“Diagnostic criteria of dementia” (Canadian journal article)

I’ve been looking lately into the definition of dementia. When caregivers of those with progressive supranuclear palsy (PSP) call me for the first time, I often ask “does your loved one have dementia,” knowing that at least half of those with PSP have dementia as a primary symptom. Often the caregivers will say “no,” and then go on to tell me how their loved one can no longer balance a checkbook, make investment decisions, or make any sort of decisions. Perhaps these caregivers are embarrassed to say that their loved ones are demented. Or perhaps the only kind of dementia they are aware of is Alzheimer’s Disease, and they know their loved ones don’t have that. Or perhaps we are using different definitions or criteria.

The only standard definition of dementia I’m aware of is the DSM IV criteria. (DSM = Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, published by the American Psychiatric Association, Washington, DC.) According to a University of Alberta website:

“Dementia is a clinical state characterized by loss of function in multiple cognitive domains. The most commonly used criteria for diagnoses of dementia is the DSM-IV. Diagnostic features include: memory impairment and at least one of the following: aphasia, apraxia, agnosia, disturbances in executive functioning. In addition, the cognitive impairments must be severe enough to cause impairment in social and occupational functioning. Importantly, the decline must represent a decline from a previously higher level of functioning. Finally, the diagnosis of dementia should NOT be made if the cognitive deficits occur exclusively during the course of a delirium.”

(Wikipedia definitions: aphasia = loss of the ability to produce and/or comprehend language; apraxia = loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements; agnosia = loss of knowledge or loss of the ability to recognize objects, persons, sounds, shapes, or smells)

The problem is that there are many different types of dementia (70 or 80 types) and their characterizations are all so different. And, as the abstract below indicates, not all types of dementia have memory impairment.

Robin

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The Canadian Journal of Neurological Sciences. 2007 Mar;34 Suppl 1:S11-8.

Bouchard RW.
Clinique de mémoire et unité de recherche Alzheimer, CHA Hôpital de I’Enfant-Jésus, Québec, QC, Canada.

In the past two decades there has been a tremendous effort among clinicians and searchers to improve the diagnostic criteria of the dementias on the basis of the differential neurological and neuropsychological profiles. This was an obligatory requirement for clinical trials and the development of treatments. Over the years it became rapidly evident that the cohorts of patients in studies had some degree of heterogeneity, making it difficult to interpret the results of some studies, particularly in the vascular dementias and the mild cognitive impairment (MCI) group. For example, many sub-types of the vascular group were included in clinical trials, such as the cortical strokes, the lacunar states and the diffuse white matter disease cases, and some of the patients might have had also mixed pathology. In addition, the standard DSM IV criteria for dementia no longer represent our present knowledge of the clinical profile of some of the dementias such as vascular dementia (VaD) and fronto-temporal dementia where the memory impairment is not necessarily the first requirement. To improve the validity of clinical trials and eventually help developing more appropriate treatments, we revised the present diagnostic criteria and made recommendations for some changes in the context of the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004 and reviewed in the light of the recent literature as of early 2006. It is expected that in the near future, these dementia criteria for clinical trials will have to be revised again in order to include specific subtypes of the dementias as well as biomarkers, structural and functional imaging.

PubMed ID#: 17469675 (see pubmed.gov for the abstract only)

Riluzole study – MSA+PSP

This news article was sent to me by a local support group member whose mother with MSA died a few months ago. She regularly reads Medscape and saw a news article on the results of a study of the drug riluzole in MSA and PSP. Rather than being disappointed by the results (that showed that riluzole had no effect on survival), she finds it cheering to know that researchers are actually studying these diseases. Also, she says: “The interesting point is the study design, which included a lot of people fairly early in their diseases and may be a good model for future drug studies.”

The study was done through the European group NNIPPS (Neuroprotection and Natural History in Parkinson Plus Syndromes). The lead author was P. Nigel Leigh, MD, PhD, from King’s College, London. I don’t know of an equivalent group in the US that is looking into all the atypical parkinsonism disorders.

Here’s a link to the news article, and a copy of the full text. To gain access to anything on Medscape, you must log in, which requires (free) registration.

http://www.medscape.com/viewarticle/557908

NNIPPS: No Benefit of Riluzole on Survival in MSA and PSP

Susan Jeffrey
Medscape Medical News 2007.

June 7, 2007 (Istanbul) — A randomized trial of the neuroprotectant drug riluzole (Rilutek, Sanofi-Aventis) in patients with the “Parkinson plus syndromes” of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) shows no effect on survival, either in the population as a whole or within the PSP or MSA strata, with treatment vs placebo.

However, the study supports the idea that large trials in neurodegenerative disorders can use survival as an end point and that it is feasible to include patients with these conditions quite early in their disease using the Parkinson-plus-syndrome concept.

The concept, for which this group has developed and validated diagnostic scales based on these data, “may be worthwhile when we have drugs that are promising,” lead author P. Nigel Leigh, MD, PhD, from King’s College, London, United Kingdom, who presented the results on behalf of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) Consortium, told attendees here.

“It has simple, pragmatic diagnostic criteria, which I suggest have some merit,” he added, as well as high sensitivity and specificity for these difficult-to-diagnose conditions. The results were presented here at the 11th International Congress of Parkinson’s Disease and Movement Disorders.

No Survival Benefit

PSP and MSA often present as Parkinson plus syndromes — that is, having some of the classical features of Parkinson’s disease but with some additional features. Early in the disease course, it can be very difficult to distinguish these conditions from each other, but for any intervention to be useful, it is important to enroll patients before diagnosis of PSP vs MSA is definitive.

PSP and MSA each have roughly the same frequency as amyotrophic lateral sclerosis (ALS), Dr. Leigh told Medscape, and “so are not insignificant adversaries.” The idea of NNIPPS was to design a trial that would give a definitive answer, he said. “The whole field is deviled by small trials that never, ever, could have gotten a result. If we’re going to choose a drug that’s not ideal, like riluzole — no one was really expecting it to be a cure — let’s at least be 80% or 90% sure that we’re going to know in the end that it doesn’t work or it does work.”

They decided to use survival as an end point for this trial. “Everybody said, you can’t do it, it takes too long, but I think we’ve shown you can do it. It’s tough, and it takes a long time, but maybe that will be worth it when we do have really good drugs,” he noted.

Still, they had started out with the hope that riluzole might be effective. The natural history of MSA and PSP is poorly understood, they note in their abstract, but excitotoxicity may contribute to the neuronal damage. Riluzole, already approved for use in ALS, is a glutamate-release inhibitor and has been shown to prolong survival by about 2 months in clinical ALS trials and possibly between 6 and 19 months in retrospective data.

The NNIPPS trial, then, was a European multicenter, randomized, and stratified trial of riluzole in a dose of 50 to 200 mg per day vs placebo in patients with PSP and MSA. At the same time, investigators meant to investigate the natural history of these conditions presenting as Parkinson plus syndromes, acquiring prospective data on diagnostic criteria, MRI changes, and pathology.

The primary outcome was survival at 36 months; secondary outcome measures included functional status, cognition, quality of life, healthcare costs, and MRI abnormalities.

Power calculations were based on published estimates of survival in these conditions. In total, they enrolled 766 subjects from participating centers in the United Kingdom, France, and Germany. Six were later excluded because they either were found not to have proper informed consent or did not actually receive the drug, leaving 362 patients diagnosed clinically as PSP and 398 as MSA.

They used their own NNIPPS diagnostic criteria rather than the retrospectively validated existing criteria, he pointed out, because “we decided they were operationally extremely difficult in the setting of a clinical trial; they’re too complicated, too complex,” he said. In addition, “they’re very good on specificity but they’re weak on sensitivity, and we wanted sensitivity as well.”

Median survival from onset was 7.8 years for PSP and 8.7 for MSA, with 171 deaths occurring in the PSP group and 171 in the MSA group.

Blinded Data

In his presentation of the primary results here, Dr. Leigh noted that they have not yet unblinded the riluzole/placebo comparison because they hope still to do the other secondary analyses in a blinded fashion. Instead, he simply presented the survival results as “treatment A” vs “treatment B.” Looking at the survival curves, however, he pointed out, “It doesn’t take much to show you that there was no significant difference, with the log rank clearly not significant. There was no difference, despite having adequate power.”

Analysis of the intent-to-treat population showed no evidence of a significant treatment effect of riluzole either in the population as a whole or in the PSP or MSA strata.

“So the very least we can say is that riluzole does not work in this condition, but maybe this is a model for looking at other drugs, which we hope indeed it will be,” he said.

Pathological diagnosis was confirmed in 112 cases where brain tissue has been donated and analyzed; another 20 brains have been donated but not yet analyzed, he noted. Overall, pathology-confirmed diagnosis showed that clinical diagnosis using the NNIPPS diagnostic criteria had an overall positive predictive value of 90% for PSP and 93% for MSA, “so we were encouraged by that,” Dr. Leigh noted.

In an interview, Dr. Leigh pointed out that an earlier session here on the genetics of movement disorders underlines the “scary” genetic diversity of these diseases, making finding specific treatments for each subgroup with a different molecular mechanism a daunting task. “If you’re going to find disease-modifying therapy in neurodegenerative diseases, the real challenge is to try to break across the boundaries of individual diseases and find common mechanisms.”

They were disappointed with these results not only because they had hoped to help patients, but because if it had been positive that would have pointed to a common mechanism and provided some insight into how riluzole may be working in ALS as well, since this has not been well described.

“Still, I think, after recovering from the bad weekend when we got the news, that there’s still a huge resource there,” Dr. Leigh said.

Rich Resource

Despite the fact that the trial was ultimately negative, NNIPPS provides a rich data set for understanding motor, cognitive, neuroimaging, and genetic factors in MSA and PSP.

For example, they devised and validated 2 diagnostic scales, the Parkinson Plus Scale and the Short Motor Scale, specifically designed for early use before a diagnosis of PSP or MSA is certain. They also have quality-of-life data and health costs that can be used in healthcare planning, he noted.

In addition, they have 633 baseline MRIs in these patients, with follow-up scans done at the end of the study in 187 patients; 521 DNA samples; and brains now from 131 patients, prospectively collected and being analyzed. Dr. Leigh invited any researchers interested in accessing these data to contact him about it.

The study was supported by the European Community. Study drug was provided by Sanofi-Aventis. Dr. Leigh disclosed has worked as a consultant for ONOPharma, Teva, Trophos, and GlaxoSmithKline.

11th International Congress of Parkinson’s Disease and Movement Disorders: Oral Platform Presentations 4602: Abstract 10. June 3-7, 2007.

Distinguishing Alzheimer’s from Dementia with Lewy Bodies

Here’s an easy-to-read newspaper article from Science Daily (sciencedaily.com) on using “changes in alertness and cognition” to help distinguish Alzheimer’s Disease (AD) from Dementia with Lewy Bodies (DLB).  A local support gorup member suggested this is a good article to give family and friends about Lewy Body Dementia.

Robin
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www.sciencedaily.com/releases/2004/01/040116080751.htm

New Method Of Distinguishing Alzheimer’s From Lewy Body Dementia
Source: American Medical Association
Science Daily
Published 1/16/04

NEW YORK — Looking at specific changes in alertness and cognition may provide a reliable method for distinguishing Alzheimer’s disease (AD) from dementia with Lewy bodies (DLB) and normal aging, according a new study from the January 27, 2004, issue of Neurology, the official journal of the American Academy of Neurology, co-authored by Tanis J. Ferman, Ph.D., an expert on DLB.

Lewy bodies are round collections of proteins in the brain that are considered the pathological hallmark of Parkinson’s disease. Lewy bodies are never found in healthy normal brains. In Parkinson’s disease the Lewy bodies are largely localized to an area of the brain stem called the substantia nigra. In DLB, Lewy bodies are also found in brain’s cortex.

Although DLB accounts for as much as 20 to 35 percent of the dementia seen in the United States, treatment and diagnosis is often complicated by a lack of information about the disease. In the study, Dr. Ferman and colleagues examined episodes of fluctuation in cognition (problems in thinking or concentration) experienced by individuals with AD or DLB or normal older adults who had no signs of dementia.

“Fluctuating cognition is an important symptom of DLB but has been the center of some controversy because it is comprised of a number of behaviors, some common to all dementias and perhaps even found in normal aging,” said Dr. Ferman, assistant professor and clinical neuropsychologist in the department of psychiatry and psychology at the Mayo Clinic in Jacksonville, Fla. “Even though attempts have been made to carefully describe these behaviors, they have not been used reliably as diagnostic tools.” Dr. Ferman spoke today at an American Medical Association media briefing on Alzheimer’s disease in New York City.

Some of the common behaviors of DLB that comprise fluctuating cognition include episodes of confusion, excessive sleepiness, a waxing and waning of cognition, inattention, incoherent speech and varying ability to perform tasks. When this occurs, family members often describe their loved ones as “zoned out,” or “not with us.” This collection of behaviors is called fluctuations because these behaviors come and go. In the study, 200 normal older adults, 70 patients with AD and 70 patients with diagnosed DLB were compared on aspects of fluctuating cognition. Spouses, adult children or others involved with the subject on a day-to-day basis provided information.

Four characteristics significantly distinguished patients with DLB from persons with AD and normal elderly controls: daytime drowsiness and lethargy despite getting enough sleep the night before; falling asleep two or more hours during the day; staring into space for long periods and episodes of disorganized speech.

“For the normal elderly control group, one or two of these behaviors was found in only 11 percent of the group,” said Dr. Ferman. “For the patients with AD, one or two of these behaviors were not uncommon, but over 63% of the patients with DLB had three or four of these behaviors. This gives us a clear set of behaviors to use to reliably distinguish the fluctuations of Lewy body dementia from Alzheimer’s.”

“Medications that may be helpful to an Alzheimer’s patient may actually aggravate DLB symptoms such as hallucinations and symptoms of parkinsonism. Other medications that are only marginally helpful in AD sometimes have a dramatic impact on Lewy body dementia,” said Dr. Ferman. “It’s very important to diagnose correctly because proper treatment can help us manage symptoms and help caregivers cope.”

Both AD and DLB are dementias, that is, classified by a decline in thinking skills greater than expected by age that interferes with the activities of daily living, explained Dr. Ferman. In AD the first loss in thinking skills is in memory; in DLB the earliest loss appears to be with attention and visual perception. These differences may be related to different patterns of damage to the brain. In addition, patients with DLB may have fully formed hallucinations, Parkinson-like movement problems and/or fluctuating cognition. These symptoms may be present in late-stage AD, but one or all of them are present in early DLB.

“As our understanding and ability to recognize Lewy body dementia has improved, there has been an explosion of research,” said Dr. Ferman. “As we develop effective treatments to prevent or delay progression of DLB, early diagnosis will be key.”

Note: This story has been adapted from a news release issued by American Medical Association.

Mayo Clinic Jacksonville Protocol and Shipping Instructions

Brain Support Network helps families make arrangements to donate a loved one’s brain for research and so the neurological diagnosis can be confirmed.

Most of the time, the Mayo Clinic in Jacksonville, Florida (“Mayo Jax”) is the brain bank where these brains are donated.

Below, we will keep the latest research protocol for Mayo Jax along with their shipping instructions.  Note that the whole brain is donated.

In short, the whole brain must be removed within 24 hours of death though note that 12 hours of death is preferred.  (And even sooner is better.)  The brain is split in half.  The right half is frozen while the left half is fixed.  (I remember this by noting that frozen contains an “R” as does right.)  Mayo Jax provides containers and dry ice, and pays for FedEx shipping.

Plus, we list below Brain Support Network’s shipping suggestions.  These have been developed over many years of stories using FedEx as the shipping agent.

Robin
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Mayo Clinic Jacksonville – Research Protocol
Last Updated:  February 2016

Thank you for enabling us to establish a diagnosis of neurological disease and to obtain tissue for special studies and research in neurological diseases. Please perform the harvest as soon as possible after death, preferably within 12 hours (up to 24 hours is still acceptable). The time lapse between death and autopsy should be noted as well as the fresh brain weight when drained of CSF.

Split the brain down the middle through the corpus callosum, cerebellar vermis and brainstem. Put the right hemisphere in a plastic bag into the coldest possible freezer (preferably at -70˚C). In order to prevent distortion of the specimen, put the medial aspect of the brain down flat, so that it will freeze in its normal shape. The left hemibrain is simply immersed in formalin, buffered to neutrality.

We will send the report of our findings to you. We can also provide an extra set of slides, if desired. We will provide a letter and a copy of the report to next-of-kin regarding our findings.

Please call Dr. Dickson at one of the numbers given above if you have any questions.


Mayo Clinic Jacksonville – Shipping Instructions
Last Updated:  February 2016

When ready to ship, the frozen specimen is packed in 48 hours worth of dry ice in a Styrofoam shipping container. The formalin fixed specimen is wrapped in paper towels that are damp with formalin, put into a leak-proof plastic bag in a separate shipping container, wrapped separately from the frozen one.

The Autopsy Information Form should be filled out and sent along with the tissue. Both boxes (do not tie together) are to be sent overnight by Federal Express, Priority One Delivery. We can provide shipping containers and dry ice if needed, and will be happy to provide you with our FedEx number to cover the cost of shipping the tissue.

Both packages should be addressed to:

Dennis Dickson, M.D.
Mayo Clinic Jacksonville
Birdsall 347
4500 San Pablo Road
Jacksonville, FL 32224
(904) 953-2439 or (904) 953-7137

Please send the tissue early in the week so as to avoid delivery during the weekend when no one will be here. Do not ship on Thursdays or Fridays.


Brain Support Network’s Shipping Suggestions
Last Updated:  December 2018

1.  Many pathology service providers prefer to send the frozen hemisphere as soon as possible (keeping in mind Mayo Jax’s shipping requirements) and wait until the hemisphere in formalin is fully fixed before sending it.  It is our understanding from discussions with Mayo Jax, that Mayo Jax does not require the tissue in formalin to be fully fixed before sending.

2.  The formalin fixed-specimen (left hemibrain) should be wrapped in formalin-soaked towels and double-bagged.  Take care not to over-fill the “inside” bag with formalin as leakage/spoilage was a recent problem that resulted in FedEx suspending transport of a shipment.  Any good quality Styrofoam shipping container can be used.

3.  Double bag both the formalin and frozen hemibrains prior to shipping.  Avoid using RED biohazard bags, altogether. Dry ice damages this type of plastic.

4.  Label the outside of the bags in both shipping containers with the donor’s name and DOB using a dark colored Sharpie marker.

5.  Under no circumstances should wet ice be used for shipping.  Dry ice only should be used for the right hemibrain.  Any good quality Styrofoam shipping container can be used.

6.  The information sheets (with any attached pages) should be included in each of two containers.

7.  The brain must be shipped early in the week because there’s no one at Mayo Jax to receive the shipment on the weekends.  Never ship on Thursday or Friday, and do not ship when the next day is a holiday. Given recent problems with FedEx and the container with dry ice we strongly advise against shipping on Wednesday.  Best to ship on Monday or Tuesday and track the shipments closely.

8.  Before shipping, please check the FedEx website for service alerts to be sure that there are no weather conditions in Florida, Tennessee (FedEx hub), or other locations that would delay shipping.  FedEx’s webpage is:

www.fedex.com/us/servicealerts/index.html 

FedEx has a link on its website to the National Weather Service’s weather map, showing severe weather.

9.  Note that some pathology service providers have reported that FedEx has been unwilling to pick up or accept containers with dry ice.  Please double-check with FedEx delivery staff who pick up from a usual location as to whether they have a problem with this.  Regular FedEx locations will accept containers with dry ice; however, many FedEx Office locations will not.

10.  We’ve also had the situation where FedEx has accepted a container with dry ice, only to return it or delay delivery.  Once, in January 2016, a regular FedEx location accepted the package containing dry ice and then returned it to the pathology specialist’s address a few hours later, offering no explanation as to why it had been accepted earlier at the FedEx location only to be rejected later.  Twice in May 2016, FedEx delayed the delivery to Mayo of two containers where the label showed dry ice (“ICE”) was included.  Fortunately in both cases, tissue was shipped out on a Monday so we had a couple of days’ leeway to address the problem with FedEx.

11.  Immediately after shipping, please send a cell phone photo via text to Robin Riddle (cell phone 650-814-0848 – accepts texts) of the tracking numbers of the two containers.  Or, send an email containing the two tracking numbers to Brain Support Network.  This way Brain Support Network can monitor the shipments.  It is best that the pathology service provider monitor the shipments as well, in case any issues arise during transit.

12.  Around the year-end holidays, Mayo will often request that shipment be delayed.  It is best around the year-end to check with Mayo or Brain Support Network in advance of shipping.

13.  Note that hurricane season officially begins on June 1st every year.