Nonalzheimer's Dementias

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Alzheimer's disease (AD) is the most common form of dementia in the United States, with more than 5 million patients living with the disease in 2007.1 Many pharmacists work with AD patients on a regular basis and are familiar with its pathophysiology, clinical presentation, and pharmacotherapy. Furthermore, excellent articles reviewing the management of AD are available elsewhere. 2-4 With the increasing longevity in the U.S. population, the number of patients living with AD or with other, less commonly encountered dementias will rise. Therefore, community pharmacists should also become familiar with some of the other types of dementias they are likely to encounter in clinical practice. This article attempts to summarize the major therapeutically encountered points of four other major causes of dementia: vascular dementia, dementia with Lewy bodies, Parkinson's disease with dementia, and frontotemporal dementia.

Jeffrey T. Sherer. Nonalzheimer's Dementias. US Pharm. 2007;32(12):26-34.


Vascular Dementia

Vascular dementia (VaD), formerly referred to as multi-infarct dementia, is the second most commonly encountered dementia after AD.5 One case series of over 600 demented patients ages 75 years or older found that 47% of patients had AD and 23% had VaD.6 Worldwide, approximately 15% to 20% of all dementias are thought to be due to vascular causes, a figure that is expected to increase as cerebrovascular disease rates rise.7

VaD frequently coexists with AD in elderly patients, and this complicates the discussion of the disease. In fact, it has been suggested that "pure" AD or "pure" VaD simply do not exist late in life, though this is not necessarily true in younger patients.8 The two diseases share common risk factors, including hypertension, diabetes mellitus, and cigarette smoking.9 Thus, while it has traditionally been thought that AD was neurodegenerative in origin and is distinct from the ischemic pathophysiology of VaD, it is quite possible that the two diseases exist on a spectrum and are more similar pathophysiologically than is often believed.

Despite the overlap between AD and VaD and the fact that a definitive diagnosis can only be made at autopsy, specific criteria for diagnosing probable VaD do exist.10 To summarize, a diagnosis of probable VaD requires each of the following: a decline in cognitive function, including memory, from the patient's previous baseline; the presence of cerebrovascular disease by neurologic findings and/or imaging studies; and a temporal relationship between the previous two findings such as the worsening of cognitive symptoms within three months of a cerebrovascular event. Though commonly used, these criteria have been criticized as underdiagnosing VaD, and other diagnostic tools have been proposed.11

VaD is caused by ischemic changes to the brain and can be either sudden in onset due to an acute event or more chronic and caused by ongoing ischemia. Among patients over the age of 65 who suffer an acute cerebrovascular event, approximately 25% will experience VaD, a reason why poststroke disability is so common.8,12 This also explains the classic stepwise pattern in the loss of cognitive function in VaD, as patients are relatively stable between ischemic events and then suffer a sudden, significant loss with recurrent strokes. While historically only larger, discreet ischemic events were believed to predispose a patient to VaD, ongoing "silent" ischemia is felt to be an underappreciated cause of this disorder.13

The clinical presentation of VaD is comparable to that of AD, though some subtle differences may exist. Memory disturbances are probably more of an issue with AD than with VaD, though in either condition they are often what causes patients to seek medical attention. VaD is more likely to cause gait alterations and personality changes than AD but is less likely to cause language difficulties.8

Because the pathophysiology of both VaD and AD involve the loss of cholinergic neurons, the mainstay of treatment is drugs affecting cholinergic neurotransmission. Several clinical trials have been performed and published, though most are small, open label, or of short duration, or suffer from other significant methodological flaws. The most well-known study was performed by Erkinjutti, et al.,14 who compared galantamine to placebo in nearly 600 patients with VaD or the combination of AD and cerebrovascular disease. Patients with diagnoses of VaD accounted for less than half of the study participants, reflecting the infrequency of "pure" VaD. Those who received galantamine in the six-month trial experienced less progression of their disease than those who received placebo, and the degree of benefit was comparable to what has previously been observed in trials of cholinesterase inhibitors for AD. However, a subgroup analysis revealed that patients with AD and cerebrovascular disease benefited somewhat more from treatment than did those with probable VaD. As expected, gastrointestinal complaints were the most common adverse effects observed in the trial. Clinical trial results with donepezil,15 rivastigmine, 16 and memantine17 have also been largely positive.

Preventing or minimizing further cerebrovascular ischemia is probably the most important treatment outcome for patients with VaD. A small study suggested that aspirin therapy may slow down cognitive decline.18 Guidelines for prevention of stroke in those with a previous stroke are available (TABLE 1).19


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Table 1. Major recommendations for secondary prevention of cerebrovascular disease

- Blood pressure management

- Lipid management

- Smoking cessation

- Moderation of alcohol use

- Weight loss, if appropriate

- Avoidance of physical inactivity

- Antiplatelet therapy, unless contraindicated

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Source: reference 19
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Dementia with Lewy Bodies and Parkinson's Disease with Dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) with dementia are slightly less prevalent than VaD6 and differ significantly from AD and VaD in terms of pathophysiology. The abnormal neuroanatomical structures known as Lewy bodies were first described in patients with Parkinson's disease by the German-American physiologist Frederick Lewy in the early 1900s, but an association between them and dementia was not noted until the 1960s.20 Lewy bodies are distinct from the neuritic plaques and neurofibrillary tangles characteristic of AD, though older patients who have been diagnosed with DLB or PD with dementia may have both neuritic plaques and Lewy bodies present. Neurofibrillary tangles are relatively unusual in DLB and PD with dementia.21 Though Lewy bodies are present in both DLB and PD with or without dementia, in DLB they are present in the subcortical and frontotemporal areas of the brain, while in PD they are located primarily in the substantia nigra region.21

Some controversy still exists as to whether DLB and PD with dementia are two separate diseases or just different manifestations of the same underlying disease process. Most experts will label patients whose dementia symptoms predate their motor symptoms or whose motor symptoms were present for less than a year before the onset of dementia as DLB. Those individuals who have PD for at least a year before dementia symptoms start are typically labeled as having PD with dementia. Since the management of the two conditions is, with few exceptions, very similar, this is largely a matter of semantics.22 The idea that DLB may be a distinct disease is relatively new and was not put forward until the 1980s.23

Criteria for the diagnosis of DLB are available.24 The central feature of the condition is the presence of a progressive loss of cognitive function significant enough to interfere with normal work or life activities. The core features are 1) fluctuating cognition with significant variation in alertness; 2) recurrent visual hallucinations; and 3) symptoms of parkinsonism. Two of these three are necessary for a probable diagnosis of DLB, and one of the three for a possible diagnosis. Other suggestive features, supportive features, and features making a diagnosis of DLB less likely are also listed in the diagnostic criteria, but it is the core features that truly help display how DLB differs from other dementias, so these will be discussed in more detail.

The fluctuations in cognitive function can be significant in DLB. Day-to-day or even hour-to-hour variation is typical and one of the major ways DLB can be differentiated from AD. AD patients may have good days and bad days in terms of alertness and cognitive function, but the variation is typically much less pronounced. Hallucinations are also prominent in DLB. Typically, patients will have highly detailed visual hallucinations that, somewhat surprisingly, they will report as not particularly bothersome. Stereotypically, the hallucinations are of children, though this does not have to be the case. Finally, the parkinsonian features including tremor, rigidity, and bradykinesia, are a common finding in patients with DLB, though the tremor in particular tends to be less pronounced than in PD.

Though not often useful for diagnosing DLB, one of the suggestive features of the disease is an exaggerated sensitivity to neuroleptic agents. As many as half of patients with DLB and 40% of those with PD with dementia experience severe adverse reactions to these drugs and other agents that antagonize dopaminergic receptors.24,25 Many clinicians feel that newer, atypical antipsychotic agents pose a lower, though not negligible, risk. Because hallucinations and, to a lesser extent, agitation are common manifestations of DLB and PD with demenia, this potential sensitivity to neuroleptic agents is something all pharmacists should be aware of. Given the benign nature of the visual hallucinations and also that agitation can often be treated with nonneuroleptic agents such as trazodone, minimizing the use of dopamine antagonists in patients with DLB or PD with dementia is critical. Patients and their caregivers should also be informed of the risks associated with neuroleptics, as many prescribers are unfamiliar with this particular complication of DLB. Unfortunately, early in the course of disease DLB can be difficult to differentiate from AD, and it is common that one of the early clues that a patient may have DLB rather than the more common AD is a severe adverse reaction to a prescribed neuroleptic.

Few data from clinical trials exist to help guide treatment of the cognitive dysfunction. One of the more widely discussed trials was performed by McKeith and colleagues, who randomized 120 patients with DLB to the cholinesterase inhibitor galantamine or to placebo.26 At the end of the 20-week trial period, those randomized to galantamine experienced improvements in hallucinations, delusions, apathy, and anxiety. Adverse effects, though more common in the active treatment group, were generally mild and self-limited. Some evidence suggests that patients with DLB may respond better to cholinesterase inhibitors than do AD patients, so a trial of one of these agents is warranted in most individuals.27 Additional trials have shown benefit of a cholinesterase inhibitor in individuals with PD with dementia, and rivastigmine's FDA-approved labeling includes the indication of PD with dementia.28,29 No treatment is currently FDA approved for DLB ( TABLE 2).


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Table 2. Indications listed in the FDA-approved labeling

Donepezil:
- Alzheimer's: Yes
- Vascular dementia: No
- Dementia with Parkinson's: No
- Dementia with Lewy bodies: No
- Frontotemporal dementia: No

Rivastigmine:
- Alzheimer's: Yes
- Vascular dementia: No
- Dementia with Parkinson's: Yes
- Dementia with Lewy bodies: No
- Frontotemporal dementia: No

Galantamine:
- Alzheimer's: Yes
- Vascular dementia: No
- Dementia with Parkinson's: No
- Dementia with Lewy bodies: No
- Frontotemporal dementia: No

Memantine;
- Alzheimer's: Yes
- Vascular dementia: No
- Dementia with Parkinson's: No
- Dementia with Lewy bodies: No
- Frontotemporal dementia: No
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Parkinsonian symptoms in patients with DLB are treated conventionally with a few caveats. Patients may be at increased risk of adverse effects from anti-parkinsonian drugs, and a small study suggested that the response to levodopa may be suboptimal.30 Slow initiation and close monitoring are critical. As many individuals with DLB are already suffering from hallucinations, this particular adverse effect of antiparkinsonian drugs may be especially troublesome because neuroleptic therapy, as discussed earlier, is often not an option due to the sensitivity to these agents.


Frontotemporal Dementia

Frontotemporal dementia (FTD) is an umbrella term that incorporates more specific disorders including Pick's disease, primary progressive aphasia (PPA), and others. It is believed to be responsible for approximately 5% of all dementia cases, though this figure is much higher in younger (<65 years) patients.31 Unlike AD and other more common forms of dementia, the mean age of onset is probably the 50s rather than the 60s or beyond as is typical for AD, VaD, and DLB.32,33 FTD has a stronger genetic component that the other forms of dementia discussed above, with around 40% of patients having a family member affected.34 Pathophysiologically, FTD is characterized by atrophy of the frontal and temporal lobes of the brain noted on magnetic resonance imaging or other imaging technique, hence the "frontotemporal" nomenclature.

Particularly when the frontal lobe itself is primarily involved, FTD is characterized by what is typically referred to as executive dysfunction. Patients with FTD in whom executive dysfunction is the major problem are often labeled as having Pick's disease. Broadly speaking, executive function is the process of responding to stimuli in a goal-directed manner. The mnemonic SOS-MOMMI is sometimes used to describe executive dysfunction (TABLE 3).35 Stereotypically, patients with this form of FTD may display inappropriate behavior (especially sexual), apathy, loss of empathy, or lack of interest in grooming or appearance. Although memory loss may not be present early in the course of the disease, executive dysfunction correlates strongly with poor functional outcomes in patients with mild cognitive impairment and may result in myriad problems by itself.36


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Table 3. SOS:MOMMI mnemonic for executive dysfunction

S - Selection
O - Organization
S - Sequencing
MO - MOtivation
M - Monitoring
M - Memory
I - Inhibition
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As expected based on its name, loss of language function is the defining characteristic in patients with the PPA form of FTD. Memory issues may also present later in the course of PPA, however.

Very few clinical studies have been performed in patients with frontotemporal dementia. Treatment is generally symptom focused. Agents affecting serotonin, particularly the selective serotonin reuptake inhibitors and trazodone, are often prescribed if depression, anxiety, insomnia, or apathy is present.37,38 Compulsive behavior may also be positively impacted by serotonin reuptake inhibitor use. Aggression or agitation is often treated with antipsychotics, but caution should be used, as extrapyramidal symptoms may develop as the disease progresses.39 Cholinesterase inhibitors and memantine have not been well studied in this population, but clinical experience has shown that most patients do not substantially benefit. Because of the overall disappointing results with drug therapy, nonpharmacologic interventions against FTD, such as patient education, redirection, and caregiver support, continue to be the mainstays of treatment.


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Table 4. Major therapeutic points

Vascular dementia
- Cholinesterase inhibitor or memantine helpful
- Cerebrovascular risk reduction critical

Dementia with Lewy bodies or Parkinson's diseae with dementia
- Cholinesterase inhibitor beneficial
- Sensitivity to neuroleptic agents common

Frontotemporal dementia
- Cholinesterase ihibitor of limited usefulness
- Serotonergic agents may be helpful
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Summary and Conclusion

Demographic changes and increasing life expectancy due to continued improvements in medical care all but ensure that pharmacists will be assisting in the care of more demented patients in the future. While AD, VaD, DLB, PD with dementia, and FTD share many common characteristics and the treatments often overlap, there are subtle differences and special points with each condition of which all pharmacists should be aware (TABLE 4). Ensuring that patients are receiving appropriate cerebrovascular risk reduction therapies in VaD and avoiding the use of neuroleptic agents in those with DLB or PD with dementia are two areas in particular where pharmacists can have a major impact on patient care. Being familiar with the drugs used to improve cognition will also be helpful ( TABLE 5). Hopefully, the next several years will produce much more published research and lead to better decisions about treatment of dementias.


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Table 5. Summary of drugs to improve cognitive function

Donepezil (Aricept)
- Cholinesterase inhibitor
- IR tablet ODT
- Starting dosage 5 mg/day
- Goal dosage 10 mg/day

Galantamine (Razadyne
- Cholinesterase inhibitor
- IR tablet starting dosage 4 mg bid or 8-12 mg/day
- ER tablet starting dosage 8 mg/day, goal dosage 16-24 mg/day


Memantine (Namenda)
- NMDA inhibitor
- IR tablet ODT
- Starting dosage 5 mg/day
- Goal dosage 10 mg bid

Rivastigmine (Exelon)
- Cholinesterase inhibitor
- Patch starting dosage 4.6 mg per 24 h, goal dosage 9.5 mg per 24 h
- IR capsules, oral solution starting dosage 1.5 mg bid, goal dosage 6 mg bid
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Jeffrey T. Sherer, PharmD, MPH, BCPS, CGP
Clinical Assistant Professor,
University of Houston College of Pharmacy
Clinical Specialist, St. Luke’s Episcopal Hospital
Houston, Texas