Functional Anatomy of the Dementias

Dementia results from the disruption of cerebral neuronal circuits; the quantity of
neuronal loss and the location of affected regions are factors that combine to cause the
specific disorder (Chap. 27). Behavior and mood are modulated by noradrenergic,
serotonergic, and dopaminergic pathways, while acetylcholine seems to be particularly
important for memory. Therefore, the loss of cholinergic neurons in Alzheimer's disease
(AD) may underlie the memory impairment, while in patients with non-AD dementias,
the loss of serotonergic and glutaminergic neurons causes primarily behavioral
symptoms, leaving memory relatively spared. Neurotrophins (Chap. 360) are also
postulated to play a role in memory function, in part by preserving cholinergic neurons,
and therefore represent a pharmacologic pathway toward slowing or reversing the effects
of AD.

Dementias have anatomically specific patterns of neuronal degeneration that dictate the
clinical symptomatology. AD begins in the entorhinal cortex, spreads to the
hippocampus, and then moves to posterior temporal and parietal neocortex, eventually
causing a relatively diffuse degeneration throughout the cerebral cortex. Multi-infarct
dementia is associated with focal damage in a random patchwork of cortical regions.
Diffuse white matter damage may disrupt intracerebral connections and cause dementia
syndromes similar to those associated with leukodystrophies, multiple sclerosis, and
Binswanger's disease (see below). Subcortical structures, including the caudate, putamen,
thalamus, and substantia nigra, also modulate cognition and behavior in ways that are not
yet well understood. The effect that these patterns of cortical degeneration have on
disease symptomatology is clear: AD primarily presents as memory loss and is often
associated with aphasia or other disturbances of language. In contrast, patients with
frontal lobe or subcortical dementias such as frontotemporal dementia (FTD) or
Huntington's disease (HD) are less likely to begin with memory problems and more
likely to have difficulties with attention, judgment, awareness, and behavior.

Lesions of specific cortical-subcortical pathways have equally specific effects on

behavior. The dorsolateral prefrontal cortex has connections with dorsolateral caudate,
globus pallidus, and thalamus. Lesions of these pathways result in poor organization and
planning, decreased cognitive flexibility, and impaired judgment. The lateral orbital
frontal cortex connects with the ventromedial caudate, globus pallidus, and thalamus.
Lesions of these connections cause irritability, impulsiveness, and distractibility. The
anterior cingulate cortex connects with the nucleus accumbens, globus pallidus, and
thalamus. Interruption of these connections produces apathy and poverty of speech or
even akinetic mutism.

The single strongest risk factor for dementia is increasing age. The prevalence of
disabling memory loss increases with each decade over age 50 and is associated most
often with the microscopic changes of AD at autopsy. Slow accumulation of mutations in
neuronal mitochondria is also hypothesized to contribute to the increasing prevalence of
dementia with age. Yet some centenarians have intact memory function and no evidence
of clinically significant dementia. Whether dementia is an inevitable consequence of
normal human aging remains controversial.

Dementia: Treatment

The major goals of management are to treat any correctable causes of the dementia and to
provide comfort and support to the patient and caregivers. Treatment of underlying
causes might include thyroid replacement for hypothyroidism; vitamin therapy for
thiamine or B12 deficiency or for elevated serum homocysteine; antibiotics for
opportunistic infections; ventricular shunting for NPH; and appropriate surgical,
radiation, and/or chemotherapeutic treatment for CNS neoplasms. Removal of sedating or
cognition-impairing drugs and medications is often beneficial. If the patient is depressed
rather than demented (pseudodementia), the depression should be vigorously treated.
Patients with degenerative diseases may also be depressed, and that portion of their
condition may respond to antidepressant therapy. Antidepressants that are low in
cognitive side effects, such as SSRIs (Chap. 386), are advisable when treatment is
necessary. Anticonvulsants are used to control seizures.

Agitation, hallucinations, delusions, and confusion are difficult to treat. These behavioral
problems represent major causes for nursing home placement and institutionalization.
Before treating these behaviors with medications, a thorough search for potentially
modifiable environmental or metabolic factors should be sought. Hunger, lack of
exercise, toothache, constipation, urinary tract infection, or drug toxicity all represent
easily correctable factors that can be treated without psychoactive drugs. Drugs such as
phenothiazines and benzodiazepines may ameliorate the behavior problems but have
untoward side effects such as sedation, rigidity, and dyskinesias. Despite their
unfavorable side-effect profile, second-generation antipsychotics such as quetiapine (25
mg qd starting dose) are increasingly being used for patients with agitation, aggression,
and psychosis. When patients do not respond to treatment, it is usually a mistake to
advance to higher doses or to use anticholinergics or sedatives (such as barbiturates or
benzodiazepines). It is important to recognize and treat depression; initial treatment can
be with a low dose of an SSRI (e.g., escitalopram 10 mg/d) while monitoring for efficacy
and toxicity. Sometimes apathy, visual hallucinations, depression, and other psychiatric
symptoms respond to the cholinesterase inhibitors, obviating the need for other more
toxic therapies.

Cholinesterase inhibitors are being used to treat AD, and other drugs, such as anti-
inflammatory agents, are being investigated in the treatment or prevention of AD.
Depression should be recognized and treated, initially with a low dose of an SSRI
(Lexapro 10 mg), closely monitoring for efficacy and toxicity. These approaches are
reviewed in the treatment section for AD, above.

A proactive strategy has been shown to reduce the occurrence of delirium in hospitalized
patients. This strategy includes frequent orientation, cognitive activities, sleep-
enhancement measures, vision and hearing aids, and correction of dehydration.
Nondrug behavior therapy has an important place in the management of dementia. The
primary goal is to make the demented patient's life comfortable, uncomplicated, and safe.
Preparing lists, schedules, calendars, and labels can be helpful. It is also useful to stress
familiar routines, short-term tasks, walks, and simple physical exercises. For many
demented patients, memory for facts is worse than that for routine activities, and they
may still be able to take part in preserved physical activities such as walking, bowling,
dancing, and golf. Demented patients usually object to losing control over familiar tasks
such as driving, cooking, and handling finances. Attempts to help or take over may be
greeted with complaints, depression, or anger. Hostile responses on the part of the
caretaker are useless and sometimes harmful. Explanation, reassurance, distraction, and
calm statements are more productive responses in this setting. Eventually, tasks such as
finances and driving must be assumed by others, and the patient will conform and adjust.
Safety is an important issue that includes not only driving but the environment of the
kitchen, bathroom, and sleeping area. These areas need to be monitored, supervised, and
made as safe as possible. A move to a retirement home, assisted-living center, or nursing
home can initially increase confusion and agitation. Repeated reassurance, reorientation,
and careful introduction to the new personnel will help to smooth the process. Provision
of activities that are known to be enjoyable to the patient can be of considerable benefit.
Attention should also be paid to frustration and depression in family members and
caregivers. Caregiver guilt and burnout are common. Family members often feel
overwhelmed and helpless and may vent their frustrations on the patient, each other, and
health care providers. Caregivers should be encouraged to take advantage of day-care
facilities and respite breaks. Education and counseling about dementia are important.
Local and national support groups can be of considerable help, such as the Alzheimer's
Association