Research findings: clearing tau in mice by targeting Hsp70

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This is a report on some basic research involving the protein tau and an update of sorts of the tau-busting drug Rember.

This University of South Florida press release was posted earlier this week to EurekAlert! Byrd Alzheimer’s Institute neuroscientist Chad Dickey studies how the protein tau can be removed from the brain through drugs or gene therapy. Tau is the protein involved in Alzheimer’s Disease, PSP, CBD, and some other disorders.

A study in mice (genetically modified to develop tau tangles) revealed that inhibiting the protein Hsp70 rapidly reduced the level of tau in the brains. “Hsp70 is a one of several ‘chaperone’ proteins that supervises the activity of tau inside nerve cells. The normal function of tau is to support the structure of nerve cells, much like the skeleton provides a scaffold to support the body. Tau is inside nerve cells, while another hallmark protein associated with Alzheimer’s, beta amyloid, is outside the neurons.”

Several compounds were tested in cell models and genetically modified mice to see if they had any effect on Hsp70. According to the abstract of the journal article about this research, this is the first time that Hsp70 has been targeted and the first time a “newly developed high-throughput screening system” was utiilized.

“One of the more effective Hsp70-inhibitor drugs the researchers discovered was a derivative of methylthioninium chloride, or Rember™, the first experimental medication reported to directly attack the tau tangles in patients with Alzheimer’s disease. Rember™ was heralded as a major development in the fight against Alzheimer’s when results in early clinical trials were announced last year at the International Conference on Alzheimer’s disease. But Rember™ and its derivatives do have some inherent problems; they’re not very potent so effective therapy would require fairly high doses, Dickey said.”

“The drug does help prevent the protein (tau) from clumping together, but that in itself doesn’t mean it’s actively getting rid of the toxic tau,” he said. “Now that we know Hsp70 is a target of Rember™, we can develop similarly-acting drugs that will more specifically target this chaperone protein in affected areas of the brain, resulting in fewer side effects.”

I’ve copied the USF Health press release below. This research was supported by a Pollin CBD research grant from CurePSP. (Abe Pollin has a clinical diagnosis of CBD.) Too bad that the press person at USF couldn’t get the acronym for the disorder spelled correctly (“CDB”) or the disorders CBD and PSP put into the article. (I guess money doesn’t buy accurate publicity.)

I’ve also copied the abstract of the Journal of Neuroscience article.

Robin

http://www.eurekalert.org/pub_releases/ … 092809.php

University of South Florida Health Press Release

Protein inhibitor helps rid brain of toxic tau protein
Laboratory study shows drug targets chaperone Hsp70 to reduce Alzheimer’s protein

Tampa, FL (September 30, 2009) — Inhibiting the protein Hsp70 rapidly reduces brain levels of tau, a protein associated with Alzheimer’s disease when it builds up abnormally inside nerve cells affecting memory, neuroscientists at the University of South Florida found. The study is reported online today in the Journal of Neuroscience.

“Now that we’ve discovered that targeting the chaperone protein Hsp70 can clear tau, it could be helpful in finding more effective drugs for Alzheimer’s disease,” said the study’s senior author Chad Dickey, PhD, assistant professor of molecular medicine who works out of the Byrd Alzheimer’s Institute at USF Health “The therapeutic strategy may also be applicable to other neurodegenerative diseases involving Hsp70, such as Huntington disease, amyotrophic lateral sclerosis (ALS), and some cancers.”

Hsp70 is a one of several “chaperone” proteins that supervises the activity of tau inside nerve cells. The normal function of tau is to support the structure of nerve cells, much like the skeleton provides a scaffold to support the body. Tau is inside nerve cells, while another hallmark protein associated with Alzheimer’s, beta amyloid, is outside the neurons.

Working with researchers at the University of Michigan, the USF team tested the effects of several compounds on Hsp70 in cell models and brain tissue from mice genetically modified to develop the memory-choking tau tangles. Some compounds activated Hsp70, and others were Hsp70-inhibitors.

One of the more effective Hsp70-inhibitor drugs the researchers discovered was a derivative of methylthioninium chloride, or Rember™, the first experimental medication reported to directly attack the tau tangles in patients with Alzheimer’s disease. Rember™ was heralded as a major development in the fight against Alzheimer’s when results in early clinical trials were announced last year at the International Conference on Alzheimer’s disease.

But Rember™ and its derivatives do have some inherent problems; they’re not very potent so effective therapy would require fairly high doses, Dickey said.

“The drug does help prevent the protein (tau) from clumping together, but that in itself doesn’t mean it’s actively getting rid of the toxic tau,” he said. “Now that we know Hsp70 is a target of Rember™, we can develop similarly-acting drugs that will more specifically target this chaperone protein in affected areas of the brain, resulting in fewer side effects.”

The USF researchers originally thought activating Hsp70 would direct the chaperone protein to decrease the tau gone bad — preventing tau from stacking up into tangles inside cells involved in memory and destroying them. But instead of restoring tau to its normal supportive function, activating Hsp70 actually led to tau’s preservation and even more accumulation, Dickey said. “Basically we think the chaperone binds to the tau, and somehow in the process of trying to fix things decides to keep holding onto tau when it shouldn’t. So, activating Hsp70 is not necessarily what we want to do; we ultimately want to inhibit Hsp70 to promote the release or clearance of tau …to kill the bad tau.”

Dr. Dickey emphasizes that problems with Hsp70 alone do not cause Alzheimer’s. It likely develops from a convergence of various factors in the brain, he said, including deposits of the other featured Alzheimer’s protein beta amyloid, or a genetic defect; disruption of cell signaling; a breakdown in the neuron’s support structure, and then accumulation of tau into the memory-choking tangles.

Dr. Dickey’s team at USF focuses on how to manipulate with drugs or gene therapy the chaperone proteins that regulate tau’s fate ­ determining whether it’s preserved or cleared from the brain. The University of Michigan team works on identifying and developing compounds that may be effective against Alzheimer’s disease and other tauopathies.

###

The study was supported by the national Alzheimer’s Association, the National Institute on Aging, the Abe and Irene Pollin Fund for CDB from the Society for Progressive Supranuclear Palsy (CurePSP), and the National Institute of Neurological Disorders and Stroke.

The study’s other authors were Umesh Jinwal (lead author), Yoshinari Miyata, John Koren III, Jeffrey Jones, Justin Trotter, Lyra Chang, John O’Leary, David Morgan, Daniel Lee, Cody Shults, Aikaterini Rousaki, Edwin Weeber, Erik Zuiderweg, and Jason Gestwicki.

USF Health is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of medicine, nursing, and public health; the schools of biomedical sciences as well as physical therapy & rehabilitation sciences; and the USF Physicians Group. With more than $380.4 million in research grants and contracts last year, USF is one of the nation’s top 63 public research universities and one of 39 community-engaged, four-year public universities designated by the Carnegie Foundation for the Advancement of Teaching. For more information, visit www.health.usf.edu

Here’s the abstract of the recently-published research article:

Journal of Neuroscience. 2009 Sep 30;29(39):12079-88.

Chemical manipulation of hsp70 ATPase activity regulates tau stability.

Jinwal UK, Miyata Y, Koren J 3rd, Jones JR, Trotter JH, Chang L, O’Leary J, Morgan D, Lee DC, Shults CL, Rousaki A, Weeber EJ, Zuiderweg ER, Gestwicki JE, Dickey CA.
Departments of Molecular Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, Florida.

Alzheimer’s disease and other tauopathies have recently been clustered with a group of nervous system disorders termed protein misfolding diseases. The common element established between these disorders is their requirement for processing by the chaperone complex. It is now clear that the individual components of the chaperone system, such as Hsp70 and Hsp90, exist in an intricate signaling network that exerts pleiotropic effects on a host of substrates. Therefore, we have endeavored to identify new compounds that can specifically regulate individual components of the chaperone family.

Here, we hypothesized that chemical manipulation of Hsp70 ATPase activity, a target that has not previously been pursued, could illuminate a new pathway toward chaperone-based therapies. Using a newly developed high-throughput screening system, we identified inhibitors and activators of Hsp70 enzymatic activity.

Inhibitors led to rapid proteasome-dependent tau degradation in a cell-based model. Conversely, Hsp70 activators preserved tau levels in the same system. Hsp70 inhibition did not result in general protein degradation, nor did it induce a heat shock response.

We also found that inhibiting Hsp70 ATPase activity after increasing its expression levels facilitated tau degradation at lower doses, suggesting that we can combine genetic and pharmacologic manipulation of Hsp70 to control the fate of bound substrates.

Disease relevance of this strategy was further established when tau levels were rapidly and substantially reduced in brain tissue from tau transgenic mice. These findings reveal an entirely novel path toward therapeutic intervention of tauopathies by inhibition of the previously untargeted ATPase activity of Hsp70.

PubMed ID#: 19793966 (see pubmed.gov for this abstract, available for free)

Photos of PSP patient’s eyes over 4+ years

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A Korean medical journal recently published a neat little article on a single patient with the clinical diagnosis of PSP. Photos were taken of this gentleman over a four-year period (age 62, age 62, and age 66). There’s also a photo of this gentleman’s eyes when he was in his 40s. The photos show his eyes before the onset of ocular symptoms and after. Some MRI images are included as well. The full article is available for free online. I’ve copied the abstract and some excerpts below.
Robin

Journal of Korean Medical Science. 2009 Oct;24(5):982-4. Epub 2009 Sep 24.

Exodeviated ophthalmoplegia in a patient with progressive supranuclear palsy.

Kim C, Lee HW, Park MY.
Department of Neurology, Han Family Hospital, Daegu, Korea.

We report a patient with progressive supranuclear palsy (PSP) with his serial photographs before the onset of ocular symptoms and after the onset with two year intervals. These photographs show his progressive eyeball deviations toward complete exotropia. There were no effective voluntary eyeball movements, Bell’s phenomenon, doll’s eye movements, and vestibulo-ocular reflexes. These signs indicate the involvement of the oculomotor nuclear complex by the disease. We suggest that PSP may cause not only ‘supranuclear’ but also ‘nuclear’ complete ophthalmoplegia with exodeviation of the eyes.

PubMed ID#: 19795006

Here’s a link to the full article (available online for free) and some excerpts:

http://www.pubmedcentral.nih.gov/articl … d=19795006

Introduction
“Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by progressive dystonic axial rigidity, postural instability, pseudobulbar palsy, subcortical dementia, and impaired of voluntary eye movements. Facial appearances are characteristic in PSP. The patients usually show a fixed ‘surprised’ stare, retracted head, raised eyebrows, markedly decreased blinks (less than 4 per min), and progressive downward gaze palsy. Previously, only a few reports describe PSP patients with photographs. We report a probable PSP patient with progressive eyeball deviations which was documented with serial photographs.”

Case Report
“A 66-yr-old man was admitted because of dysphagia with repeated aspirations in March 2007. In October 2003, he was evaluated in a hospital because of blurred vision, dislike of bright lights and easy falls. He remembered several episodes of falling while riding a motorcycle since 2000. These episodes were not associated with feelings of dizziness or faintness and were independent of specific situation or body position. He visited several local eye clinics where he was diagnosed with bilateral cataracts and presbyopia, and underwent bilateral lens implantation in 2000. He did not benefit from the surgery, but felt a progressive worsening toward imbalance and unsteadiness when walking. Eye evaluation, in October 2003, revealed bilateral surgical pseudophakias and moderate exodeviation. Pupils were irregularly shaped and direct light reflexes were sluggish bilaterally. Fundoscopic examinations showed mildly increased cup to disk ratio (0.6 OD and 0.7 OS) with peripapillary atrophy in both eyes. Vertical ocular movements for willed gaze as well as following objects were slow and limited, though full ocular movements were elicited during passive head motions. Volitional horizontal gaze and pursuit of a visual target were also slow with bilateral adduction paresis. However, convergence was normal. Goldmann visual fields were also normal. He was slow and made errors when performing distal rapid alternating movements. He tended to topple backwards. There was neither resting nor action tremor. He was diagnosed with ‘parkinsonism’ and treated with levodopa/benserazide and other dopamine agonists, but his symptoms did not improve. His illness progressively worsened thereafter. He experienced frequent falls and needed a cane to walk. His head was retracted, and his voice was reduced to a slurred growl. He became unable to look down and had difficulties in swallowing. In November 2006 and January 2007, he suffered from aspiration pneumonias, and underwent tracheostomy and gastrostomy. Magnetic resonance imaging of the brain demonstrated moderate atrophy of the whole cerebrum and brainstem, as well as mild bihippocampal atrophy.”

“He was admitted to our hospital in March 2007. His medical history was otherwise unremarkable. His previous medications included levodopa/carbidopa, ropinirole, selegiline, and afloqualone. His family history was negative for gait, cognitive, or other neurological disorders. He responded correctly to simple verbal commands. His eyes deviated up and lateral, and his vertical and medial eye movements were absent. When the patient attempted to look laterally, only brisk quick lateral eyeball movements were observed on the same side, but the opposite eye showed no movement at all medially. He could not converge his eyes. There was neither Bell’s phenomenon nor optokinetic nystagmus. Caloric stimulations with both warm and cold water did not evoke any nystagmus bilaterally. Doll’s eye maneuver did not evoke any eyeball movements at all. However, because of the patient’s severe nuchal rigidity and retrocollis, the examination was suboptimal. He could not sit in bed by himself, and he repeatedly fell backward without support. His axial rigidity made his distal limb movements appear ataxic but when reaching for close objects with his back supported, his ataxic movements decreased markedly. Reflexes were symmetrical and minimally brisk in the upper and lower extremities with bilateral flexor plantar responses. There was no resting tremor.”

Discussion
“Among the earliest signs of PSP is supranuclear gaze palsy. It includes slowing of voluntary downward saccades, a high percentage of errors in the antisaccade task, and frequent presence of square-wave jerks, and progression to a complete vertical gaze palsy. The doll’s head maneuver may generate a normal vertical vestibular-ocular response that demonstrates the integrity of the third nerve nuclei and confirms that the eye movement disorder is supranuclear. Internuclear ophthalmoplegia (INO), which is an adduction paresis on conjugate horizontal gaze (usually with abduction nystagmus of the contralateral eye), has been described previously in an apparently milder form in a series of 4 patients with PSP.”

“In our case, we could not elicit any effective eyeball movements in his eyes. From the patient’s serial photographs, it is evident that his ophthalmoplegia had been accompanied by progressive eyeball deviation in the upward and outward directions.”

“We suggest that the earliest ocular findings in PSP may be supranuclear gaze palsy, but as the disease progresses, nuclear level gaze control may also be affected, and exodeviation of the eyeballs may be a clinical manifestation in advanced PSP patients.”

Short update on PSP/CBD genetics study

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As many of you know, CurePSP (the new name for the Society for PSP) began the multi-year Genetics Consortium a couple of years ago. This description is from the 2008 CurePSP annual report:

“The CurePSP Genetics Program is a multi-year venture sponsored and supported by CurePSP (The Society for Progressive Supranuclear Palsy). Our goal is to search the entire genome for genes related to PSP and CBD and to identify previously unsuspected abnormal biochemical pathways against which scientists may be able to target therapeutic interventions. All activities will be carried out by the CurePSP Genetics Consortium, composed of neurologists, geneticists, and other scientists from the United States, the United Kingdom, and Germany working in collaboration with neuroscientists throughout the world.”

You can find a good layperson-oriented description of the genetics program starting on page 51 of the CurePSP 2008 annual report.

Last year, about this time, it was reported that the goal was to have 1000 PSP brains included in the study but they ended up with 1300 PSP brains. I’m unclear as to how many CBD brains were examined but I’m assuming it’s several hundred.

Certainly all of the PSP and CBD brains donated to Mayo Jax were included in the study, as the brain bank there has several hundred PSP brains and around 100 CBD brains, and Mayo Jax is part of the research consortium (though it’s not the lead institution).

If your loved one has donated brain tissue to a brain bank other than Mayo Jax, perhaps you can inquire if the tissue was sent to the Genetics Consortium for study.

This is a genome study or a DNA study. The goal is to find out what genes or genetic mutations are implicated in PSP and CBD. Some gene chip technology that became available in 2007 (out of the Human Genome Project) has made the study possible, along with the brain donations and some serious funding.

Recently, long-time CurePSP Forum moderator Ed Plowman described the study in this way:

“Each brain tissue sample had a computer chip assigned to it. The project is attempting to analyze what all PSP brains might have in common genetically that is different from non-PSP brains. As I understand it, hundreds of thousands of bits of data from each tissue sample are cataloged and the findings compared with all the other samples. It may be quite some time before the analysis is complete and findings released.”

Paul Freeman, the CurePSP Board’s Treasurer attended our most recent local support group meeting (September 2009), and sat with the PSP/CBD group. He indicated that four genetic mutations have been discovered as being culprits in PSP. (He didn’t say if these genes were also implicated in CBD.) He said that the researchers are going through the data again to confirm these findings, and then a paper will be written. This gets us a step closer to being able to do genetics testing and to find therapeutic interventions. It does seem like important progress along the way.

Robin

 

Undiagnosed PSP patient who died after receiving Haldol

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I stumbled across this 2007 medical journal article this week when someone in Texas (whose mother has a clinical diagnosis of PSP) asked me to evaluate whether the University of Texas Southwestern would be a good brain bank to donate her mother’s brain. (Answer: No.)

This is a case report of a 35-year-old woman who died due to neuroleptic malignant syndrome, caused by Haldol (an antipsychotic). Upon brain autopsy, it was discovered this woman had PSP.

I find this article timely because this morning I heard that an Arizona-based woman with CBD was given Haldol by hospice and reacted badly to the medication. (The term NMS wasn’t used.) Note that Haldol is common included in hospice medication kits given to families for emergencies. And I heard last week of a local person with Parkinson’s Disease who died after being given Haldol in the hospital.

Here’s my layperson soapbox… Why Haldol is given at all to anyone is beyond me. But why it’s given to those with parkinsonism symptoms or the elderly with dementia is really hard to fathom. (There’s an FDA black-box warning on all antipsychotics for the elderly with dementia.) The information about Haldol in particular is readily available in language that laypeople can understand. Speak with your MD! Many in the Lewy Body Dementia group avoid the administration of Haldol in emergency situations by reporting in patient records (and on MedicAlert bracelets) that family members are allergic to Haldol.

The abstract of the March 2007 article is copied below along with extensive excerpts. (You can see from the first sentence of this excerpt that this woman had very bad luck.)

Robin

American Journal of Forensic Medicine & Pathology. 2007 Mar;28(1):59-62.

Undiagnosed progressive supranuclear palsy in a patient with neuroleptic malignant syndrome due to use of neuroleptics: the
utility of autopsy in deaths due to known drug reactions.

Kemp WL, Fitzgerald J, White CL 3rd.
Department of Pathology, Division of Forensic and Autopsy Pathology, University of Texas Southwestern at Dallas, Texas.

Medical examiners must decide whether or not a complete autopsy is warranted in evaluation of deaths that have been referred to their
office. This decision is influenced by many factors. In most cases, the choice to perform only an external examination occurs in deaths where the decedent had previously documented potentially lethal natural disease or well-documented trauma. We report a patient who apparently died of the sequelae of a well-known complication of pharmacotherapy (neuroleptic malignant syndrome following Haldol administration). The death was referred to the medical examiner’s office, where, based upon the history, an external examination was performed. Subsequently, the family requested an autopsy by the treating hospital. The autopsy established the diagnosis of progressive supranuclear palsy (PSP). The patient’s presenting signs and symptoms were not typical of the disease; however, PSP most likely played a role in the neuroleptic malignant syndrome-like manifestations the patient exhibited following the Haldol administration. The results of the complete autopsy highlight its importance in identifying and enhancing our understanding of the underlying conditions in natural disease-based causes of death involving known therapeutic complications.

PubMed ID#: 17325467 (see pubmed.gov for abstract only)

Excerpts:

Case Report
“This 35-year-old woman with Staphylococcus aureus osteomyelitis occurring after an injury of the finger sustained while cooking was admitted for a partial amputation of the digit after failing outpatient antibiotic therapy. Her past medical history was remarkable for hypertension, obesity, hypoventilation syndrome, schizoaffective disorder, and a progressive but ill-defined movement disorder of 2 years duration that was felt to represent akathisia or tardive dyskinesia. The patient also exhibited progressive apathy, which
was attributed to her underlying psychiatric disorder and use of major tranquilizers. Notably, there was no history of frequent falls. Baseline medications included quetiapine (Seroquel) and sertraline (Zoloft).”

“Following surgery, she was noted to have frequent writhing movements involving her arms and shoulders, without lip-smacking or tongue protrusion. Antipsychotics and benzodiazepines were administered in increasing doses over several days, with no decrease in choreoathetosis. Two weeks into her hospital stay, the patient developed an acute delirium associated with dyspnea, tachycardia, hypertension, and fever (39.5°C). Within hours, she became profoundly hypotensive, necessitating aggressive fluid and pressor support. She developed disseminated intravascular coagulation, rhabdomyolysis, acute renal and hepatic failure, brain infarcts, and a non–ST-segment-elevation myocardial infarct. Although the patient did not manifest increased muscle tone, a diagnosis of NMS was
made and she was treated. A seizure disorder was ruled out with an electroencephalogram (EEG). Cultures were unrevealing,
and no source of sepsis could be identified. The psychiatric service was consulted and opined that she might have catatonic agitation or a conversion disorder. After recovering from multisystem organ failure, the patient was transferred to a nursing home for long-term care. She experienced additional complications, including aspiration pneumonia, and expired a month after discharge from the hospital. Because of the history of trauma inducing the osteomyelitis, her death was referred to the medical examiner’s office. At the
time of her evaluation, an external examination only was performed, and the cause of death ruled as complications of schizoaffective
disorder, with osteomyelitis with right finger amputation being listed as a significant contributory condition.”

“An autopsy was subsequently performed by the treating hospital at the family’s request. … These histologic features are consistent
with a diagnosis of progressive supranuclear palsy (PSP).

Discussion
“PSP is a neurodegenerative hypokinetic movement disorder. Patients usually present later in life (around 50–70 years of age) and characteristically have parkinsonism (rigidity, slowed movements, and tremor) and abnormal eye movements (supranuclear gaze palsy). Patients also commonly have postural instability and present with falls. However, as the areas affected within the brain are heterogeneous, the clinical features may be variable. Other features can include dysarthria, dysphagia, cognitive changes, and aphasia. Although the classic clinical finding is supranuclear ophthalmoplegia, many patients may not manifest this symptom until
late in the course of the disease or, in some cases, not at all. One percent to 8% of patients diagnosed with Parkinson disease clinically are found to have PSP, and some patients diagnosed with dementia are found to have PSP. Apathy, anxiety, disinhibition, and dysphoria are also commonly associated symptoms, and abnormal motor behaviors, including chorea and limb dystonia, are sometimes present. In this case, it is possible that the patient’s progressively worsening choreoathetosis and mood disturbances were caused by PSP, rather than a true schizoaffective disorder and the associated neuroleptic treatment (tardive dyskinesia).”

“The underlying pathologic mechanism of PSP is hyperphosphorylation of tau. Importantly, patients with PSP potentially have multiple neurotransmitter abnormalities, including those affecting dopamine, acetylcholine, Y-aminobutyric acid, and norepinephrine.”

“NMS is a rare adverse reaction (0.2% of patients) associated with the use of neuroleptics (including atypicals such as olanzapine), some nonneuroleptic medications such as tricyclic antidepressants, and following the rapid withdrawal of antiparkinson medications (including levodopa). The proposed mechanism of NMS is widespread block of dopaminergic activity in the brain. The diagnostic criteria for NMS are not agreed upon, but the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) requires severe muscle rigidity and elevated temperature and 2 of the following: diaphoresis, dysphagia, tremor, incontinence, changes in consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and laboratory evidence of muscle injury. However, the literature includes reports of patients presenting with other than the classic symptoms, and one paper reports that less than 50% of cases manifest classic symptoms. The symptoms may be related to which portion of the dopaminergic system is most prominently involved, with nigrostriatal involvement causing rigidity and temperature elevation, mesocortical involvement causing changes in mental status, and tuberoinfundibular involvement causing temperature dysregulation. As hinted at above, patients with Parkinson disease are at increased risk for the development of NMS. NMS has also been described in Shy-Drager syndrome, olivopontocerebellar atrophy, and multisystem atrophy. One paper in the literature reports a case in which a patient with pure akinesia developed hyperthermia, muscle rigidity, abnormal blood pressure, and elevated muscle-derived serum enzymes, which was considered to be NMS. Autopsy revealed the patient to have PSP.”

“While the patient presented in this case report did not fit the demographics or have the clinical symptoms normally associated with PSP, her pathologic features were consistent with the disease. Also, outside of 1 reported case, PSP per se has not often been associated with the increased risk of development of NMS, though clinical parkinsonism has, both in patients receiving antiparkinson medication and in those receiving antipsychotics, such as Haldol. As patients with PSP have abnormalities in the dopaminergic system, it seems reasonable to suggest that patients with this disease have an increased risk for the development of NMS. Indeed, the difficulties in distinguishing PSP from other causes of Parkinsonism clinically raise the possibility that some patients with Parkinsonism who develop NMS may, in fact, have PSP or some other cause of movement disorder besides idiopathic (Lewy body) Parkinson disease.”

“In conclusion, this case illustrates the importance of the autopsy even in patients with known, well-reported reactions to medications. This patient most likely manifested a form of NMS after exposure to neuroleptics in the treatment of her psychiatric condition; however, the patient’s underlying PSP likely increased the risk of its development. As is evident from this case, the discovery of an underlying disease process which may have helped precipitate the observed reaction can have importance for the treating physician and hospital, as well as the correct certification of the cause of death.”

Ataxia, OPCA, and MSA-C Webinar with Susan Perlman, MD – Notes

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Tonight’s webinar with UCLA neurologist Dr. Susan Perlman was terrific!

Lily, in our local support group, said that Dr. Perlman provided the first diagnosis of MSA to Lily’s mother.

Dr. Perlman’s powers of explanation are impressive.  She seems very interested in educating patients.  She thinks patients must be aggressive about getting education and information from their MDs.  She had interesting things to say about stem cell therapy in China.  My notes from the webinar are below.  If you attended, please add to or correct anything I’ve said below.

Robin

——————–

Robin’s Notes from

Susan Perlman, MD, UCLA Ataxia Clinic Director
Topic:  Ataxia, OPCA, and MSA-C
September 17, 2009

Ataxia is a lack of coordination of muscle movements

It is caused by problems in the brain or nerves

Problems in the balance center of the brain (cerebellum) –> “cerebellar ataxia”

Other types:  sensory ataxia, vestibular ataxia

The causes are different of the different types of ataxia

Tonight we are talking about cerebellar ataxia

Image of the brain found here:
content.answers.com/main/content/img/McGrawHill/Encyclopedia/images/CE093200FG0010.gif

It’s important to know the brain areas and be able to speak with your MD about them.

Types of cerebellar ataxia include:
* Pure cerebellar ataxia
* Cerebellar ataxia with problems in the brainstem = OPCA (olivo ponto cerebellar atrophy)
* Cerebellar ataxia with problems in the spinal cord = spinocerebellar ataxia
* Cerebellar ataxia with problems that look like Parkinson’s = MSA or PSP (also called Parkinson’s Plus syndromes)
* Cerebellar ataxia with problems that look like Parkinson’s and have memory problems = PSP

A neurological exam will tell you what type you have.  This is important because the causes are different, and the treatment may be different.  Some causes are genetic (inherited), some are not.

MDs usually refer to cerebellar ataxia and OPCA as the same thing.

Two types of MSA:  MSA-C (cerebellar) and MSA-P (parkinsonism)

PSP and CBD have problems of dementia (memory and thinking).

Educational organizations:
National Ataxia Foundation – ataxia.org
Friedreich’s Ataxia Research Alliance – curefa.org
Cooperative Ataxia Group – cooperative-ataxia-group.org
WeMove – wemove.org
CurePSP – curepsp.org

The UCLA Ataxia Clinic has seen 1565 patients in the past 10 years.  The clinic evaluates about 150 new patients each year.  40% of cases have either FA or a known genetic (inherited) ataxia.  So 60% of cases have an unknown gene or non-genetic cause.  (24% have pure cerebellar ataxia.  The next largest group is OPCA.  The next largest group is MSA.  The next largest group is PSP.)  The Ataxia Clinic has a DNA bank and works with two tissue banks.

Questions our patients ask:
* what do I have?
* what is the cause?
* are my children at risk?
* can it be cured?
* will it get worse?
* how bad will it get?  how soon?
* is there any research?

Patients with ataxia coming on after 50 years of age might be misdiagnosed and in reality have an atypical parkinsonian disorder or Parkinson’s Plus.

Diagnosis can be made by
* symptoms, signs, rate of progression
* lab tests (MRI may be helpful)
* response to treatment

Symptoms that may occur in late-onset ataxia – usually from the cerebellum:
* staggering, wide-based walk (which means there is a risk of falling)
* incoordination of fine hand movements (which can include tremors with hand use)
* slurred or uneven speech
* choking
* jumpy, double vision, eye “tremors” (nystagmus)
* mild bladder control problems

Symptoms from the brainstem (midbrain, pons, medulla)
* reduced or slowed eye movement
* dizziness
* speech difficulties
* swallowing difficulties; risk of choking
* tightness of speech or breathing (called stridor)
* neck weakness
* spasticity of arms and legs

“Hot cross bun” sign – often appears on an MRI in MSA
Increased white shadows

In PSP on an MRI scan, the midbrain is atrophied

Symptoms from the basal ganglia (Parkinson’s symptoms):
* stiffness or rigidity of muscles
* freezing or slowed movements
* soft speech

Autonomic symptoms from the autonomic nervous system:
* orthostatic hypotension (significant fall in BP when standing), causing dizziness, blurred vision, lightheadedness
* trouble emptying urine in bladder
* constipation
* male sexual dysfunction

Other symptoms that may sometime come on before the ataxia or years after the ataxia comes on:
* bladder urgency, often at night
* breathing problems at night, sleep apnea
* parasomnias, eg sleep talking, leg movements during sleep, vivid dreams, nightmares
* fatigue, slowed thinking, dementia
* depression or anxiety
* weight loss, bedsores, infection.  These complications can lead to death.

In AD (Alzheimer’s Disease), there is atrophy in the front of the brain (in the cerebral cortex).

In CBD, there is atrophy in the back of the brain.

Rate of progression of symptoms can help determine the cause or uncover complications:
* Acute/rapid (overnight) – traumatic, vascular, metabolic/toxic, infectious, inflammatory causes
* Sub-acute (weeks or months) – post-traumatic, metabolic/toxic, infectious, neoplastic
* Slowly progressive (months to years) – atypical parkinsonism disorders fall into this category of progression

Everyone deserves testing for:
* which part of the brain is involved (MRI)
* medical factors (prior illnesses, toxic exposures, thyroid disease)
* immune or paraneoplastic
* possible genetic disease (SCA6 and FXTAS screening should always be given)

Why is there no family history of ataxia?
* no one asked
* information is unavailable (such as through adoption, loss of contact, non-cooperation, paternity issues)
* prior generations may have died before showing symptoms
* maybe it really is non-genetics
* a genetic counselor can help determine possible causes

Approach to late-onset predominantly cerebellar syndromes:
* use the history and neurological exam, imaging or other diagnostic tests
* detailed family and environmental history
* rule out genetic causes
* work with MD to minimize risks

Differential diagnosis:  late-onset ataxia vs. Parkinson’s Plus
Late onset ataxia:  slow progression
OPCA: slow progression
FXTAS: slow progression;
MSA-C: moderate progression (less than 10 years to wheelchair, especially if they have symptoms of PD)
MSA-P: moderate
PSP: moderate
CBD: moderate
PD:  slow progression

Many times an MRI can can help diagnose these disorders

Environmental causes – pesticides, chemicals, vascular (stroke)

MSA and PSP have a possible response to levodopa.  CBD has a poor response to levodopa.

MSA – most common form of Parkinson’s Plus or atypical PD
* all forms of MSA have symptoms of ataxia, Parkinson’s, and autonomic failure
* 80% start with parkinsonian symptoms, 20% start with cerebellar ataxia

25% of patients with sporadic cerebellar ataxia go on to develop MSA, within 5 years, especially if over 50 years.

The term OPCA has been used interchangeably for MSA-C but it is not the most accurate term.

18F-fluorodopa PET scan can be helpful in separating MSA for pure cerebellar ataxia.

When is MSA not the likely diagnosis:
* onset after age 75
* family history of ataxia or Parkinson’s
* classic pill-rolling rest tremor
* chorea (involuntary twitches)
* slowed or limited eye movement
* dementia

Treatment of MSA:
* medications used to treat the symptoms become less effective as the disease progresses
* PT and OT always help
* levodopa and dopamine agonists are somewhat helpful for the slowness and stiffness of MSA but they may make low BP worse.
* OH can be treated with medications
* incontinence may be treated with bladder medication or catheterization
* constipation may be improved with dietary fiber or laxatives
* male impotence can be treated
* speech therapy may be able to help swallowing
* sleep disturbances may respond to medication or breathing devices

Once the causes are known, disease-modifying treatment and ultimately a cure will be possible

Neural replacement therapy (stem cell therapy and growth factor therapy) is under development

Active research study in South Korea on stem cell therapy for MSA:  NCT00911365

She does NOT recommend any other stem cell programs at this time

Another useful website:  hopes.stanford.edu/treatmts/index/trhome.html
Designed for Huntington’s Disease but has very useful info about medications and nutritional supplements

ClinicalTrials.gov studies on MSA:
* stem cell trial in South Korea
* rasagiline trial
* L-DOPS augmentation
* others

Questions and Answers (by Dr. Perlman, unless indicated):
[Robin’s note:  I’ve grouped the questions by topic — ataxia, OPCA, SCA, MSA-C, treatment, caregiving and support, and education.]

ATAXIA
Q:  Exactly what is ataxia?
A:  Thinning of nerve cells of the cerebellum are usually seen on an MRI.  There are many types of cerebellar ataxia (as we learned in the presentation).

Q:  Is ataxia hereditary?  Will my children get this?  I am age 70, and have just been diagnosed with ataxia.
A:  As this person is over 70, it’s unlikely that this is genetic.  It’s unlikely it will turn in to MSA.  She should have an MRI to look for signs of MSA.  She should have testing for the two genes discussed earlier.  Perhaps the cause of this person’s ataxia is nutritional imbalance, numbness of feet (causing imbalance), etc.

Q:  My husband was diagnosed with ataxia.  What type of ataxia is it?
A:  It’s important to speak with the MD as to what evidence he/she has of the diagnosis.  Even a simple brain MRI can help identify what type of ataxia it is.  Blood work is helpful to know about vitamin deficiencies, poisons, etc.  The patient must be proactive.  The patient must know the terminology.  The patient must actively pursue information and knowledge.  40% of people have genetic or inherited ataxias.

Q:  I saw a general neurologist and got an ataxia diagnosis.
A:  A general neurologist thinks of disorders associated with older people.  A general neurologist may never have seen anyone with ataxia.  A common misdiagnosis for someone over 50 or 60 is something other than ataxia.  A general neurologist may miss blood pressure problems.  If you have any question about your diagnosis, you should ask to be referred to an ataxia specialist or a movement disorder specialist.

The most common reasons for a misdiagnosis are:
* Inexperience on the part of the neurologist
* Tendency for the MD to think of the common things, and not the rarer things
* The MD not thinking of diagnostic tests that can be done

Q:  [didn’t catch it] A:  80% of what Dr. Perlman knows about ataxia she has learned from patients.

OPCA
Q:  Is all sporadic OPCA MSA-C?  If so, why is the term OPCA still used?
A:  The diagnosis OPCA came from looking at the brain on autopsies and on MRI scans.  Atrophy was seen in certain areas of the brain.  OPCA is basically an MRI diagnosis.  OPCA isn’t the final diagnosis.  25% of those people with symptoms of cerebellar ataxia will go on to develop MSA.  MSA-C is a separate condition.  There may be common causes.  The two terms are not interchangeable.

We don’t yet know how to identify these people in advance.  Part of the research at UCLA is trying to understand why the 25% go on to develop MSA and why the other 75% do not.

SCA
Q:  I have SCA6.  What treatment is there?  What about gabapentin?  What about creatine?
A:  There are many medications used to treat the symptoms of ataxia and eye tremors (nystagmus).  Gabapentin can help with nystagmus.  Creatine may protect nerves from deterioration.  Creatine is an anti-oxidant.

The Stanford HOPES website has a complete list of supplements.  Supplements or medications should be added one at a time.

Q:  What is the status of gene therapy trials with SCA?
A:  We are about 5 years away from human trials with gene therapy in SCA.  Two avenues:  blocking the bad gene and stimulating the good gene.  To block the bad gene, we are using RNAi (a technique).

We are about one year away from human trials for another technique (histone acetylase inhibitors or something like that).

Q:  What is the prognosis for SCA1?  My son saw improvement with Chinese stem cell therapy.
A:  SCA-type 1 slowly progresses with time.  Most people with the genetic ataxias will progress over 15-25 years until they are completely disabled.  The earlier a genetic ataxia comes on the more rapidly it progresses.   For example, someone who gets SCA-type 1 in their 20s, might be disabled in their 30s.

She’s seen several cases who have been to China for stem cell therapy.  The organization in China is not forthcoming.  They have published nothing in reputable journals.  They do not follow up with people so how can this organization know how these people are doing?  Nerves grow and become stronger slowly.  Don’t expect to see improvements in stem cell therapy for at least 6 months.  Any improvements before six months are not from the stem cell therapy.  The treatment in China includes other things such as acupuncture, Chinese herbs, etc.  The benefits from that other treatment should decline upon leaving China.  The Chinese organization does admit that those with genetic ataxias don’t derive as much benefit from the second and third rounds of stem cell treatment in China as they do from the first round.

Q:  I have SCA-type 1.  Is this the same as OPCA?
A:  SCA-type 1 is a genetic form of ataxia.  SCA-type 1 on an MRI shows thinning of the cerebellum.  This is different from OPCA.  OPCA is a general term.  OPCA can have multiple causes.

MSA-C
Q:  I have MSA-C.  What is the latest research being done to treat and cure this disorder?
A:  The oldest and largest research project to date is a natural history study being done in Europe and the US.  In the US, the leader is Dr. Sid Gilman at the University of Michigan.  The focus is finding the cause of MSA.  We must first know the cause before we can know the cure.

See clinicaltrials.gov for MSA trials.  The South Korean stem cell trial’s early results look very good.  Work with your treating neurologist to find a promising study.  Even if there’s no study near you, many of the drugs being studied in the trials can be tried off-label, under the direction of your physician.

Note that when you look on clinicaltrials.gov for multiple system atrophy, you will also see trials for multiple sclerosis (usually at the bottom of the list).

Q:  I have MSA-C.  What is 4-AP and will this help?
A:  4-AP is being developed by a company in Ireland for use in multiple sclerosis.  This drug may be helpful for nystagmus.  It is available now through compounding pharmacists (over the counter) but it should be used under an MD’s guidance.  A serious side effect is epileptic seizures.  This medication is similar to gapapentin.  Hopefully this will be available by prescription soon.  The compounded form available now may or may not be covered by insurance.

TREATMENT
Q:  Anything new about stem cell therapy?
A:  There is now active research in the US on stem cells.  We aren’t ready in the US for the sort of clinical trials that are going on in South Korea.  You shouldn’t pay $30K for unproven stem cell therapy.  Most funded research in the US allows patients to participate without charge.

She’s in favor of exploring alternative therapies — herbs, homeopathic therapies.  These should be monitored by an MD.  If in 6-12 months you don’t feel better from a therapy, you should discontinue and move on.

Q:  What medications are used to treat depression?
A:  Most anti-depressants affect the serotonin pathways.  Others affect the adrenaline pathways.  Lexapro is a very good drug but it doesn’t affect serotonin or adrenaline.  If Lexapro doesn’t work, she tries Wellbutrin, Cymbalta, etc.

Q:  I frequently undergo IVIG treatment and it seems to help my ataxia.
A:  IVIG is immunoglobulin given intravenously.  Perhaps this person’s ataxia is caused by the immune system.  When the immune system is not involved, IVIG should not help.  The immune system isn’t involved in a genetic form of ataxia.

Sometimes chemotherapy drugs are tried in those where the immune system is involved.

CAREGIVING AND SUPPORT
Q:  What can I do to help my mother accept her condition?
A:  Acceptance is a lot to ask of someone diagnosed with a neurodegenerative illness where the cause is unknown and there is no cure.  There are amazingly strong individuals who are able to accept the diagnosis and take advantage of research.  The encouragement of others with the same condition can be a strong motivation.

You have to encourage and support.  Start with little steps — try PT, try exercising together.

MDs shouldn’t say “there’s nothing can be done.”  There is a lot that can be done.

Q:  It’s expensive to hire caregivers for someone.  Is there help?
A:  In short, no.  Resources that are available include IHSS (in-home supportive services) in CA.  There are some respite care grants.  A few insurance companies are starting to cover nursing home care.  Hospice care can be applied for and provides various levels of care in the home.  It’s impossible to predict when someone is within six months of death.  Hospice care can be renewed.

With proper care, we can put people on plateaus for long periods of time.

EDUCATION
Q:  How do I get a copy of the book you wrote?
A:  The National Ataxia Foundation sponsored the development of a booklet on ataxia.  It is written for physicians about diagnosing ataxia.  Patients or family members will find it readable.  Or take the booklet to an MD, PT, or OT and ask for an explanation.

For webinar participants, the National Ataxia Foundation will reduce the price and offer free shipping of this booklet.  Send an email to Susan at the National Ataxia Foundation, [email protected], with “Dr. Perlman’s Book” in the subject line to take advantage of this offer.

Q:  Can I get a copy of this presentation?
A (by the moderator):  CurePSP is trying to make this presentation available.  Maybe it can be emailed out.  It will be available on the psp.org website later this year or early next year.

Q:  Next webinars?
A:  The next five will all be movement disorder specialists:
10/8 – Dr. Neal Hermanowicz, from UC Irvine – Fundamentals and diagnosis of PSP, CBD, and MSA
10/22 – Dr. Robert Hutchman – Interventions
11/5 – Dr. Yvette Bordelon – Latest research
11/19 – Dr. Lawrence Golbe – Research for dummies
12/3 – Dr. Panel of movement disorder specialists, led by Dr. Jerome Lisk