• 252 patients randomly assigned to placebo or 20 mg of memantine for 28 weeks
• Memantine superior to placebo on – CIBIC-plus
– ADCS-ADL severe
– Severe Impairment Battery (SIB)
• No AEs observed
• Memantine recently FDA approved for moderate to severe AD
Summary
• AChE inhibitors and dual ChEIs are proven effective in the treatment of the ABC of AD
• Patients with severe AD maintain robust behavioral responses to ChEI
• Behavioral disturbances often result in patient institutionalization
• As AD progresses, the number and severity of behavioral disturbances increases
• ChE inhibitors can reduce the need for concomitant antipsychotics, antidepressants and anxiolytic
medications
Summary
• AD associated with vascular risk factors, cerebral vascular disease, and vascular angiopathy
• Cholinergic deficits in VAD, AD, and mixed dementias
• There is increasing evidence of efficacy for ChEIs in PDD, DLB, and VAD, which may result in an extended role for these agents
• All ChEIs have differing modes of action and
pharmacokinetic profiles; therefore, switching can be efficacious
I'll show you how the proteotype, the type of protein that each dementia accumulates, determines the phenotype, the clinical picture of the patient with dementia disorder.
I'll emphasize the neuropsychiatric phenotype of dementias.
Then, I'll talk about the response of these neuropsychiatric symptoms both to antidementia therapies and to the
usual use of psychotropic agents.
J L Cummings
These are very intense psychometric tests,
and there is no difference in these 2 groups at baseline, which is important because one of the ideas is that there
may be some anticipatory cognitive changes that will point to AD in the future. But the routine research tests are quite negative in this population.
These are the learning points.
Degenerative dementias have abnormal proteins within cells.
Every degenerative dementia that we know has a corresponding unique abnormal protein.
Moreover, specific cell populations are differentially vulnerable.
That is, these diseases don't involve all of the cells of the brain. Rather some proteins accumulate in some cells and they produce Parkinson's disease.
Some proteins accumulate in other cells and they produce AD.
Some proteins accumulate in other cells and they produce a frontal dementia. So the vulnerability of the cell populations interacting with the specific protein creates the individual disease.
Then the neural systems are involved, and we have primarily 3 neural systems that we'll deal with.
They are the frontal-subcortical circuits involved in the frontal dementias,
the association cortex/hippocampus involved in AD, and the brain stem-limbic projections, particularly
dopamine, involved in Parkinson's disease and dementia with Lewy bodies.
We have all of these dementias (AD, Parkinson's disease with dementia, frontal dementias),
but more than 90% of all degenerative dementias are caused by abnormalities of only 3 proteins.
So there's a kind of uniformity that can be seen underneath this tremendous clinical heterogeneity
• Tau protein is the abnormality of the frontotemporal dementias and several related conditions.
• Alpha-synuclein protein is the abnormality involved in Parkinson's disease and dementia with Lewy bodies.
The Lewy body is present in the brain stem of the patient with Parkinson's disease, and when the patient with
Parkinson's disease gets dementia, you will find Lewy bodies in the cortex of the brain. Therefore, the major
correlate of the presence of dementia is the corresponding presence of Lewy bodies that now involve the cortex in terms of Parkinson's disease.
• Finally, there's amyloid beta (A-beta) protein producing AD.
Similarly, if you look at tau, which is the other marker
of tangles, there is a marked increase in tau levels in AD vs controls.
• What does the future hold in terms of therapy? I think there is a 3-fold future.
• One is symptomatic treatments, which is now. We have the ChEIs, memantine, and other drugs to
follow, as well as drugs such as the psychotropics, which are really the mainstay of treatment for those who do clinical work for this population,
• the modifying drugs, which include possibly estrogen, statins,
nonsteroidals, and antioxidants.
• Finally, the preventative strategies, which are the most exciting but futuristic strategies that we don't have yet, that include the vaccine as well as the gamma- and the beta-secretase inhibitors.
Let me end by talking a little bit about how we may define AD in the future.
Right now, how do we define AD?
It's cognitive testing and memory decline over 6 months, and we have to exclude other illnesses.
It's a very simple, clinical exclusionary diagnostic approach.
But in the future it may have a genetic profile.
I showed the Apo E data, as just an example of the genetic testing that we might use in the profile and build upon that to get refinement.
That certainly will be a part of our diagnostic and prognostic approaches in the future.
We will still be using paper and pencil tests.
That will not disappear, but I think it will become less important in the approach to diagnosis.
We will be using hippocampal volume, and not just
looking at hippocampal volume cross-sectionally, but over time.
Finally, we will be looking at biomarkers.
I discussed 2 biomarkers just as hints.
One is CSF and other is using PET scans, PET scans with amyloid markers in particular.
The concept of a drive-through PET scan just might be part of our future.