Thursday, February 23, 2012


Numerous researchers have extrapolated from dementia and AD prevalence rates in younger people that all centenarians should have at least some degree of cognitive impairment. Yet our studies, as well as those of other centenarian studies, indicate that approximately 20% to 30% are cognitively intact.
Dr. Silver, our lead neuropsychologist, examined a series of 74 centenarians during a 3-year period. Some of their characteristics are noted in Table 2.1, and Table 2.2 lists the neuropsychological tests performed. We are collaborating with other centenarian studies to establish norms for components of the Mattis Dementia Rating Scale and other tests.

The neuropsychological examination, as well as other phenotyping, is performed where the person lives. Specific maneuvers are performed to accommodate for hearing and vision deficits. Multiple visits are performed to prevent fatigue from factoring into the testing, and family is often invited to participate in order to help language barriers.

Table 2.3 summarizes Dr. Silver's neuropsychological test results of 74 subjects. The neuropathological findings for 14 of these participants are summarized in Table 2.4.

It is noteworthy that evidence of microvascular disease was conspicuously absent in the 14 cases found in Table 2.4. We have noted the absence of diagnoses and blood pressure measurements for many of our participants, which would predispose to vascular disease.
We are now in the process of recruiting individuals who are willing to eventually proceed to postmortem autopsy, following them longitudinally with annual detailed neuropsychological examinations. Our aim is to recruit 33 centenarians per year, who live in close enough proximity to the Massachusetts ADRC to ensure that the brain can be obtained within 4 hours of death.

TABLE 2.1 Centenarians Who Have Undergone Neuropsychological Testing
Age range 100-110 years
Gender 86% women, 14% men
Living situation 7% live alone, 26% with family, 67% in nursing homes
Country of origin 50% foreign born

Most frequent birthplaces Italy, Ireland, and Canada Education Mean = 11 years
Range = 1-20 years

TABLE 2.2 Neuropsychological Test Battery

Mini-Mental State Exam
• Mattis Dementia Rating Scale
• Boston Naming Test (CERAD)
• Trail Making Tests
A and B
• Clock Drawing
• Drilled Word Span
• Cowboy Story
• Presidents since FDR
Inventory: Self report and Observer report
• Spiers' Calculations

Geriatric Depression Scale
* Telephone Interview for Cognitive Status
• Test for Severe Impairment
• Tactile Naming
• Cognition and Health History (Informant)
• Psychiatry History (Informant)
• Clinical Dementia Rating Scale
• NEO-Five Factor Personality

Thursday, February 16, 2012

Intrathecal corticosteroids might slow Alzheimer’s disease progression

Anti-inflammatory drugs for treatment and prevention of Alzheimer’s disease have to date proved disappointing, including a large study of low-dose prednisone, but higher dose steroids significantly reduced amyloid secretion in a small series of nondemented patients. In addition, there is a case report of a patient with amyloid angiopathy who had complete remission from two doses of dexamethasone, and very high dose steroids are already used for systemic amyloidosis. This paper presents the hypothesis that pulse-dosed intrathecal methylprednisolone or dexamethasone will produce detectable slowing of Alzheimer’s progression, additive to that obtained with cholinesterase inhibitors and memantine. A protocol based on treatment regimens for multiple sclerosis and central nervous system lupus is outlined, to serve as a basis for formulating clinical trials. Ultimately intrathecal corticosteroids might become part of a multi-agent regimen for Alzheimer’s disease and also have application for other neurodegenerative disorders.

Epidemiological evidence suggests that drugs which counteract inflammation might have efficacy for the prevention and treatment of Alzheimer’s disease, but up to now clinical trials have failed to show any clear-cut benefits for nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, anti-leprosy agents or prednisone. In the case of prednisone, however, it may be that much higher doses might be effective where lower doses were not. In the largest clinical trial to date, patients were given prednisone starting at 20 mg per day for one month, followed by one year at 10 mg daily and then tapering off over another 4 months. By contrast, in a series of 16 nondemented patients aged 25 to 82 who were given prednisolone 30–60 mg per day for at least month for treatment of various conditions, there was significant reduction in cerebrospinal fluid amyloid beta peptides in 15 out of 16 patients, up to about a 50% decline for patients receiving 50 and 60 mg of prednisolone. If amyloid is indeed a cause of Alzheimer’s disease, the above data suggests high dose steroids could suppress Alzheimer’s disease by reducing amyloid.

If the above line of reasoning is on the right track, it is important to note that high dose corticosteroids are already used clinically for treatment of primary systemic amyloidosis, in amounts orders of magnitude greater than those used in the Alzheimer’s disease trial. For example, in one recently published study of a regimen combining dexamethasone and interferon, patients were given several days of dexamethasone in an amount of 40 mg per day, which would be equivalent to 400 mg of prednisone daily.

Finally, there is a case report of a 64-year-old man with multiple myeloma who had a temporary remission of Alzheimer’s disease while receiving chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone.

Obviously megadose of anabolic steroids or cytotoxic chemotherapy as a treatment for Alzheimer’s disease would be hard to justify, but if one can knock down amyloid production, inflammation or both with corticosteroids alone, there should be at least some therapeutic effects. The key is delivering high enough doses of corticosteroids to have efficacy without devastating or killing patients with steroid-induced side effects in the process. Building on several case reports of patients with central nervous system lupus erythematosus and multiple sclerosis who responded to intrathecal prednisolone, dexamethasone, or triamcinalone after failing oral and intravenous steroids, this paper proposes that a similar therapeutic strategy could be pursued for patients with Alzheimer’s disease. Studies in rhesus monkeys and pigs indicate that that intrathecal steroids maximize biodistribution within the brain and minimize it within the rest of the body.

Thursday, February 9, 2012

Genetic Correlates of Successful Cognitive Aging


The hypothesis driving this study is that centenarians are a select group of people who have a history of aging relatively slowly and who have either markedly delayed or entirely escaped diseases normally associated with aging, such as Alzheimer's disease (AD), cancer, stroke, and heart disease.
The ultimate challenge in this area of research is to identify the genes that are associated with such a survival advantage and the ability to age so well for such a long time without cognitive impairment. We have very exciting preliminary results revealing that centenarians can be the
key to discovering these genes.
Primarily because of funding by the Institute for the Study of Aging, continue careful annual neuropsychological testing and eventual neuropathological study of the centenarian subjects.

Approximately 20% of our participants wish to be postmortem brain donors, but we anticipate
increasing this rate to 50%, again, in part, due to the generosity of the Institute. These neuropsychological-neuropathological correlations will help us better understand what disease-free aging of the brain means and what it looks like; if causes of dementia are different in the extremely old compared with younger individuals; and the type and quantity of changes in the brain that correlate with different levels of cognitive impairment.

At the same time, we are studying the centenarians for genes that may play pivotal roles in determining how centenarians markedly delay or, in some cases, escape cognitive impairment. We have obtained the largest collection of centenarian sibships in the world (N ~ 200). Genome-wide scans from these individuals were performed and the data was given to our statistics colleagues at the Whitehead Institute and Rutgers University for linkage analyses. Based upon scans of 308 individuals making up 137 families, currently we have noted statistically significant linkage to a 20 cM region on chromosome 4. A manuscript reporting these results is currently in the review process. Discovery of genes that powerfully affect processes as broad as rates of aging and/or susceptibility to diseases, such as AD and stroke, would have dramatic impact upon understanding the underpinnings of aging and could, ultimately, lead to promising targets for drug discovery.

In our attempts to locate and recruit sibships, we have enrolled five families with many members achieving extreme old age. Such clustering lends itself to linkage studies similar to those performed in families with clustering for rare diseases (such as Tay-Sachs, cystic fibrosis, and sickle-cell anemia).
In this instance, we are not looking for the cause of a disease but rather a fantastic advantage. Four of these families are described in a recent article published in the Journal of the American Geriatrics Society. Unfortunately, because there is likely to be more than one gene (or the lack of a specific mutation) increasing the probability of achieving exceptional old age, we believe that even 10 members of one family being included in a linkage study is unlikely to produce statistically significant results. However, as we include cousins and perhaps children, such studies might prove to be feasible.
In another approach to gene discovery, we have established a collaboration with gene - expression expert Steven Gullens, PhD, from the Brigham and Women's Hospital. Because we are able to obtain brain tissue at postmortem autopsy within 4 hours of death, we will provide Dr. Gullens with ideal brain tissue samples from regions of specific interest regarding AD, as well as regions that play critical roles in cognition (e.g., frontal lobe and its influence upon executive function) for differential gene expression studies. Determining which genes are active in cognitively intact participants versus those with various causes of cognitive impairment versus
other younger controls should be an efficient approach to discovering genes critical to AD pathogenesis.