“Does corticobasal degeneration exist?”

This is a terrific article reviewing all of the cases in the Queen Square Brain Bank in London with a pathologically confirmed CBD diagnosis (19) or a clinical diagnosis of CBS (21). In both cases, the diagnostic accuracy was about 25%. Of “21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer’s disease and the remaining five had other non-tau pathologies.”

New terminology is proposed for a large group of pathologically confirmed CBD cases: “Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson’s syndrome, and we propose the term corticobasal degeneration-Richardson’s syndrome for this subgroup. Cases of corticobasal degeneration-Richardson’s syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology.”

The researchers conclude: “Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.”

This UK team consistently produces great research articles. I wish we could get these sorts of brain bank reports out of any US institution with large numbers of CBD and PSP brains. I think Mayo Jax has nearly 100 CBD brains.

Robin

Brain. 2010 Jul;133(Pt 7):2045-57.

Does corticobasal degeneration exist? A clinicopathological re-evaluation.

Ling H, O’Sullivan SS, Holton JL, Revesz T, Massey LA, Williams DR, Paviour DC, Lees AJ.
Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, UK.

Abstract
The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies.

We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls.

Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity = 26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years.

On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer’s disease and the remaining five had other non-tau pathologies.

Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson’s syndrome, and we propose the term corticobasal degeneration-Richardson’s syndrome for this subgroup. Cases of corticobasal degeneration-Richardson’s syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology.

In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%).

Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.

PubMed ID#: 20584946 (see pubmed.gov for this abstract only)

“The Caregiving Boomerang” by Gail Sheehy

Here’s a Newsweek article on caregiving by Gail Sheehy, author of the recently-published book “Passages in Caregiving: Turning Chaos Into Confidence.”

http://www.newsweek.com/2010/06/18/the- … erang.html

The Caregiving Boomerang
by Gail Sheehy
Newsweek
June 18, 2010

The most devoted family caretakers are at risk of dying first themselves. Survival strategies from the author of ‘Passages.’

Fifty is the gateway to the most liberating passage in a woman’s life. Children are making test flights out of the nest. Parents are expected to be roaming in their RVs or sending postcards of themselves riding camels. Free at last! Women can graduate from the precarious balancing act between parenting and pursuit of a career. Time to pursue your passion. Climb mountains. Run rapids. Rediscover romance. You have a whole Second Adulthood ahead of you!

That has been the message of my books since I wrote New Passages 15 years ago. What I didn’t see coming was the Boomerang.

With parents living routinely into their 90s, a second round of caregiving has become a predictable crisis for women in midlife. Nearly 50 million Americans are taking care of an adult who used to be independent. Yes, men represent about one third of family caregivers, but their participation is often at a distance and administrative. Women do most of the hands-on care. The average family caregiver today is a 48-year-old woman who still has at least one child at home and holds down a paying job.

It starts with The Call. It’s a call about a fall. Your mom has had a stroke. Or it’s a call about your dad—he’s run a red light and hit someone, again, but how are you ever going to persuade him to stop driving? Or your husband’s doctor calls with news that your partner is reluctant to tell you: it’s cancer.

When that call came to me, I froze. The shock plunges you into a whirlpool of fear, denial, and feverish act-ion. You search out doctors. They don’t agree on the diagnosis. You scavenge the Internet. The side effects freak you out. You call your brother or sister, hoping for help. Old rivalries flare up. You haunt the corridors of the hospital, always on duty to prevent mistakes.

It begins to dawn on you that your life is also radically changing. This is a caregiving role that nobody applies for. You don’t expect it. You aren’t trained for it. And, of course, you won’t be paid for it. You probably won’t even identify yourself as a caregiver. So many women tell me, “It’s just what we do.”

We’d like to think that siblings would be natural allies when parents falter. In countless of my interviews with family caregivers, I hear the same stories: Brothers bury their heads in the sand. The farther away a sister lives, the more certain she will call the primary caregiver and tell her she doesn’t know what she’s doing. A major 1996 study by Cornell and Louisiana State universities concluded that siblings are not just inherent rivals, but the greatest source of stress between human beings.

There are many rewards in giving back to a loved one. And the short-term stress of mobilizing against the initial crisis jump-starts the body’s positive responses. But this role is not a sprint. It usually turns into a marathon, averaging almost five years. Demands intensify. Half of family caregivers work full time. Attention deficit is constant. But most solitary caregivers who call hotlines like Family Caregiver Alliance wait until the third or fourth year before sending out the desperate cry: “I can’t do this anymore!”

The hypervigilant caregiver becomes exhausted, but can’t sleep. Chronic stress turns on a steady flow of cortisol. Too much cortisol shuts down the immune-cell response, leaving one less able to ward off infection. Many recent clinical studies show that long-term caregivers are at high risk for sleep deprivation, immune-system deficiency, depression, chronic anxiety, loss of concentration, and premature death.

Ailing elders seldom say thank you. On the contrary, they often put up fierce resistance to the caregiver’s efforts. “A major component of psychological stress that promotes later physical illness is not being appreciated for one’s devoted work,” explains Dr. Esther Sternberg, a stress researcher and author of The Balance Within: The Science Connecting Health and Emotions. She places caregivers at the same risk for burnout as nurses, teachers, and air-traffic controllers.
Once the solitary caregiver gets so stressed out emotionally that her own health declines, she can no longer provide the care. The only option left is to place the family member in a nursing home—the last choice of everybody, the most expensive for taxpayers, and guaranteed to leave the caregiver burdened with guilt.

It doesn’t have to be this way. From hundreds of interviews with caregivers and my own experience of 17 years in the role, I can suggest some survival strategies:

Ideally, have the conversation with your siblings before the crisis with Mom and Dad. Make it clear that you cannot do this alone. If the crisis is already upon you, hold a family meeting—in -person—but don’t set yourself up as the boss. Ask a neutral professional—your parent’s primary doctor or a social-worker—to act as mediator. Everyone will be informed of the diagnosis and care plan at the same time. Ask your siblings to come prepared with “What I can do best…” One may contribute money, another has more free time. Everyone has to feel valued.

Download a free Internet-based care calendar that is totally private and can function as the family’s secretary, coordinating dates and tasks to be shared.

Join a support group. Learn from veteran caregivers, who are eager to offer practical short-cuts and know instinctively what you need emotionally. Regular exercise is vital to break the cycle of hy-pervigilance and prepare the body for more refreshing sleep. Ask for appointments for your physical checkups or tests at the same time and place where you take your family member.

You must take at least one hour a day—but every day—to do something that gives you pleasure and refreshment. Have a manicure. Take a swim. Call a friend for coffee. Window-shop. Try a yoga class. All this allows your nervous system to reset.

You will also need longer breaks every few months. Call your local Area Agency on Aging and ask where you can take your family member for a respite stay. Rehab facilities often have some beds for the purpose. Under Medicaid, the caregiver is entitled to three or four days away every 90 days.

Above all, do not fall into the trap of Playing God. When the devoted caregiver comes to believe that she is responsible for saving a loved one’s life—often reinforced by the care-recipient—any downturn will feel like a personal failure. It’s not. No mere human can control disease or aging.

When it becomes clear that your loved one does not have long to live, the caregiver who survives must begin the effort of coming back to life. There is peril in remaining so attached to your declining loved one that you lose your “self.” Palliative care or hospice is invaluable to support and advise you on how to pace yourself at this stage. Medicare or Medicaid will pay for a home health aide to stay with your loved one.

This is the time to replenish your emotional attachments. Reach out for old friends, grandchildren, your church or temple. Take a class at the local Y or community college. Join a book club or a baseball league. I know, I know, you’re too tired. But meeting new people is a natural antidote to late-stage caregiving. New attachments are a bridge to your new life.

You will be answering one of the most profound questions that trouble the dying: what will become of you when I leave you? To see the caregiver joyful again can be a gift of relief.

Sheehy is author of 16 books. Her most recent, Passages in Caregiving: Turning Chaos Into Confidence, was published in May.

Cognitive impairment in PSP and MSA

This article is from the NNIPPS Study Group, a European research team studying PSP and MSA. The sample sizes are huge (311 PSP and 372 MSA) so the findings are significant, though there’s no autopsy confirmation of *all* cases. (I wish we Americans could conduct such large studies.) There are no big surprises here for PSP (but there are for MSA).

Findings include:

* “For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group.”

* “The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy).”

* “Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment.”

* “The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.”

Robin

Brain. 2010 Jun 24. [Epub ahead of print]

Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy.

Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B, Agid Y, Ludolph A, Bensimon G, Payan C, Leigh NP; for the NNIPPS Study Group.
King’s College London, MRC Centre of Neurodegeneration Research, Institute of Psychiatry, Department of Psychology, London, UK.

Abstract
This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n = 372) or progressive supranuclear palsy (n = 311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort.

The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively.

On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy.

Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale.

The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy).

Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole.

These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson’s disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

PubMed ID#: 20576697

Where in brain PSP may start (Japanese research)

This article by Japanese researchers describes a 78-year-old woman with what looks like early PSP. Since the pathological changes were in the substantia nigra and the subthalamic nucleus in this woman, the authors suggest that this is where PSP starts in everyone. The SN plays a major role in movement. The SN is also affected in Parkinson’s Disease. Both the SN and the STN are parts of the basal ganglia.
Robin

Neuropathology. 2010 Jun 21. [Epub ahead of print]

Early-stage progressive supranuclear palsy with degenerative lesions confined to the subthalamic nucleus and substantia nigra.

Sakai K, Yamada M.
Department of Neurology, Noto General Hospital, Nanao, Japan.

Abstract
We describe a 78-year-old Japanese woman with early-stage progressive supranuclear palsy (PSP). She had a 3-week history of postural instability and gait disturbance. On examination, upper vertical gaze palsy, akinesia, hyperreflexia with pathological reflexes, hesitation, and postural instability were observed. Rigidity and resting tremors were not apparent. Brain MRI revealed atrophy of the frontotemporal lobes and dilatation of the third ventricle. A month later, she died of cerebral infarction. The total duration of her clinical course was approximately 2 months. The brain weighed 1180 g after fixation. Macroscopically, mild atrophy of the frontal lobes and mild depigmentation of the substantia nigra were observed. The conspicuous findings included degeneration confined to the subthalamic nucleus and substantia nigra and widespread but infrequent tau-positive neurofibrillary tangles/pretangles and glial fibrillary tangles (tuft-shaped astrocytes, coiled bodies and argyrophilic threads) in the brain. It has been reported that the most affected areas in PSP are the globus pallidus, subthalamic nucleus and substantia nigra. We suggest that degeneration in PSP would start with involvement of the substantia nigra and subthalamic nucleus.

PubMed ID#: 20573028

Using grape seed extract to treat PSP and CBD?

This article out of Mount Sinai School of Medicine reviews studies in lab animals of GSPE (grape seed-derived polyphenolic extracts) in the treatment of tauopathies such as PSP, CBD, and AD. My impression is that most of the studies reviewed were done by researchers at Mount Sinai School of Medicine!

The researchers note: “Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates.”

The abstract indicates that this research team “initiated a series of studies exploring the role of GSPE (Meganatural-Az® GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP…”

You can find more information on this product from this website promoting it:
http://www.meganaturalbp.com/polyphenolics/
They say they have FDA GRAS status (generally recognized as safe). This simply means the FDA views the chemical as safe, not that the FDA has approved of it as a drug that can be used for certain medical conditions. The disclosure section of the article indicates: “Drs. Pasinetti, Wang and Ho are named inventors of a pending patent application filed by Mount Sinai School of Medicine (MSSM) for grape seed polyphenolic extract.”

I assumed GSPE was the same thing as resveratrol. According to the article, “no detectable resveratrol is found in Meganatural-Az® GSPE.”

I couldn’t glean much about the “series of studies” in PSP. I don’t know if these are all biochemistry studies done in petri dishes or studies using lab animals. Some human studies must be going on as well because the article says: “Tolerability and dose escalation studies in PSP subjects are presently underway in our Institution, and will provide fundamental information for the characterization of appropriate doses of Meganatural-Az® GSPE in the treatment of PSP.”

The authors state: “In conclusion, our studies tentatively support the hypothesis, for the first time, that certain forms of bioavailable polyphenolic compounds in Meganatural-Az® GSPE may promote tau anti-oligomerization activities in the brain, ultimately delaying clinical PSP onset, and possibly therapeutically attenuating the clinical progression of PSP and other tauopathies.”

If anyone looks into this further, please share!

Robin

Journal of Neurochemistry. 2010 Jun 20. [Epub ahead of print]

Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies.

Pasinetti GM, Ksiezak-Reding H, Santa-Maria I, Wang J, Ho L.
Center of Excellence for Novel Approaches to Neurodiagnostics and Neurotherapeutics, Brain Institute, Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer’s Disease, Department of Neurology, Mount Sinai School of Medicine, New York, NY.

Abstract
A diverse group of neurodegenerative diseases – including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease (AD) among others, collectively referred to as tauopathies – are characterized by progressive, age-dependent intracellular formations of misfolded protein aggregates that play key roles in the initiation and progression of neuropathogenesis.

Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates (Ho et al., 2009).

Based on our extensive bioavailability, bioactivity and functional pre-clinical studies, combined with the safety of GSPE in laboratory animals and in humans, we initiated a series of studies exploring the role of GSPE (Meganatural-Az((R)) GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP, a neurodegenerative disorder involving the accumulation and deposition of misfolded tau proteins in the brain characterized, in part, by abnormal intracellular tau inclusions in specific anatomical areas involving astrocytes, oligodendrocytes and neurons (Takahashi et al., 2002).

In this mini-review article, we discuss the biochemical characterization of GSPE in our laboratory and its potential preventative and therapeutic role in model systems of abnormal tau processing pertinent to PSP and related tauopathies.

PubMed ID#: 20569300 (see pubmed.gov for this abstract)