The Tangled Neuron

Patty's Video

Patty Doherty has posted a video about her father, Alzheimer's and funding Alzheimer's research at The Unforgettable Fund. Her family does a good job telling a story that's both personal and universal.

Diabetes and Alzheimer's

I was sorry to hear that Paula Martinac’s father died last month. As she writes in Dementia Blues, he had both diabetes and dementia. Gail Rae Hudson’s (The Mom and Me Journals) mom is a Type 2 diabetic, and has had what Gail refers to as “dementia-lite” since suffering a mini-stroke. “I think that her diabetes is definitely linked to her mental acuity,” Gail emailed me. “The better control we have of her blood glucose levels, the better her mental acuity.”

Bad for your memory?

These connections between insulin problems and dementia in real life are reflected in recent scientific theories and study results:

- Diabetes may increase the risk of Alzheimer’s

- Diet-induced insulin resistance [a condition in which the body fails to properly use insulin] increases beta amyloid production in mice, and is associated with increased memory problems and increased levels of plaque in the brains of these mice

- Alzheimer’s might be a “type 3 diabetes”

- Mutations in the IDE (insulin degrading enzyme) gene are associated with a higher risk of both diabetes and Alzheimer’s

- IDE degrades or decreases both insulin and beta amyloid [the protein thought to cause Alzheimer’s].

Diabetes and insulin resistance are clearly linked to dementia, but no one knows exactly how. Theories about the mechanism by which insulin problems may cause dementia include:

- Insulin affects glucose utilization in the brain [glucose provides the brain’s energy]

- Insulin modulates acetylcholine [a neurotransmitter involved in learning and memory] levels in the brain

- Insulin increases abnormal changes in tau, the protein that makes up the tangles found in neurons in Alzheimer’s brains

- Insulin makes cortisol [a stress hormone, chronically high levels of which are sometimes linked to cognitive impairment] more toxic to neurons

- Insulin increases inflammation in the brain, damaging cells and increasing production of beta-amyloid, which further increases inflammation

- Insulin problems may increase vascular disease, clogging blood vessels, and reducing blood flow to the brain

- Increased insulin uses more IDE, so less IDE is available to degrade the beta amyloid thought to cause Alzheimer’s.

Even before they can understand how insulin problems contribute to dementia, researchers are studying whether diabetes medicines can help treat or prevent Alzheimer’s and dementia. Scientists at the Veterans Affairs Puget Sound Health Care System and the University of Washington found that raising insulin levels in some patients [those without the APOE4 genetic mutation associated with Alzheimer’s] improved their memories. These researchers are also testing nasal insulin in people diagnosed with early Alzheimer’s or Mild Cognitive Impairment. In a small trial, “nasal insulin improved the ability to retain story details about 25 percent,” says Dr. Suzanne Craft, one of the researchers and Professor of Psychiatry and Behavioral Sciences at the University of Washington.

The idea of increasing insulin levels to improve memory seems counterintuitive, since high insulin levels may damage the brain. “In a healthy physiology, optimal levels of insulin that are secreted and cleared quickly are likely beneficial,” Dr. Craft explains. “But excessive or prolonged elevations are likely detrimental because of induction of insulin resistance and inflammation.” So we may need just the right level of insulin to keep our brains humming along.

Scientists are also studying drugs that increase sensitivity to insulin, instead of increasing insulin levels. “It’s too early to tell about the comparative benefits of the two approaches,” says Dr. Craft. Results of one study using this approach were disappointing. A twenty-four week trial of Rosaglitazone, a drug that increases sensitivity to insulin, in people diagnosed with mild to moderate Alzheimer’s disease showed no benefit over placebo. (Trial results did show that the drug may have helped participants who did not have the APOE gene mutation, but this needs further study.)

Even if it’s not clearly effective in treating Alzheimer’s, perhaps this approach will work to prevent mild memory problems from progressing to full-blown dementia. A preliminary study of Rosiglitazone in 30 people diagnosed with Mild Cognitive Impairment showed improvements in memory and attention. Researchers are now recruiting for a larger trial of the drug in people with Mild Cognitive Impairment. The study will measure the drug’s effects on attention and memory in 120 people 55 and older.

Whether or not diabetes drugs are useful in preventing or treating Alzheimer’s, this research shows how important it is to prevent insulin resistance and diabetes. “Our work strongly suggests that preventing insulin resistance by increasing physical activity, optimizing diet and preventing obesity will ameliorate the risk of Alzheimer’s disease, or at least delay onset,” Dr. Craft says.

Antipsychotic Medicines and Alzheimer's, continued

I wrote in an earlier post about a new study concluding that the side effects of antipsychotic medicines often outweigh the advantages for Alzheimer’s patients. In some situations, modifying the dementia patient’s environment may reduce agitation or other behavioral symptoms without medications. “In many treatment contexts (home, nursing home, group living situations), behavioral management techniques are probably under-utilized and medications are probably over-utilized,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine.

Patty Doherty of The Unforgettable Fund commented on the problems her family had when her father became agitated by “that guy,” who was his own reflection in the mirror. The dose of Risperdal needed to stop her father’s hallucinations made him sleep day and night. Instead, Patty’s family simply covered all the reflective surfaces in her dad’s environment.

Several web sites offer high level descriptions of environmental changes and behavioral management techniques for agitation, aggression, hallucinations and delusions in Alzheimer’s patients:

- Alzheimer’s Foundation of America
- U.S. National Institute on Aging
- The Alzheimer’s Association.

When environmental changes and behavioral management techniques aren’t enough, and antipsychotics aren’t well tolerated or effective, doctors may try medications approved for other uses. Several clinical trials are underway to determine how effective these drugs already on the market are in reducing agitation in dementia patients. These medications include:

-Cholinesterase inhibitors such as donepezil (Aricept – currently used for treatment of Alzheimer’s disease)
-Memantine (currently used for treatment of Alzheimer’s disease)
-Anticonvulsants such as Valproate and Depakote
-Antidepressants such as Citalopram (Celexa).

Tegretol, another anticonvulsant, is also sometimes prescribed for agitation.

In the meantime, research is underway to find new antipsychotic medications with fewer side effects. One such effort at The Fisher Center for Alzheimer’s Research at the Rockefeller University focuses on Fisher Center scientists’ discovery that some of the adverse effects of the current antipsychotic medicines stem from the fact that they block dopamine receptors. Dopamine is a neurotransmitter, or chemical messenger in the brain, and too little of it has been associated with Parkinson’s disease and some of the Parkinson’s-like side effects of antipsychotic medicines.

“Much of this research deals with a protein called DARPP-32, which is located inside brain cells involved in dopamine signaling,” explains Dr. William Netzer, a researcher at The Fisher Center and scientific liaison to the Fisher Center for Alzheimer's Research Foundation and the Michel Stern Parkinson's Disease Research Foundation. “DARPP-32 is a master regulator protein, integrating numerous signals from its cellular environment and orchestrating the cell's responses. [Fisher Center Director] Dr. Greengard and colleagues found that DARPP-32 connects several major signaling systems in the brain. They are the dopamine, serotonin and glutamate systems, and each is involved at various levels in agitation and other behaviors. It may be possible to fine-tune the way DARPP-32 regulates these systems so that certain side effects of antipsychotic and anti-agitation drugs may be avoided, either by directly or indirectly affecting the functions of DARPP-32.”

I hope some of these existing drugs or new antipsychotic medicines will be prove to be more effective than current antipsychotics and environmental changes. In the meantime, Alzheimer’s patients, their caregivers and doctors are left with a trial and error process for managing psychiatric symptoms.

Grand Rounds 3.07

Grand Rounds 3.07 is up at Mssp Nexus Blog - happy reading!

Antipsychotic Medications and Alzheimer's

Throughout his life, my father laughed away any worries. He never locked doors; he trusted everyone. When lightning struck a transformer ten feet from where he stood, he brushed it off. Nothing kept him awake at night.

But when I visited my parents for Dad’s 73rd birthday last year, he was confused and seemed to be hallucinating. “Where are the others?” he asked over and over. “They were here a little while ago – I’m sure I saw them.” I had flown up by myself, and no one was with us in the house.

Later that week, he told Mom he couldn’t sleep because he thought the vibrating box fan in the doorway of the bedroom was going to attack him. He was upset, and it was hard for my mother to reassure him.

Symptoms like Dad’s are common in Alzheimer’s patients, and add to caregivers’ burdens. According to the U.S. National Institute for Mental Health (NIMH), antipsychotic drugs are widely used to treat psychiatric symptoms in people with Alzheimer’s. More than 27% of patients in American nursing homes receive these drugs, which were initially developed for schizophrenia. But, at least in the U.S., these drugs carry “black-box” warnings that they are not approved for the treatment of patients with dementia-related psychosis.

Results of a five year study of antipsychotic medicines in Alzheimer’s patients were published earlier this month in the New England Journal of Medicine. The “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease” study tested three antipsychotic medications against a placebo in 421 Alzheimer’s patients living in their own homes, in family members’ homes, or in assisted living. The medications tested were:

- olanzapine (Zyprexa)
- quetiapine (Seroquel) and
- risperidone (Risperdal).

Input from caregivers was used to help with doctors’ assessments of any improvements or side effects. Although these drugs showed some benefit for some patients, the researchers concluded that “adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”
Side effects seen in some patients included problems with coordination of movement, sedation, confusion and psychotic symptoms. Antipsychotic medicines have also been shown to increase the risk of developing diabetes and stroke.

Despite recent headlines about this research (“Little Benefit Seen in Antipsychotics Used in Alzheimer's,” etc.), it’s hard to say what the study results mean for each individual patient. Dr. Constantine Lyketsos, Chair of Psychiatry at Johns Hopkins Bayview and Vice Chair of Psychiatry at Johns Hopkins Medicine, co-authored the study. “Neither the CATIE study nor other studies suggest that these medicines shouldn’t be used,” he says. “If you look at the CATIE study, it’s not that the medicines weren’t effective, but the risk/benefit ratio has changed. For the sub-groups of trial participants for whom the medications weren’t discontinued because of side effects, they were more effective than placebo. If a patient’s symptoms are high-risk, then doctors can try antipsychotics with careful safety monitoring. If one of these drugs is well-tolerated, then I can tell you from clinical practice that it’s often effective.”

Constantine (Kostas) G. Lyketsos, M.D., MPH

“I think it would be unfortunate if everyone stopped prescribing any medication solely on the basis of one study,” agrees Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine. “Contrary to what many people believe about the study results (and I'll agree that the presentation is confusing), I would not argue that it shows that antipsychotics don't work. It simply shows that antipsychotics aren't enormously effective and that they have lots of side effects. Physicians should prescribe what's appropriate for their individual patients while being aware of the risks and benefits of any given treatment.”

In a “Question and Answer” page on this study, the NIMH recommends caution in prescribing these drugs:

Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer's patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer's patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

In a future post, I’ll write about potential alternatives to these drugs, and efforts to develop antipsychotic medications with fewer side effects. But right now, there are no easy answers for doctors or for caregivers.

In the weeks after Dad’s birthday, things got better. Although he was still confused sometimes, he didn’t seem to be hallucinating, and wasn’t as agitated. His doctor thought maybe his symptoms were the result of heat exhaustion (he had mowed the lawn in the summer heat just before these incidents). I now wonder if he’d had a small hemorrhagic stroke that day. If my father had lived longer, he might have gone through more periods when he was anxious, agitated and confused. As the anniversary of his death approaches, we all miss him terribly. But I’m glad we didn’t have to agonize over whether antipsychotic medicines would help him or hurt him.