A method perturbing this loop might reduce or delay neurodegeneration and hold therapeutic promise in C9ORF72-ALS/FTD. The study was recently published in Nature Communications (https://www.nature.com/articles/s41467-017-02495-z).

New Johns Hopkins Atlas Of Surgical Neuropathology iPad App Review

November 29th, 2017

 

The following review recently appeared in the journal Neuropathology and Applied Neurobiology:

 

The long awaited surgical neuropathology mobile application (app) for iPAD is finally here! This one of a kind app for surgical neuropathology is well organized and contains beautiful representative images of neoplasms of the central nervous system and pseudo-neoplastic lesions encountered in surgical neuropathology. The Johns Hopkins Atlas of Surgical Neuropathology utilizes the updated WHO 2016 classification of tumours, including details of molecular information required for integrated diagnoses.

The table of contents is divided into the introduction, diagnoses albums, feature albums, my albums, teaching algorithms, a quiz and flashcards. Navigation through the headings, subheadings and contents is easy and allows rapid access to any particular feature of interest.

The diagnoses albums list more than one hundred entities in alphabetical order from abscesses to yolk sac tumours and contain more than 800 high resolution images. Microscopic images in colour are supplemented by intra-operative smear pictures, examples of immunohistochemical findings and radiological studies. On tapping each image, the diagnosis and a concise description appear in the top left hand corner of the screen. The images and descriptions provided cover conventional features as well as various rarer morphologies and immunophenotypes which may be encountered in neuropathological practice. Some of the descriptions provided for identifying the more unusual patterns are akin to useful pearls for future reference. Icons in the top right hand corner of the screen permit navigation to images previously viewed or to any other image in the database as required.

The feature albums contain information on characteristic molecular findings and lists of recognized morphological terms which link to microscopic images of clear and detailed examples. With the option of My Albums, images of eosinophilic granular bodies, floating neurons, microvascular proliferation or rhabdoid change can also be incorporated into the creation of multiple personalized files for quick reference and revision.

The teaching algorithm is a very useful tool for differentiating glial tumours and formulating a final integrated diagnosis based on the criteria of morphology, mitotic activity and molecular findings. This tool also enables the comparison of two images simultaneously. A concise algorithm maps the diagnostic decision making tree to assist the learner with each integrated diagnosis.

I found the quiz and flashcards sections very useful for revision and private study. The quiz comprises 100 multiple choice questions based on the image bank. A brief description of the correct answer is provided with one tap.

I highly recommend this extensive, beautifully illustrated, easily portable and affordable resource for neuropathologists, neurosurgeons, neuro-oncologists and trainees in these fields.

Abel Devadass

Addenbrooke’s Hospital, Cambridge, UK

E-mail: ad77@doctors.org.uk


Dr. Nikolaos Ziogas receives top finalist award at National Neurotrauma Symposium 2017

September 12th, 2017

Nikolaos Ziogas M.D., postdoctoral fellow at the Koliatsos Laboratory, was recognized as a top finalist at the 35th National Neurotrauma Society’s Annual Symposium, Snowbird, Utah for his work “Primary traumatic axonopathy after impact acceleration: characterization of pathology with 3D high-resolution methods”. The combination of brain clearing with 2-photon microscopy to 3D reconstruct the mouse brain stem, allowed for the first time a new level of qualitative and quantitative understanding of axonal injury, including its progressive nature and its proclivity for sites of geometrical complexity and intertwinement of various axon tracts after traumatic brain injury.

Dr. Nikolaos Ziogas Wins First Place; Post-Doctoral Fellow Poster Awards at National Capital Area TBI Research Symposium 2017

September 12th, 2017

Nikolaos Ziogas M.D., postdoctoral fellow at the Koliatsos Laboratory, was the winner of the “Post-Doctoral Fellow Poster Awards” at the annual National Capital Area Traumatic Brain Injury Symposium held at the National Institutes of Health, Bethesda, DC for the second consecutive year for his work “Diffuse axonal injury, blood brain barrier disruption and neuroinflammation after a single concussion with impact acceleration in the mouse”. A novel brain clearing technique, CLARITY, has been developed as a neuropathological tool for this work in order to visualize the whole mouse brain stem after concussion in single axon resolution, revealing widespread diffuse axonal injury.

Mouse study on serotonin in Alzheimer’s Disease by Alena Savonenko expanded to human patients

August 19th, 2017

Brain Scan Study Adds to Evidence That Lower Brain Serotonin Levels Are Linked to Dementia

In a study looking at brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter—a natural brain chemical that regulates mood, sleep, and appetite. Their results, the researchers say, suggest that lower serotonin transporters may be drivers of the disease rather than a byproduct.

A report on the study, published in Neurobiology of Disease, also suggests that finding ways to prevent the loss of serotonin or introducing a substitute neurotransmitter could slow or stop the progression of Alzheimer’s disease and perhaps other dementias.

“Now that we have more evidence that serotonin is a chemical that appears affected early in cognitive decline, we suspect that increasing serotonin function in the brain could prevent memory loss from getting worse and slow disease progression,” says Gwenn Smith, professor of psychiatry and behavioral sciences and director of geriatric psychiatry and neuropsychiatry at the School of Medicine.

Smith notes that researchers have tried with limited success to treat Alzheimer’s disease and cognitive impairment with antidepressants such as SSRIs, which bind to the serotonin transporters and block the brain’s “reuptake” of the chemical. But because these transporters are at much lower levels in people with Alzheimer’s, she speculates that the drugs can’t serve their purpose without their target.

The Johns Hopkins research team paired 28 participants with mild cognitive impairment, which may be an early harbinger of Alzheimer’s disease or other forms of dementia, with 28 healthy matched controls. People with mild cognitive impairment were defined as those who have a slight decline in cognition, mainly in memory in terms of remembering sequences or organization, and who score lower on tests such as the California Verbal Learning Test, which requires participants to recall a list of related words, such as a shopping list. According to Smith, the inability to do this test accurately reflects changes in memory and cognitive impairment indicative of Alzheimer’s disease.

Participants were an average age of 66 and about 45 percent were women.

Each participant underwent an MRI and PET scan to measure brain structures and levels of the serotonin transporter. During the PET scans, participants were given a chemical—similar in structure to an antidepressant but not a high enough dose to have a pharmacological effect—labeled with a radioactive carbon. The chemical binds to the serotonin transporter and the PET scanner detects the radioactivity.

The researchers found that people with mild cognitive impairment had up to 38 percent less of the serotonin transporter detected in their brains compared to each of their age-matched healthy controls. And not a single person with mild cognitive impairment had higher levels of the serotonin transporter compared to their healthy control.

Each participant also underwent learning and memory tests. In the California Verbal Learning Test, on a scale of 0 to 80, with 80 reflecting the best memory, the healthy participants had an average score of 55.8, whereas those with mild cognitive impairment scored an average of 40.5. During a Brief Visuospatial Memory Test, participants were shown a series of shapes to remember and draw later. From a scale of 0 to 36, with 36 being the top score, healthy people scored an average of 20.0 and those with mild cognitive problems scored an average of 12.6.

The idea for Smith’s study was inspired by the work of co-author Alena Savonenko, an associate professor of pathology who showed that loss of serotonin neurons was associated with more protein clumps, or amyloid, in mouse brains. Savonenko and Smith say their group will investigate whether PET imaging of serotonin could be a marker to detect progression of disease, whether alone or in conjunction with scans that detect amyloid, which has also been shown to accumulate in the brains of those with Alzheimer’s disease.
Read more from School of Medicine

Experimental “Enhancer” Drug May Boost Conventional Therapies for Deadly Pediatric Brain Cancers

July 14th, 2017

Laboratory studies suggest that an experimental drug already in early clinical trials for a variety of adult cancers might enhance radiation and chemotherapy for two childhood brain cancers that currently are virtually always fatal.

In a report on two studies conducted by Johns Hopkins Kimmel Cancer Center researchers, the drug, known as TAK228, suppressed the growth of human cancer cells cultured in the laboratory and significantly extended the lives of mice implanted with cells from the two cancers, diffuse intrinsic pontine glioma (DIPG) and atypical teratoid/rhabdoid tumors (AT/RTs).

DIPG — a cancer in the brainstem affecting about 3,000 children worldwide each year — is universally fatal even with currently available treatments including surgery, chemotherapy and radiation. AT/RTs, the most common brain cancer in infants, have a similarly poor prognosis, with most patients surviving between six and 11 months after diagnosis.

Hoping to help beat these odds, Johns Hopkins researchers and their colleagues, led by Eric H. Raabe, M.D., Ph.D., assistant professor of oncology and instructor of pathology at the Johns Hopkins Kimmel Cancer Center, focused their attention on TAK228. Previous research showed the drug (also known as MLN0128) can cross the blood-brain barrier and reduces the production of a protein called mTOR, which appears to sustain cancer by combining with other proteins to signal the cells to grow, invade tissues and survive therapy. Both pediatric cancer types typically have genetic alterations that lead to increases in mTOR activity, thus Raabe and his team’s hypothesis that TAK228 could be an effective treatment for these cancers.

In one set of experiments, Raabe and his colleagues applied the drug to cells of each cancer type isolated from human patients. Results showed that TAK228 reduced proliferation of DIPG cells cancer cells by about 30 percent compared with control (untreated) cells and killed about 6 percent of the cells.

However, when combined with radiation — currently the most effective treatment for extending life in children with DIPG — nearly double the number of cells were killed compared with radiation alone, suggesting that TAK228 might sensitize cells to make radiation more effective, Raabe says.

When the team tested TAK228 on AT/RT cells, they found similar reductions in tumor cell proliferation and increases in cancer cell death. Further, when they gave a combination of TAK228 and cisplatin, a chemotherapy commonly used to treat AT/RTs, to mice bearing implanted human AT/RT tumors, the mice receiving the combined treatment lived approximately 30 days longer than those that received either treatment alone. Some 40 percent of the combination-treated mice were long-term survivors (living more than 60 days after tumor injection), while none of the mice treated with either chemotherapy or TAK228 alone lived longer than 25 days.

A report of the experiments in DIPG is published online April 25 in Cancer Letters, and the AT/RT report is published June 3 in Neuro-Oncology. Together, Raabe says, these results suggest that TAK228 could hold promise for human patients.

“Both of these papers set the stage for clinical trials for TAK228,” he says. “Our experiments show that TAK228 can make traditional chemotherapy and radiation more effective, which may offer hope to patients for whom current therapy doesn’t work very well.”

The team is currently investigating further how the drug works with radiation and chemotherapy, and if other drugs might be able to heighten this synergistic effect.

Other Johns Hopkins researchers who participated in the DIPG study include Hiroaki Miyahara, Manabu Natsumeda, Jeffrey A. Rubens, Isabella C. Taylor, Harpreet Kaur, Laura Asnaghi and Charles G. Eberhart. Other Johns Hopkins researchers who participated in the AT/RT study include Jeffrey A. Rubens, Sabrina Z. Wang, Antoinette Price, Melanie F. Weingart and Charles G. Eberhart.

The DIPG research was funded by the Cure Starts Now Foundation, the Giant Food Pediatric Cancer Research Fund, the National Institutes of Health’s National Cancer Institute (P30 CA006973, T32CA60441), Smashing Walnuts/Piedmont Community, the Goldwin Foundation and the St. Baldrick’s Foundation.

Funding for the AT/RT research was provided by Alex’s Lemonade Stand, the Giant Food Pediatric Cancer Research Fund, the National Institutes of Health’s National Cancer Institute (P30 CA006973, T32CA60441) and the St. Baldrick’s Foundation.

A New Therapeutic target and Potential Biomarkers Identified in Alzheimer’s Disease

June 19th, 2017

Significant progress has been made over the past two decades on the pathogenesis of individual neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, different neurodegenerative syndromes have been mainly studied mechanistically in isolation. There has been a lack of concerted effort to ascertain whether and how these pathogenic processes may be linked to one another. In the most recent issue of journal Acta Neuropathologica, Dr. Mingkuan Sun, William Bell and Katherine LaClair, co-first authored a report about cryptic exon incorporation in Alzheimer’s disease cases exhibiting TDP-43 pathology. This is the first evidence on how loss of TDP-43 function from neurons, a common shared feature with ALS and FTD, could contribute to pathogenesis of AD.

It has been known for years that other factors besides Aβ and tau also contribute to neurodegeneration and cognitive failure in AD. The most convincing evidence is that 20-40% of cognitively normal older individuals have levels of Aβ and tau pathology that are indistinguishable from patients with severe clinical symptoms of AD. Recent work showed that non-canonical pathologies occur in up to 75% of AD cases, including TDP-43 proteinopathy, α-synuclein “Lewy bodies”, and tau “Pick bodies” that are associated with neurodegeneration in separately classified diseases. TDP-43 proteinopathy is characterized by cytoplasmic aggregation of the transactivation response element DNA-binding protein 43 (TDP-43) accompanied by its nuclear clearance, and was first identified in another neurodegenerative disease spectrum, ALS-FTD. Identified as an essential gene, TDP-43 is also required for aspects of neuronal physiology in mice, fruit flies and zebrafish. Notably, TDP-43 proteinopathy is one of the most common non-canonical pathologies observed in AD cases and is strongly associated with worsened neurodegeneration and cognition, suggesting a convergent mechanism of neurodegeneration with ALS and FTD.

In their paper, Sun et al. found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Most importantly, cryptic exon incorporation could be detected in AD brains lacking TDP- 43 inclusions, but exhibiting nuclear clearance of TDP-43. These data support the notion that the functional consequence of nuclear depletion of TDP-43, as determined by cryptic exon incorporation, likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. This study has opened new direction in AD research as early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.

Co-authors were Jonathan Ling, Heather Han, Yusuke Kageyama, Olga Pletnikova, and Juan Troncoso of Johns Hopkins Brain Resource Center.  The work was supported in part by the Johns Hopkins Neuropathology Pelda fund and the NIH Grant to Dr. Philip Wong; McKnight Award for Memory and Cognitive Disorder and the Johns Hopkins Alzheimer’s Disease Research Center pilot grant to Dr. Liam Chen. 

Presentations at the 93rd Annual Meeting of the American Association of Neuropathologists.

June 10th, 2017

The 93rd Annual Meeting of the American Association of Neuropathologists was held June 8–11, 2017 in Garden Grove, CA. Neuropathology faculty members Liam Chen and Charles Eberhart, as well as a second year fellow, Heather Ames, all had abstracts selected for platform presentations. An incoming AP/NP resident, James Nix, also gave a platform talk, and second year fellow Andrew Guajardo presented a case at the diagnostic slide session. Many posters from incoming, current and recently departed trainees were also featured. The titles and authors of the platform presentations are shown below.
– Cryptic exon splicing repression by TDP-43 represents its major function compromised in Alzheimer’s disease and ALS/FTD. Liam Chen, Mingkuan Sun, Robert Bell, Olga Pletnikova, Juan Troncoso, Philip Wong
– Identifying corneal infections in formalin fixed specimens using next generation sequencing. Charles Eberhart, Zhigang Li, Florian Breitwies, Jennifer Lu, Albert Jun, Steven Salzberg
– Insulinoma-associated 1 (INSM1) is a novel nuclear marker of immature neuronal central nervous system neoplasms. Heather Ames, Lisa Rooper, Charles Eberhart, Fausto Rodriguez
– Neuropathology In Social Media. James Nix, Jerad Gardner, Murat Gokden, Brian Moore, Fausto Rodriguez, Maria Martinez-Lage, Felipe Costa, Douglas Anthony