Dementia Research Paper

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Dementia, as it is used in this research paper, refers to a persistent decline in intellectual functioning in multiple cognitive domains relative to a previous level of performance. A separate paper discusses Alzheimer’s disease. Although Alzheimer’s disease (AD) accounts for 45 to 80% of all dementias, the absence of a definite biological marker of AD in living patients continues to necessitate the exclusion of less common but sometimes treatable dementing conditions and differentiation among degenerative dementias. Given that some non-Alzheimer’s dementias are potentially treatable (i.e., further cognitive deterioration can be avoided or minimized) and/or reversible (i.e., cognitive functioning can be improved), a thorough consideration of all potential etiologies is imperative. This research paper will describe the non-Alzheimer’s dementias along a continuum of relatively untreatable, progressive disorders to treatable and potentially reversible causes. Many of these conditions represent diagnostic challenges given their rarity, and clinical diagnostic criteria for these disorders are either nonexistent or highly variable. The degenerative, non-Alzheimer’s dementias will be considered first, the majority of which have limited treatment options available. Next, dementias due to cerebrovascular disease will be surveyed, some of which may be treated to avoid further progression of cognitive impairment. Dementias due to infectious processes will be reviewed subsequently, many of which may also be treatable if discovered in their early stages. Dementia due to toxic or metabolic conditions may be among the most treatable etiologies and are potentially reversible if detected and corrected relatively early. Finally, dementia due to other causes, many of which are treatable and reversible, will be examined.

Dementia Research Paper Outline

I. Degenerative Dementias

A. Frontal Lobe Degeneration and Pick’s Disease

B. Parkinson’s Disease

C. Diffuse Lewy Body Disease

D. Huntington’s Disease

E. Progressive Supranuclear Palsy

F. Cortical-Basal Ganglionic Degeneration

G. Hallervorden-Spatz Syndrome

H. Wilson’s Disease

I. Cerebellar and Olivopontocerebellar Degeneration

II. Dementia Due to Cerebrovascular Disease

A. Multi-Infarct Dementia

B. Thalamic Vascular Dementia

C. Lacunar State

D. Binswanger’s Disease (Subcortical Arteriosclerotic Encephalopathy)

E. Vasculitis

III. Dementia Due to Infectious Agents

A. Viral Infections

1. HIV Encephalopathy

2. Subacute Sclerosing Panencephalitis (SSPE)

3. Herpes Simplex Encephalitis

4. Viral Infections Associated with Underlying Systemic Illness

5. Limbic Encephalitis

B. Bacterial Infections

1. Bacterial Meningitis

2. Syphilis

3. Brain Abscesses

C. Mycotic (Fungal) Infections

D. Parasitic Infections

E. Prion Disease

IV. Dementia Due to Toxic or Metabolic Disorders

A. Systemic Illnesses

1. Thyroid Dysfunction

2. Parathyroid Dysfunction

3. Cushing’s Disease and Addison’s Disease

4. Cardiovascular Disease

5. Pulmonary Disease and Anoxic States

6. Renal Disease and Dialysis

7. Hepatic Disease

B. Vitamin Deficiencies

1. Thiamine (Vitamin B1)

2. Vitamin B12

3. Folate Deficiency

4. Niacin (Bz) Deficiency (Pellagra)

C. Toxic Conditions

1. Occupational and Environmental Toxic Exposure

2. Toxic Effects of Medications

3. Toxic Effects of Drugs of Abuse

V. Dementia Due to Other Causes

A. Hydrocephalus

B. Head Trauma

1. Closed Head Injury

2. Dementia Pugilistica

C. Tumors

D. Psychiatric Conditions

1. Depression

2. Schizophrenia

I. Degenerative Dementias

A. Frontal Lobe Degeneration and Pick’s Disease

1. Clinical Features

Patients with degenerative changes confined principally to bilateral frontal or fronto-temporal brain regions often demonstrate a characteristic clinical pattern with early onset of personality changes associated with inappropriate social or personal behavior, followed by cognitive deficits that are evident later in the course of the disorder. With the exception of elicitation of primitive reflexes (e.g., grasp, suck, snout), neurological signs are typically absent. Computed tomography (CT) and magnetic resonance imaging (MRI) scans commonly reveal prominent atrophy of the frontal or fronto-temporal cerebral cortex. Positron emission tomography (PET) and SPECT (single photon emission computed tomography) typically reveal diminished glucose metabolism and cerebral blood flow in the frontal and fronto-temporal cortex.

Frontal lobe dementia tends to first become manifest in younger individuals in their 50s or early 60s, although cases have been reported in patients as young as 20. Women are affected nearly twice as often as men. Approximately half of patients diagnosed with frontal lobe degeneration have a first-degree relative who has shown similar behavioral and cognitive changes. Because of the striking and frequently problematic personality changes, frontal lobe degeneration is often misdiagnosed as a psychiatric disorder. Impaired judgment and lack of insight commonly lead to inability to manage instrumental activities of daily living, together with occupational impairment. Personality changes may reflect prominent apathy and lack of motivation at one extreme, or disinhibited, reckless, and hyperactive behavior at the other extreme. Language changes sometimes reflect terse, stereotyped, repetitive phrases, gradually progressing to echolalia (repetition of phrases said by others) and palilalia (repetition of single syllables uttered by themselves or others). Memory and orientation, visuospatial skills, and basic language abilities are surprisingly well-preserved during the early stages of this disorder, although neuropsychological measures of executive functioning may reveal perseveration, diminished word list generation, cognitive rigidity, and difficulty formulating and sequencing complex behaviors.

Pick’s disease is a specific type of frontal lobe degeneration that is characterized by the presence of distinctive neuropathological markers known as “Pick bodies” that disrupt neuronal cytoskeletal organization and displace the neuronal nucleus toward the periphery of the cell body. Approximately half of the patients diagnosed with frontal lobe degeneration show evidence of Pick bodies at biopsy or autopsy.

2. Treatment

Frontal lobe degeneration may be treated only symptomatically. Behavioral agitation and aggression are typically treated pharmacologically with neuroleptics. Activities of daily living must be routinized, and frequent supportive guidance and reality orientation may be used in an attempt to minimize disruptive behavior.

B. Parkinson’s Disease

1. Clinical Features

Parkinson’s Disease (PD), a degenerative disorder mainly involving the pigmented cells in the substantia nigra and other pigmented brain stem nuclei, affects approximately 1% of all individuals over the age of 65. Dopamine depletion in the frontal cortex and striatum (particularly in the anterodorsal portion of the head of the caudate nucleus), is the major neurochemical deficit associated with PD, although reduced levels of norepinephrine, acetylcholine, and somatostatin, and diminished serotonin receptors have also been reported. The cause of PD is not known, although toxic agents such as manganese poisoning in industrial workers and injection of 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) in drug abusers, are known to produce PD symptoms and pathology, suggesting the possibility that an environmental factor could play a role in the etiology. Although CT and MRI exhibit little predictive value for diagnosis of PD in an individual case, PET studies using fluorodeoxyglucose may show hypometabolism in the basal ganglia and frontal cerebral cortex. Regional cerebral blood flow studies have shown reductions in frontal cortical blood flow.

PD is most prominently associated with motor abnormalities involving a resting tremor, loss of postural reflexes, stooped posture, bradykinesia (slowed movement), cogwheel rigidity, and slow shuffling gait. Small handwriting, dysarthria, reduced vocal volume, and a tendency to speak in a monotone fashion may also be seen. Between 25 and 40% of PD patients may develop dementia. When present, PD dementia typically occurs during the later stages of the disorder.

Bradyphrenia (cognitive slowing) is typically one of the earliest features of PD dementia. Language deficits tend to involve motor components of speech (e.g., dysarthria, diminished phrase length, dysprosody, micrographia) more severely than linguistic aspects of speech, such as naming and comprehension. Memory and learning deficits are also seen in the early stages of PD dementia. For example, procedural learning (ability to acquire a new perceptual-motor skill tends to be impaired. Effortful memory and spontaneous free recall are also generally impaired in PD dementia, although recognition memory is often preserved. Deficits in visuospatial abilities involving both visuoperceptual and visuoconstructional aspects have been well documented. Executive functioning deficits involving establishing, maintaining, and shifting cognitive set also are common in PD dementia and are similar to deficits in patients with discrete lesions of the frontal lobes. Depression may occur in 25 to 40% of PD patients.

2. Treatment

PD is most commonly treated with medication designed to ameliorate the central dopamine deficiency. Levodopa, a dopamine precursor that readily crosses the blood-brain barrier and is metabolized to dopamine, is the most common pharmacologic agent used to treat PD. Following levodopa administration, symptomatic improvement in movement abnormalities is seen in approximately 60% of patients, and cognitive impairment has also been shown to improve following pharmacotherapy. However, this form of treatment becomes ineffective after 1 to 4 years, presumably due to progressive neuronal loss and inability of remaining neurons to convert levodopa to dopamine. Depression in PD is not affected by levodopa therapy and sometimes may be a side effect of the medication. Tricyclic antidepressants and electroconvulsive therapy have been used successfully to improve mood and motor disability.

Surgical treatment of PD has a long history and a promising future. Before dopaminergic medications were available, the accepted method of treatment involved surgical placement of a lesion in the ventrolateral thalamus. Although this procedure improved tremor and reduced rigidity, this procedure had little effect on the akinesia associated with PD. Surgical intervention using placement of a lesion in the globus pallidus (pallidotomy) had also been attempted, although wide variability in the accuracy of lesion placement produced inconsistent and often devastating results. Using new microelectrode-guided lesion placement techniques, pallidotomy has reemerged as a potential treatment for PD with much fewer complications. Pallidotomy produces relatively rapid and substantial improvement in the motor symptoms, although there tends to be little effect on neuropsychological and psychiatric status postsurgically.

C. Diffuse Lewy Body Disease

1. Clinical Features

This disorder has received considerable attention within recent years as an important cause of dementia with parkinsonian features, although it has also been considered by some to be a variant of Alzheirner’s disease. The occurrence of diffuse Lewy body disease appears to be linked to a genetic mutation in the betaamyloid precursor protein gene on chromosome 21. Approximately 20% of patients with a clinical diagnosis of Alzheimer’s disease are thought to have concomitant diffuse Lewy body disease. This disease thus appears to reflect an overlap between Parkinson’s disease and Alzheimer’s disease.

A progressive dementia, consisting of impaired attention, memory, language (e.g., verbal fluency, praxis, and naming), and visuospatial/visuoperceptual skills, typically appears first, followed by parkinsonian features, including akinesia, tremor, and rigidity. A cognitive hallmark of early diffuse Lewy body disease is a fluctuating cognitive state in which patients can be cognitively impaired on one day and cognitively intact on the next day. Sensitivity to the effects of neuroleptic medications, sometimes resulting in obtundation or stupor, has also been reported in this dementia. Neuropsychiatric disturbances, including paranoid delusions and auditory and visual hallucinations, are present in approximately half of all patients with diffuse Lewy body disease and tend to occur early in the disease course.

Histologically, Lewy bodies are inclusion bodies (similar to Pick bodies) that disrupt neuronal cytoskeletal organization. In diffuse Lewy body disease, Lewy bodies are diffusely present in surviving cortical neurons, although they tend to favor layers V and VI of cingulate and entorhinal cortex, and they are also found in the brain stem and substantia nigra. Spongioform changes restricted to the temporal lobe help to differentiate diffuse Lewy body disease from prion diseases (described later in this research paper) in which the spongioform changes are diffusely located. However, there is no current evidence that diffuse Lewy body disease is transmissible. Efforts are currently underway to understand the nature of different Lewy body disease and its relationship with Alzheimer’s disease and with Parkinson’s disease.

2. Treatment

Symptomatic pharmacological treatment of the Parkinsonian features of this disorder is the only therapeutic option at this time. The dementia associated with diffuse Lewy body disease currently is not amenable to treatment.

D. Huntington’s Disease

1. Clinical Features

Huntington’s disease is a genetically inherited autosomal dominant condition that affects approximately 5 out of 100,000 patients. Persons with an affected parent have a 50% chance of developing the disease. The genetic locus for the disease appears on the short arm of chromosome 4. Males and females are equally likely to inherit the disorder. The disorder typically becomes manifest in persons between the ages of 25 and 45, although juvenile forms of the disease also occur. The disorder is characterized by choreiform (dancelike) movements involving the limbs and trunk, bradykinesia, and psychiatric disturbances (particularly affective disorders). Neuropathologically, a characteristic loss of the medium-sized spiny neurons in the caudate and putamen, which project to the globus pallidus and pars reticulata of the substantia nigra, occurs in Huntington’s disease. Neuronal loss also occurs in the globus pallidus, ventrolateral thalamus, and subthalamic nucleus. This neuronal loss is associated with marked neurotransmitter reductions in the GABA-synthetic enzyme glutamate decarboxylase, neuropeptides (enkephalin, substance P, cholecystokinin), acetylcholine, and choline acetyltransferase. CT and MRI scans generally show a bilateral “wasting” of the caudate nucleus (although the entire striaturn is typically involved), with concomitant dilatation of the anterior horns of the lateral ventricles. Cortical atrophy is also commonly present. SPECT scans show decreased blood flow in the basal ganglia and frontal cortex, and PET studies also demonstrate diminished glucose utilization in these regions. For a number of years, Huntington’s disease was considered to be a prototypical “subcortical” dementia, with the greatest pathological changes occurring in subcortical structures such as the basal ganglia. However, it is now clear that pathological changes occur in cortical regions as well, thereby blurring the distinction between the terms “cortical” and “subcortical” dementia.

Early signs of Huntington’s disease include alterations in memory, affect, or movement. As the disease progresses, impaired attention and concentration and executive dysfunction become prominent. Memory is also impaired and is characterized by deficient retrieval of new information during the early stages. Cues are generally effective in facilitating patients’ recognition performance, although deficient encoding of new information becomes evident as the diseases progresses. Procedural learning tends to be impaired. Language abilities (e.g., comprehension, naming) are usually unaffected until the later stages of the disorder, although impairment in the motor aspects of speech may be associated with dysarthria and impaired writing. Diminished word list generation is also commonly seen. Approximately 50% of patients with Huntington’s disease may develop affective disturbances, and there is a high risk of depression and suicide in this population. Impulsive aggressive or sexual behavior, irritability, angry outbursts, and anxiety are also common psychiatric manifestations.

A presymptomatic genetic test was recently developed to determine whether an individual carries the abnormal gene and hence will eventually manifest the disease. However, prior to undergoing such testing, genetic counseling is extremely important, as there is a high risk of suicide in persons who test positive.

2. Treatment

Huntington’s disease has a progressive course that cannot be altered, although some control can be gained over the choreiform movements. Neuroleptic medications and tetrabenazine (a dopamine antagonist) may be helpful in this regard. The findings of reduced GABA in the basal ganglia in Huntington’s disease patients have prompted the use of GABA-ergic agents, such as isoniazid, which have also had limited success in treating choreiform movements. Intravenous injection of physostigmine has been demonstrated to reduce the movement abnormalities in Huntington’s disease, although oral administration of cholinergic compounds has not shown significant efficacy. The dementia associated with Huntington’s disease is not improved with medication. However, it is important to note that the affective disturbances, including depression, irritability, angry outbursts, and psychosis, are amenable to pharmacologic treatment. Electroconvulsive therapy has also been effective in treating the depression associated with Huntington’s disease. Psychosocial interventions, including genetic counseling, personal counseling, patient and caregiver support groups, and management of psychiatric disturbances, play a significant role in the treatment of these patients.

E. Progressive Supranuclear Palsy

1. Clinical Features

Progressive supranuclear palsy (PSP) is a relatively rare disorder that shares many of the same motoric abnormalities seen in Parkinson’s disease. However, PSP also affects brainstem nuclei, producing progressive loss of volitional eye movements, swallowing difficulties, and dysarthria associated with pseudobulbar palsy, together with rigidity in the neck and trunk, and hypererect posture with neck extension. Voluntary downward gaze is generally lost first, followed by loss of upward gaze, and finally loss of horizontal eye movements. Approximately 60 to 80% of PSP patients exhibit dementia. PET studies have shown prominent hypometabolism and hypoperfusion in the superior frontal lobes, and hypometabolism has also been observed in the caudate, putamen, thalamus, and pons.

Cognitive changes associated with PSP dementia include bradyphrenia, impaired learning, memory consolidation, and retrieval, personality changes including apathy and depression, impaired motor aspects of speech (e.g., hypophonia, dysarthria, diminished verbal output), and impaired executive functioning on tasks such as word list generation. Aphasia, apraxia, and agnosia are typically not seen in PSP.

2. Treatment

PSP has a relatively rapid, progressive course that is minimally amenable to treatment. Motor abnormalities, such as dyskinesia and rigidity, and extraocular movements are occasionally responsive to treatment with dopamine precursors and dopamine receptor agonists, although the dementia associated with PSP is generally unaffected. As with Parkinson’s disease, pharmacotherapy becomes less effective as the disease progresses.

F. Cortical-Basal Ganglionic Degeneration

1. Clinical Features

This degenerative disorder is typically associated with asymmetric neurological findings together with an overlay of cortical and subcortical neuropsychological deficits. Asymmetric rigidity and akinesia of the arms is typically seen, together with myoclonic jerking, tremor, and dystonic movements. From a neuropsychological perspective, a profound apraxia is associated with the affected limb, which gradually progresses to a loss of all executive functions associated with limb movement. Cognitive slowing, perseveration, and difficulty with cognitive flexibility is also seen. Generalized cerebral atrophy is typically present on CT and MRI scans. Asymmetric metabolic and blood flow abnormalities are often observed in the basal ganglia and associated fronto-parietal cortex on PET and SPECT.

2. Treatment

There are no effective treatments for this progressive disorder.

G. Hallervorden-Spatz Syndrome

1. Clinical Features

Hallervorden-Spatz syndrome is a rare autosomal recessive condition that first becomes manifest in late childhood or early adolescence. It is characterized by motoric spasticity and rigidity, dystonia, or chorea, together with a progressive dementia. Moodiness, depression, and angry outbursts may presage the cognitive decline. Increased deposition of iron in blood vessels and cells of the basal ganglia is associated with this disorder. The globus pallidus and pars reticulata of the substantia nigra are typically discolored, appearing rusty brown, and partially destroyed. Magnetic resonance imaging (MRI) may show hypodensity in the globus pallidus, putamen, or substantia nigra, or a gradual wasting of the basal ganglia similar to that found in Huntington’s disease may also be seen.

2. Treatment

There are no effective treatments for this condition.

H. Wilson’s Disease

1. Clinical Features

Wilson’s disease is another autosomal recessive condition that occurs in approximately 1/30,000 patients. It typically becomes manifest in the late teens or early 20s and affects males and females equally. This disorder is associated with abnormal copper metabolism, and increased deposition of copper is found in the liver, brain, and eyes. Motor symptoms include tremor, rigidity, dystonia, chorea, and dysarthria. Progressive dementia, characterized by impaired memory, poor concentration, impaired abstract reasoning and concept formation, and bradyphrenia, and psychiatric disturbances, such as psychosis, emotional lability, and childishness, occur in Wilson’s disease. Language functions are commonly spared. The cognitive and motor symptoms of Wilson’s disease are likely to be the result of the toxic effects of copper on cerebral tissue. Characteristic features of Wilson’s disease include the brownish-green Kayser-Fleischer ring found in the limbus of the cornea, low serum ceruloplasmin (a coppercarrying protein) concentration, and elevated copper excretion. CT and MRI scans frequently reveal hypodensity in the lenticular nuclei. PET scans may also demonstrate diffuse hypometabolism, together with marked hypometabolism in the lenticular nuclei.

2. Treatment

Early diagnosis is essential, as this disorder is one degenerative condition that can be effectively treated with reduction of dietary copper, administration of the copper chelating agent D-penicillamine, and administration of pyridoxine to prevent anemia, thereby inhibiting further progression and reversing both hepatic and neurological signs.

I. Cerebellar and Olivopontocerebellar Degeneration

1. Clinical Features

A heterogeneous spectrum of disorders involving progressive ataxia, some of which are genetically inherited, are also associated with dementia. Symptoms associated with cerebellar dysfunction, such as ataxic gait, hypotonia, limb unsteadiness, intention tremor, and dysarthria, are common. Extracerebellar signs, such as ophthalmoplegia, deafness, hyperreflexia, and extensor plantar responses, may also occur and tend to be more indicative of olivopontocerebellar atrophy. Cerebellar degeneration may be evident on CT or MRI scans, while PET scans may show hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brain stem. The inferior olivary and pontine nucleioften appear atrophied. Choline acetyltransferase and acetylcholinesterase tend to be diminished in olivopontocerebellar degeneration. The dementia syndrome is characterized by impaired attention and memory, apathy, and psychomotor retardation.

2. Treatment

There are no effective treatments for this disorder.

II. Dementia Due to Cerebrovascular Disease

In contrast to the degenerative dementias in which the specific etiology is generally uncertain, dementia due to ischemic, anoxic, or hemorrhagic events can often be traced to known risk factors, such as cigarette smoking, hyperlipidemia, cardiac arrhythmia, or platelet aggregation. Given knowledge of these risk factors, early diagnosis of vascular dementia may potentially minimize further cognitive deterioration. Vascular dementia can be attributed to the cumulative effect of cerebrovascular events largely confined to the cerebral cortex (multi-infarct dementia), vascular lesions in specific subcortical structures (thalamic vascular dementia and lacunar state), or to accumulated, small vessel vascular lesions confined mainly to the periventricular white matter regions (Binswanger’s disease or subcortical arteriosclerotic encephalopathy).

A. Multi-Infarct Dementia

1. Clinical Features

Multi-infarct dementia is associated with accumulated vascular damage that preferentially affects cortical gray matter areas. Men are typically affected more often than women. A rapid disease onset and stepwise clinical course characterized by plateaus and sharp declines in functioning are both associated with multi-infarct dementia, although more gradual and progressive diminution in mentation may also be seen as well. Nocturnal confusion, previous hypertension, and a history of transient ischemic attacks are also associated with multi-infarct dementia. Neurological examination typically reveals focal or bilateral pyramidal or extrapyramidal signs, including plantar extensor response, limb rigidity or spasticity, hyperreflexia, gait disturbance, or urinary incontinence. There is wide variation in the types and severity of cognitive deficits associated with multi-infarct dementia, depending on the location and number of infarcts. The prototypic neuropsychological profile is a “patchy” presentation, with relative preservation of some abilities and loss of other skills. Frequent deficits are seen in the areas of orientation and attention, recent memory, abstract reasoning and problem solving, and language deficits, such as impaired writing, frequent literal paraphasias (e.g., saying “tome” for comb), apraxia, and difficulty with complex comprehension. Coronary insufficiency with systemic hypotension tend to produce more diffuse deficits. Psychiatric features, most notably depression and emotional lability, are also common in cerebrovascular dementia.

2. Treatment

Early diagnosis is important in order to prevent or retard further progression of the dementia. Recognition of the presence of multiple risk factors for vascular disease can also facilitate diagnosis and identify targets for treatment. Controllable risk factors include cigarette smoking, hyperlipidemia, diabetes, and hypertension. Agents that inhibit platelet aggregation, such as aspirin or warfarin, may also reduce the risk of thrombotic infarction. Speech therapy may be helpful for patients who have developed aphasia, and occupational and physical therapy are beneficial to maximize the potential for continued independent living.

B. Thalamic Vascular Dementia

1. Clinical Features

Vascular lesions to the thalamus may produce a range of neurological and neuropsychological deficits depending on the specific thalamic nuclei involved. From a neurological perspective, thalamic hemorrhage may be associated with greater sensory than motor loss, memory impairment, impaired vertical gaze, and aphasic symptoms, if the lesion occurred in the dominant hemisphere. Variable arousal, including hypersomnia and loss of consciousness, have been reported with lesions (usually bilateral) to the paramedian thalamus. Disturbed attention on less-structured tasks may also be seen in thalamic lesions. Deficits that are typically characteristic of frontal lobe lesions are frequently associated with thalamic lesions as well, possibly in the region of the dorsomedial nucleus. These deficits include perseveration, increased susceptibility to interference, difficulty in sequencing information, and personality changes such as apathy, abulia, lack of concern, and euphoria. Language following ventrolateral and ventroanterior thalamic lesions is generally characterized by intact repetition, comprehension, reading, and writing, contrasted with impaired speech initiation, diminished content of speech, reduced word list generation, dysprosody, dysarthria, perseveration, and hypophonia. Lesions in the pulvinat and posterolateral thalamus have been associated with anomia, normal or increased speech output, and impaired comprehension. Visuospatial deficits may follow bilateral or unilateral right thalamic damage. Memory impairment has been attributed to lesions affecting the dorsomedial nucleus, mammillary bodies, and/or mammilothalamic tract.

2. Treatment

Thalamic vascular lesions are not reversible. Treatment involves reducing or eliminating modifiable vascular risk factors plus supportive measures including speech, occupational, or physical therapy, and managing neuropsychiatric conditions should they occur.

C. Lacunar State

1. Clinical Features

Small infarctions ranging from 0.5 to 1.5 mm in diameter that are located primarily in the basal ganglia, thalamus, internal capsule, and brain stem are referred to as lacunes. Lacunes are thought to result primarily from hypertension-related fibrinoid necrosis of arterioles resulting in occlusion, although some lacunes may be associated with hemorrhage. The lenticulostriate branches of the middle cerebral artery or the thalamogeniculate, choroidal, and thalamoperforator branches of the posterior communicating and posterior cerebral arteries are commonly involved. The term lacunar state describes the condition in which multiple lacunes are present. Hypertension, diabetes, and atherosclerotic emboli have been noted to contribute to the formation of lacunes. Lacunar state is generally associated with combined motoric and cognitive impairment. The motor symptoms include rigidity and bradykinesia (which are seen in Parkinson’s disease), spasticity, hyperreflexia, limb weakness, pseudobulbar palsy, and extensor plantar responses. Given the many motor abnormalities that are similar to Parkinson’s disease, the term “arteriosclerotic parkinsonism” was used until recently to describe deficits associated with lacunar state. Cognitive deficits typically involve impaired memory, apathy, psychomotor retardation, impaired mental control and orientation, and frontal-lobe type deficits. Mood changes and fluctuations in mental state are also observed. Lacunes may be evident on CT or MRI, although many lacunes are too small to be visualized using either imaging technique. PET scans may reveal areas of hypometabolism at the site of the lacune as well as in cortical locations receiving projections from the affected region.

2. Treatment

Once present, the cognitive and motor impairment associated with lacunar state cannot be reversed, although preventative measures such as correction of modifiable risk factors will help to reduce or retard progression.

D. Binswanger’s Disease (Subcortical Arteriosclerotic Encephalopathy)

1. Clinical Features

When ischemic damage is confined to the periventricular white matter regions, the term Binswanger’s disease or subcortical arteriosclerotic encephalopathy is applied. Occlusion of small blood vessels is commonly associated with this condition. Binswanger’s disease may resemble a degenerative dementia such as Alzheimer’s disease by virtue of its insidious onset and gradual progression. It may lack the abrupt onset and stepwise decline associated with other vascular dementias. Hypertension and smoking are the most common risk factors for Binswanger’s disease. Clinical deficits vary depending on the extent of the lesions, although incontinence, pseudobulbar palsy, asymmetric weakness, gait disturbance, parkinsonism, and dysarthria have been described. Mood disturbances include irritability, apathy, mania with hyperactivity, depression with suicidal ideation, and psychosis with paranoid delusions. From a cognitive perspective, memory deficits are usually only mild in Binswanger’s disease, although poor judgment, perseveration, abulia, and increased response latency are seen more frequently. Loss of white matter is most severe in the frontal lobes. The short arcuate “U” fibers are generally spared. Lacunar state may coexist with Binswanger’s disease. Enlarged ventricles and evidence of periventricular lucency associated with white matter ischemia are typically noted on CT and MRI.

Varying degrees of periventricular lesions have been reported in “normal” asymptomatic elderly individuals without neurological complaints, suggesting that the amount of white matter ischemia has little correlation with the extent of cognitive impairment. This finding has stimulated controversy regarding the radiologic diagnosis of Binswanger’s disease. However, there are also data to suggest that persons with radiologic evidence of white matter lesions have significantly lower intellectual performance and more motor abnormalities than persons without diffuse white matter lesions, suggesting that periventricular lucencies may be a harbinger of deficits associated with Binswanger’s disease even in asymptomatic individuals.

2. Treatment

As with the other vascular dementias, prevention of further deterioration through careful monitoring of vascular risk factors (particularly smoking and hypertension) and antiplatelet treatment with agents such as aspirin, warfarin, and ticlopidine are the only treatment strategies for this condition at this juncture.

E. Vasculitis

Dementia may also be associated with inflammation of the cranial arteries due to systemic illnesses, such as giant cell (temporal) arteritis, sarcoidosis, systemic lupus erythematosus, granulomatous arteritis, and polyarteritis nodosa, or to chemical arteritis associated with use of amphetamines, “crack” cocaine, or oral contraceptives. Amyloid angiopathy is often associated with hemorrhages but may also be associated with dementia. Dementia due to vasculitis generally presents acutely in a manner consistent with a confusional state, although gradually progressive dementia is not uncommon. Cerebral arteriography and brain biopsy are often necessary for diagnosis. Treatment with anti-inflammatory agents is frequently prescribed.

III. Dementia Due to Infectious Agents

The central nervous system can be vulnerable to infection from a variety of agents. Infectious agents producing dementia include viruses, bacteria, fungi, parasites, and atypical proteinaceous infectious agents called prions. Given an intact immune system, infection of the central nervous system is relatively rare, although infection by herpes simplex or cryptococcus can occur in immunocompetent hosts. However, in cases of immune system compromise, the brain may become vulnerable to a variety of infectious agents, some of which may be treatable if discovered early in the course of the disorder. The term encephalitis refers to inflammation and infection of brain tissue associated with any of the infectious agents described above. The term encephalopathy is broader, encompassing dysfunction of the brain due to any cause.

A. Viral Infections

A virus is a small particle of protein-encapsulated DNA or RNA that infects a host cell and replicates itself therein. Two groups of viruses that may produce dementia have been described. The first group is termed the neurotropic viruses, such as those causing rabies and poliomyelitis, which have a special affinity for central nervous system cells. The second group is known as the pantropic viruses, such as mumps, measles, and herpes simplex, which invade cells throughout the body, in addition to central nervous system cells.

1. HIV Encephalopathy

a. Clinical Features

The dementia associated with infection by the Human Immunodeficiency Virus (HIV) which produces Acquired Immunodeficiency Syndrome (AIDS) has been well-characterized, and central nervous system involvement is present in virtually all AIDS patients at autopsy. Central nervous system compromise is produced in two ways. First, by weakening the immune system, the brain becomes susceptible to rare infectious agents, such as parasites and fungi. On a second level, the virus invades and destroys neurons, glia, subcortical nuclear structures, and white matter of the brain. Numbness, tingling, muscular weakness, and coordination difficulty may frequently be indications of direct central nervous system involvement by HIV. Other early neurological manifestations may include ataxia, action tremor, dysarthria, and exaggerated lower extremity reflexes. Headache, seizures, incontinence, and rigidity may appear with later disease progression. Early cognitive features may include forgetfulness, fluctuations in attention and concentration, and difficulty maintaining a coherent stream of thought. Apathy and depression may also become prominent during the early stages of infection. Frank memory deficits emerge later, in addition to visuospatial impairment, diminished fine motor coordination, decreased cognitive flexibility, and intact simple reaction time contrasted with impaired choice reaction time. Naming and vocabulary are typically preserved throughout the disease. Confusion and disorientation, psychomotor slowing, mutism, and apathy are frequently seen in the preterminal stages. Some patients may exhibit psychotic features and/or prominent affective symptoms. Cortical atrophy with ventricular enlargement and sulcal widening is generally evident on CT or MRI scans, although MRI scans will typically also reveal deep white matter lesions. In the early stages of HIV infection, reduced cerebral glucose metabolism and cerebral blood flow is generally evident in subcortical structures, including the basal ganglia and thalamus on PET or SPECT. More prominent and focal cortical hypometabolism and hypoperfusion are noted in the later stages and is quite distinct from the pattern observed in primary degenerative dementias, such as Alzheimer’s disease.

b. Treatment

Medical management of opportunistic infections with antimicrobials, control of affective disorders with psychotherapy and medication, and careful monitoring of potential toxic and/or metabolic disruptions is important for limiting progression due to these secondary causes of dementia. Although it has significant side effects, the drug azidothymidine (AZT) has been beneficial in limiting viral replication within the individual and improving cognitive function. Individuals with mild to moderate dementia associated with HIV infection have shown improvement in cognition and in cerebral glucose metabolism following AZT treatment. The benefits from AZT are time-limited, however, typically lasting several months before the virus continues to progress. Reduction of the risk factors associated with contraction of HIV through community education, particularly related to intravenous drug abuse and unprotected and promiscuous sexual relations, should also be helpful in reducing the spread of this disease.

2. Subacute Sclerosing Panencephalitis (SSPE)

a. Clinical Features

The measles virus may sometimes cause an acute encephalitis, although it may also produce a slowly developing degenerative process known as subacute sclerosing panencephalitis (SSPE). Progressive Rubella Panencephalitis is another viral encephalitis that is clinically similar to SSPE. SSPE typically presents during childhood or adolescence several years following measles infection and produces a rapid deterioration leading to death in from 3 to 10 months. Boys are affected more frequently than girls. Behavioral changes, including oppositional behavior and angry outbursts, together with slow cognitive decline and a deterioration in school performance typically are the earliest features of SSPE. Onset of seizures and movement abnormalities, such as myoclonic jerking (short, rapid involuntary muscular contractions), gait disturbance, and rigidity, are also seen in SSPE. End stages of the disease are characterized by hypothalamic dysfunction and autonomic failure and decerebrate posturing. Cognitive features include visuospatial deficits, distractibility, inability to self-dress, apraxia, alexia, aphasia, and agnosia. General intellectual functioning declines steadily throughout the course of SSPE. The electroencephalogram (EEG) demonstrates a characteristic burst-suppression pattern exemplified by periodic high amplitude waveform complexes, making it particularly helpful in diagnosis. MRI scans may reveal hyperintensities on T2-weighted images in the basal ganglia. PET may show hypermetabolism in the basal ganglia contrasted with cortical hypometabolism in the early stages of the disorder.

b. Treatment

SSPE typically progresses to death within several months, although periods of remissions and exacerbations are common. Amantadine, isoprinosine, and intraventricular administration of interferon have been reported to be effective in prolonging life and in bringing about periods of remission. Fortunately, the number of SSPE cases has been significantly reduced by the introduction of the measles vaccine. Thus, this devastating childhood dementia is potentially preventable.

3. Herpes Simplex Encephalitis

a. Clinical Features

The Herpes Simplex Virus (HSV I) can produce an acute, severe encephalitis that results in destruction of the medial temporal and orbitofrontal cortical regions, with relative sparing of white matter. Following initial infection, HSV resides in cell bodies of the trigeminal nerves innervating cutaneous regions of the face. Reactivation of the virus can lead to viral migration along the trigeminal nerve with subsequent encephalitis. Headache and fever may be associated with early stages of the HSV encephalitis, followed by acute mental status changes, seizures, and coma. The disease is often fatal. However, in survivors, there is usually prominent memory impairment, reflecting damage to the medial temporal regions. A human condition resembling the so-called Kluver-Bucy syndrome seen in monkeys, represented by diminished responsiveness to social and emotional stimuli, increased oral exploratory behavior, reduced aggression and fearfulness, and difficulty recognizing the meaning or significance of common objects (“psychic blindness”), is sometimes associated with bilateral temporal lobe destruction. Aphasia may also be a cognitive sequel of HSV encephalitis. CT or MRI scans may show areas of lucency in the temporal lobe, and EEG may reveal diffuse or focal slowing or periodic sharp and slow-wave complexes.

b. Treatment

Early treatment with acyclovir and adenine arabinoside may substantially diminish the morbidity and mortality associated with HSV encephalitis.

4. Viral Infections Associated with Underlying Systemic Illness

a. Clinical Features

Progressive Muhifocal Leukoencephalopathy (PML) is associated with infection by the papova viruses in immunocompromised persons (e.g., AIDS) or individuals with chronic lymphoproliferative, myeloproliferative, or granulomatous diseases. This disease affects many different areas of cerebral and cerebellar white matter and may be associated with motor weakness, gait disturbance, dysarthria, blindness and other visual disorders, and seizures. The dementia associated with PML includes behavioral changes, memory deficits, poor concentration, and language deficits. MRI may show multifocal hyperintensities in the white matter associated with subcortical demyelination. Microscopic changes include abnormal oligodendrocytes that are large and contain intranuclear inclusion bodies. Abnormally shaped, multinuclear astrocytes are also found in the areas of the lesions. PET studies reveal cortical hypometabolism in regions associated with white matter changes. Simian virus 40 (SV 40) is one of the most common papova viruses associated with PML.

b. Treatment

Treatment of PML remains uncertain. There are some reports of improvement following cytarabine therapy, although clinical trials with other antiviral agents have produced mixed results.

5. Limbic Encephalitis

a. Clinical Features

Limbic Encephalitis involves a progressive cognitive decline over 1 to 2 years in individuals with an underlying malignancy. Oat cell carcinoma of the lung is one neoplasm that is frequently associated with limbic encephalitis, although the syndrome has been described in a variety of other cancers. Characteristic features include marked disturbance of affect, commonly involving anxiety and depression, in addition to prominent memory impairment. Hallucinations and variable alertness may also be seen. Pathological changes include neuronal loss and inflammatory changes concentrated in hippocampus and medial temporal lobe, although lateral temporal cortex, and other widespread brain regions may also be involved. Limbic encephalitis may result from an autoimmune response producing an attack on temporal lobe neurons, given the relatively acute presentation, inflammatory changes, and occasional presence of intranuclear inclusion bodies.

b. Treatment

There are no effective treatments for this paraneoplastic dementia.

B. Bacterial Infections

1. Bacterial Meningitis

a. Clinical Features

Most forms of bacterial meningitis (infectious inflammation of the meninges surrounding the brain) typically have a rapid onset and are associated with fever, headache, and stiff neck. Although not common, certain bacteria produce a chronic meningitis that is associated with a gradual or subacute cognitive decline. For example, tuberculosis can be associated with central nervous system involvement manifested by pyramidal, extrapyramidal, and cerebellar signs, involuntary movements, poor insight, impaired memory, and personality changes. Lyme disease is caused by a tick-transmitted spirochete (Borrelia burgdorferi). A red rash around the bite area is typically followed by mild flu-like symptoms. Arthritis, cardiac symptoms, and neurological symptoms, including meningoencephalitis may appear months later.

b. Treatment

Although it was previously a fatal condition, tuberculosis meningitis is now generally treatable and curable. Common treatments include combination therapy with isoniazid, streptomycin, and para-aminosalicylic acid or isoniazid and rifampin. However, some treatment-resistant strains of tuberculosis have been reported recently, posing a significant challenge for future treatment of this disease. Oral penicillin or tetracycline is typically used to treat Lyme disease in the early stages, although intravenous administration of antibiotics may be required in the later stages.

2. Syphilis

a. Clinical Features

The spirochete, Treponema pallidum, is responsible for syphilitic infection. If not treated, symptomatic neurosyphilis may develop in approximately 10% of cases. Symptomatic neurosyphilis tends to be more common in men. Meningovascular syphilis, a condition associated with multiple strokes, may appear approximately 2 to 10 years after the initial syphilitic infection. The condition known as general paresis may appear 7 to 15 years after the initial infection and is characterized by prominent dementia, either with or without psychiatric manifestations, such as mania, depression, or psychosis. In addition to impaired memory, some individuals with general paresis may become severely disoriented and may confabulate. Other cognitive deficits include anomia, apraxia, verbal paraphasias, and dysarthria. Coarse tremors of the jaw and tongue are common. Diagnosis of syphilitic infection is facilitated by serum detection of specific treponemal antibodies (fluorescent treponemal antibody absorption; FTA-abs), together with pleocytosis (white blood cells) present in the cerebrospinal fluid (CSF). On autopsy, significant frontotemporal cortical atrophy is evident.

b. Treatment

Standard treatment involves intravenous administration of penicillin G, although dosage recommendations and treatment duration vary. Close monitoring of CSF every three months for the first year and every six months during the second year following treatment is recommended.

3. Brain Abscesses

a. Clinical Features

A variety of bacteria may produce small pockets of pus known as abscesses in or around brain tissue. They are commonly the result of secondary infections and generally originate from middle ear infections, sinusitis, or pulmonary conditions. With increasing size, the abscess behaves as an expanding mass and may produce elevated intracranial pressure. The abscess may also produce necrosis or cell death, destroying neural tissue in the vicinity of the abscess.

b. Treatment

Abscesses may be treated with antibiotics, and they often require surgical drainage.

C. Mycotic (Fungal) Infections

1. Clinical Features

Fungal CNS infections are relatively rare. They occur most commonly in immunocompromised individuals (e.g., HIV infection, immunosuppressant therapy, systemic malignancies). Examples of such infections include cryptococcal meningitis, histoplasmosis, aspergillus, blastomycosis, and candida. These fungi may produce a chronic meningitis that has an insidiously progressive course associated with compromised intellectual functioning, variable arousal, impaired attention and orientation, and poor memory. Cranial nerve palsies are often seen.

2. Treatment

Once established, fungal infections are difficult to treat and often result in a high mortality.

D. Parasitic Infections

I. Clinical Features

The parasite Entamoeba histolytica (responsible for producing amoebiasis or amoebic dysentery) and several other protozoan and helminthic parasites may produce encephalitis, chronic meningitis, and brain abscesses. The parasite Plasmodium falciparum, responsible for producing cerebral malaria, is associated with infection of capillaries within the brain producing local hemorrhages, demyelination, and neuronal degeneration.

2. Treatment

Antimalarial agents and steroid therapy are effective in completely reversing the effects of cerebral malaria if they are administered early in the course of the infection.

E. Prion Disease

Prions are subviral, infectious, unencapsulated protein particles that resist most known forms of inactivation. They are resistant to boiling, ultraviolet light, and formalin, but they are susceptible to proteolytic treatments, such as autoclaving or immersion in a strong alkali solution. Human prion diseases include Creutzfeldt-Jacob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) syndrome, kuru and fatal familial insomnia (FFI). Animal prion diseases include bovine spongioform encephalopathy (BSE; “mad cow disease”), and scrapie (seen in sheep). These neurodegenerative diseases were previously thought to be due to “slow viruses.” Prion disease can be infectious (kuru, infectious CJD), sporadic (CJD with or without apparent somatic DNA mutation), or familial due to prion protein gene mutation (familial CJD, GSS syndrome, and FFI).

The common denominator among all of the prion diseases is an aberrant metabolism of the prion protein (PrP) usually leading to an accumulation of an abnormal isoform of intracellular PrP. All infectious prions are composed of this abnormal PrP isoform. The prion diseases are referred to as the “spongioform encephalopathies” by virtue of the characteristic “spongy” appearance of the postmortem cerebral tissue on microscopic examination. This appearance results from the formation of ubiquitous vacuoles induced by rupture of neuronal and glial membranes.

The transmissibility of prion disease via intracerebral inoculation with fresh-frozen brain tissue from humans with spongioform encephalopathy to primates is well established. Human-to-human transmission of CJD has also been documented through corneal transplants, human pituitary growth hormone therapy, human pituitary gonadotropin therapy, dura mater grafts, contaminated electroencephalographic electrode implants, and other neurosurgical procedures. Kuru was once common and was the leading cause of death among the Fore tribe in New Guinea. This disease also is associated with human-to-human transmission, as it is thought to be related to the cannibalistic consumption of dead family members. In addition to dementia, kuru is associated with gait ataxia, followed by limb ataxia, a shiver-like tremor, and dysarthria.

The recently reported epidemic of Bovine Spongioform Encephalopathy (BSE or prion disease affecting cattle) in the United Kingdom has caused increased attention to be focused on the intraspecies transmission of prion disease. There has been some speculation that byproducts of sheep infected with scrapie may have been incorporated into cattle feed and may be associated with the apparent increase of BSE in British cattle. Transmission of prion disease from cattle to humans is not well documented, although two cases of CJD in individuals who were occupationally exposed to BSE have been reported in England and Wales. Thus far, the concurrence of CJD and BSE is less than that which could have occurred by chance, and the incidence of CJD in Europe has remained static over recent years.

CJD is perhaps the most prototypical of the prion diseases with an incidence of approximately 1 case per million. In a series of 230 neuropathologically verified cases of CJD, up to 8% of the cases appear to be familial. CJD typically presents with subacute, rapidly progressive dementia and myoclonus, and in most cases, eventually demonstrates a characteristic EEG pattern of periodic sharp wave complexes that are predominantly triphasic. Cognitive deficits include concentration difficulty, fatigue, forgetfulness and depression during the early stages of illness, followed by marked aphasia and other cortical signs of dementia such as amnesia, agnosia, apraxia, and rapid intellectual decline. CT and MRI may be normal, or generalized atrophy or focal hyperintensities may be observed. PET and SPECT studies show multifocal areas of hypometabolism and hypoperfusion.

GSS is a familial disorder that typically occurs between the ages of 40 and 70, with a duration ranging from 4 to 10 years. It presents as a cerebellar syndrome and dementia. Early motor features are consistent with cerebellar dysfunction, including impaired smooth pursuit eye movements, coordination difficulty, ataxia, and ophthalmoplegia. Parkinsonian symptoms are also sometimes reported. Bradykinesia, rigidity, and extensor plantar responses are also observed during the later stages. Cognitive difficulties are more prominent toward the latter stages of the disease and typically include impaired memory, dysnomia, poor judgment, psychomotor slowing, and affective disorders.

FFI is also a familial disorder that is associated with selective degeneration of specific regions of the thalamus. Individuals with FFI exhibit an untreatable insomnia and impaired regulation of the autonomic nervous system. FFI is sometimes referred to as “thalamic CJD.”

Familial CJD, GSS syndrome, and FFI have been associated with specific mutations on the short arm of chromosome 20 in the prion protein (PrP) gene. The mutations are tightly linked to the expression of the disease. The PrP is a normal cellular protein that is synthesized by neurons and glial cells throughout life. PrP has been referred to as a “housekeeping” gene that is necessary for basic cellular functioning. PrP is located in the cellular membrane and is present in evolutionarily diverse organisms. It is thought that prion diseases are associated with a conformational change in PrP, resulting in an abnormal, protease-resistant isoform that is referred to as PrPL PrP P may result from either a genetic mutation causing synthesis of this new isoform or from post-translational modification in the gene product. The abnormal PrP P is thought to lead to cellular death by producing vacuoles and amyloid deposition.

IV. Dementia Due to Toxic or Metabolic Conditions

Metabolic derangements and toxic exposure are frequently overlooked causes of dementia, possibly due to the fact that these conditions often present acutely as confusional states, characterized by a fluctuating level of arousal, distractibility, increased motor and verbal response latencies, disorientation, and hallucinations (predominantly visual). Tremor, myoclonus, and asterixis are the most common motor findings associated with these acute conditions. However, metabolic changes or toxic exposure may also occur very slowly, producing a symptom resembling dementia. There are many causes of toxic/metabolic disorders, and a thorough description of each cause is beyond the scope of this research paper. However, some of the more common systemic illnesses associated with dementia syndromes include endocrine (e.g., thyroid disease, parathyroid disease, disorders of the adrenal medulla and pituitary gland), cardiovascular (e.g., congestive heart failure, hyperviscosity states including polycythemia and hyperlipidemia, anemia), pulmonary (e.g., pulmonary insufficiency, sleep apnea, postanoxic states), renal (e.g., uremia, dialysis encephalopathy), and hepatic (e.g., cirrhosis) dysfunction. Metabolic deficiencies and excesses (e.g., alterations in serum sodium, calcium, magnesium), and vitamin deficiency states (e.g., thiamine (B1), niacin (B2), cyanocobalamin (B12), folate) are also important considerations in the dementia evaluation. Finally, exposure to a variety of toxic agents may produce encephalopathies. These substances include medications (e.g., psychotropic medications, anticholinergic medications, antihypertensive agents), drugs of abuse (alcohol, barbiturates, solvent vapor, amphetamines), heavy metals, and industrial cleaners and solvents. If discovered early and treated aggressively, the progression of a large number of these conditions may be arrested or slowed, and the cognitive disorders may be reversed in some cases. These conditions represent perhaps the most treatable etiologies associated with cognitive impairment, although they are much less common than the degenerative or vascular dementias.

A. Systemic Illnesses

1. Thyroid Dysfunction

a. Clinical Features

Thyroid dysfunction accounts for a sizable number of metabolic disturbances, and most of these disorders are highly treatable. Hyperthyroidism tends to be most frequently seen in the late teens or early 20’s, although it may also mimic a progressive dementia in the elderly. Idiopathic thyroid overactivity accounts for most cases of hyperthyroidism, although other causes may include thyroid cancer, goiter, or pituitary adenoma that results in overproduction of thyroid stimulating hormone. In younger persons, hyperthyroidism may first present with personality changes including depression, restlessness, anxiety, emotional lability, and irritability, together with concentration and memory deficits, tremor, and tachycardia. Weight loss, skin changes, shortness of breath, and heat intolerance may also occur. These symptoms may progress to cognitive deterioration, apathy, somnolence, and coma in advanced stages. In contrast, the initial personality changes (e.g., anxiety and restlessness), tremor, and tachycardia may be completely absent in elderly persons with hyperthyroidism, and they may instead present with apathy, lethargy, and psychomotor slowing. Hypothyroidism also has prominent neurobehavioral effects including variable attention and orientation, memory deficits, psychomotor slowing, paranoia, and hallucinations. Cold intolerance and weight gain are common. Psychosis may occur in as many as 5 to 15 % of individuals with hypothyroidism, while dementia may occur in 5 % of hypothyroid individuals.

b. Treatment

Restoration of normal levels of thyroid hormones, most frequently through oral administration of synthetic thyroid supplementation (hypothyroidism) or through surgical or radioactive ablation of the thyroid gland (hyperthyroidism), commonly leads to improved cognitive and physical functioning.

2. Parathyroid Dysfunction

a. Clinical Features

Hyperparathyroidism is frequently associated with elevated serum levels of calcium. Apathy, depression, weakness, and a tendency to tire easily are seen in the early stages. As progression ensues, disorientation, poor memory, fluctuations in attention, paranoia and hallucinations may occur. Hypoparathyroidism and associated low serum levels of calcium commonly result in basal ganglia calcification that may produce parkinsonian motor features (e.g., bradykinesia and limb rigidity) or choreic movement abnormalities. Dementia associated with hypoparathyroidism includes variable orientation and concentration, apathy, and hallucinations.

b. Treatment

Restoration of normal serum calcium levels in these two metabolic disorders can reverse the cognitive and motor abnormalities in some patients, particularly if discovered early.

3. Cushing’s Disease and Addison’s Disease

a. Clinical Features

Overproduction (Cushing’s disease) or underproduction (Addison’s disease) of glucocorticoids from the adrenal gland may also produce symptoms of dementia. Cushing’s disease most commonly results from pituitary tumors (adenomas), although adrenal tumors may also be associated with this disorder. Depression, psychomotor slowing, disturbed sleep patterns, irritability, and diminished attention, concentration, and memory are seen in this disease and are correlated with the degree of serum cortisol elevation. Addison’s disease may produce apathy, impaired memory, depression, paranoia, and irritability, together with weight loss, easy fatigue, and electrolyte imbalances.

b. Treatment

Restoration of normal serum cortisol levels improves cognitive functioning in most cases.

4. Cardiovascular Disease

a. Clinical Features

Cardiac insufficiency resulting from congestive heart failure, chronic arrhythmias, or occlusion of the major cerebral arteries from atherosclerosis is associated with diminished cerebral perfusion. As a result, decreased oxygen can be supplied to the brain, and an accumulation of cellular metabolic by-products (e.g., carbon dioxide) and a corresponding decrease in pH in surrounding neural tissue take place. Somnolence, irritability, disorientation and confusion, and memory deficits are common. Repeated, prolonged vascular events may result in a stepwise deterioration. Hyperviscosity and hypercoagulable conditions such as hyperlipidemia and polycythemia (a proliferation of red blood cells) may produce sluggish blood flow and occlusive microvascular infarctions. Anemia may also produce cerebral anoxia due to the low concentration of oxygen-carrying hemoglobin in the blood. Myoclonus, restlessness, generalized cognitive deficits, and inattention are associated with chronic anemia.

b. Treatment

Improvement in cardiac output and correction of hyperviscosity and hypercoagulable states often lead to improved cognitive functioning. Treatment of anemia, often through dietary iron supplementation, commonly leads to reversal of the associated neurological and cognitive symptoms.

5. Pulmonary Disease and Anoxic States

a. Clinical Features

Chronic pulmonary encephalopathy may result from a variety of diseases that produce pulmonary insufficiency such as emphysema and chronic obstructive pulmonary disease. Tremor and asterixis, headache, and papilledema may reflect physical manifestations of pulmonary encephalopathy. Disorientation, drowsiness, forgetfulness, and variable attention are common mental status changes associated with this condition. As in cardiovascular disease, decreased cerebral oxygen and increased carbon dioxide buildup in neuronal tissue is thought to be associated with the clinical manifestations of the disorder. A similar cognitive presentation has been described in hypoxia associated with living at high altitudes for extended periods. Sleep apnea has been cited as a common cause of cognitive impairment, particularly in the elderly, by producing chronic hypoxia and sleep deprivation. Finally, postanoxic states caused by cardiopulmonary arrest, carbon monoxide poisoning, hanging, and strangulation may produce a gradient of cerebral damage ranging from complete brain death, persistent vegetative state characterized by return of autonomic functioning without apparent higher cognitive activity, or variable deficits of higher cognitive functions, depending on the extent of cerebral damage. Amnesia, aphasia, agnosia, visuospatial and visuoconstructional deficits, together with spasticity, dystonia, and ataxia have been described in variable combinations in postanoxic cases. Milder cases may present with impaired judgment, memory deficits, and disinhibition.

b. Treatment

If discovered early, improvement in pulmonary function may reverse neurological and cognitive deficits. Sleep apnea is highly responsive to treatment using a continuous positive airway pressure (CPAP) device during sleep. In survivors of postanoxic states, rehabilitation, including occupational, speech, and physical therapies, may often be necessary.

6. Renal Disease and Dialysis

a. Clinical Features

Any disease affecting renal function may produce a wide range of metabolic abnormalities. In addition to a spectrum of medical conditions, a variety of drugs may also impair renal functioning. Tremor, myoclonus, and asterixis are commonly associated with this condition. Disorientation, memory disturbance, variable arousal, irritability, hallucinations, and paranoia or affective lability occur as a result of the metabolic changes produced by chronic renal failure. Uremic encephalopathy is associated with increased serum creatinine and elevated blood urea nitrogen (BUN). The EEG can be a good index of uremic encephalopathy and is commonly characterized by background slowing and disorganization, although paroxysmal bilaterally synchronous bursts of slow wave activity may also be seen. Dialysis encephalopathy produces a progressive cognitive decline, myoclonus, depression, markedly abnormal EEG, and a distinctive progressive difficulty with expressive and motor aspects of speech (including difficulty with initiation, dysarthria, and anarthria) contrasted with relatively preserved naming and comprehension. Cognitive deficits may be seen on visuospatial and timed psychomotor tasks. Paroxysmal slow wave bursts and generalized background slowing are seen in the earlier stages of the disease, although bifrontal bursts of slow and sharp waves, and spike activity may be seen in later stages. The cause of dialysis dementia remains uncertain, although a variety of metabolic etiologies and aluminurn intoxication have been proposed as possibilities.

b. Treatment

There have been no successful treatments for dialysis encephalopathy, and the condition typically progresses to death within one to two years. Benzodiazepine administration has been temporarily effective in ameliorating the EEG, cognitive, and speech abnormalities, although these benefits subsequently abate and deterioration resumes. Desfuroximes may sometimes be used as an aluminum chelating agent.

7. Hepatic Disease

a. Clinical Features

Elevated levels of ammonia and short-chain fatty acids are commonly associated with hepatic encephalopathy and may underlie the associated cognitive impairment. There are a variety of diseases associated with hepatic encephalopathy, although alcoholic cirrhosis is the most common of these disorders. Approximately 5% of patients with cirrhosis may develop hepatic encephalopathy. Neuropsychiatric manifestations are frequent in hepatic encephalopathy and may be associated with euphoria, depression, and bizarre behavior. Variable arousal, visuoconstructional deficits, impaired attention and concentration, and memory deficits, together with irregular action tremor, asterixis, gait ataxia, exaggerated reflexes, and motor impersistence are characteristic cognitive and neurological features.

b. Treatment

Treatment typically involves strict dietary reduction of protein intake and absorption because proteins are commonly metabolized to ammonia.

B. Vitamin Deficiencies

Vitamin deficiencies can be seen in persons with poor or variable diets due to severe depression, anorexia nervosa, bulimia, social isolation in elderly persons, starvation, appetite loss associated with systemic illness (e.g., cancer), Crohn’s disease, and chronic alcoholism. Gastrointestinal malabsorption syndromes (e.g., sprue or celiac disease) is another major cause of vitamin deficiency.

1. Thiamine (Vitamin B1)

a. Clinical Features

Thiamine deficiency is most common in chronic alcoholism, but it may be seen in other nutritionally deficient states, including gastrointestinal malabsorption syndromes. The deficiency is due to consumption of a poor diet rather than to the effects of alcohol itself. Chronic thiamine deficiency produces a condition known as Korsakoff’s Psychosis. This syndrome presents with ocular movement abnormalities, ataxia (particularly of gait), and a confusional state. Impaired recent memory generally appears following resolution of the confusional state. Complete amnesia for new information is common, and existing memory exhibits a characteristic temporal gradient, with remote memory being relatively intact compared to recent memory. Confabulation (i.e., providing irrelevant, unnecessary information that was not part of the original to-be-recalled material) may be seen in the early stages of this disorder, but it tends to be less common in later stages. Personality changes are often present, and docility with relative lack of concern with their deficits (anosognosia) are common. Pathological changes are seen in the mammillary bodies and the dorsomedial nucleus of the thalamus, in addition to the periventricular gray matter surrounding the third and fourth ventricles. The mammillary bodies are often shrunken and discolored, and this structural change is sometimes evident on CT or MRI scan.

b. Treatment

Thiamine administration may reverse the eye movement abnormalities and ataxia, although it does little to reverse the memory deficit. However, thiamine supplementation is important to prevent further memory decline. Vasopressin, clonidine, and methylphenidate have been reported to improve memory performance in some patients, although there has been no treatment that has been consistently effective.

2. Vitamin B12

a. Clinical Features

Vitamin B12 (cyanocobalamin) deficiency is associated with pernicious anemia. A lack of intrinsic factor in the gastrointestinal tract resuits in deficient absorption of dietary B12 and is the most common cause of B12 deficiency. Prolonged B12 deficiency can produce peripheral neuropathy, optic atrophy, and a dementia syndrome characterized by slowed mental processing, memory impairment, depression, and confusion. Neuropsychiatric manifestations, including delusions, hallucinations, paranoia, and agitation may also be seen.

b. Treatment

Monthly intramuscular vitamin B12 injections are used to treat this deficiency, and most of the neurological symptoms improve or resolve during the first month of treatment, if it is initiated relatively early.

3. Folate Deficiency

a. Clinical Features

This deficiency state is common in Western countries but only rarely produces dementia. Diminished dietary intake or gastrointestinal malabsorption of folate are the most common causes, although the deficiency may be seen following chronic phenytoin or primidone administration. The condition may mimic B12 deficiency in many ways. Poor concentration, disorientation, memory deficits, difficulty with cognitive flexibility, perseveration, and apathy have been reported to occur in folate deficiency.

b. Treatment

Maintenance oral folate administration generally reverses the cognitive deficits.

4. Niacin (Bz) Deficiency (Pellagra)

a. Clinical Features

Symptoms of this deficiency state have been referred to as the three D’s: dermatitis, diarrhea, and dementia, indicating the prominent effects on the skin, gastrointestinal tract, and central nervous system. This deficiency can result from low dietary intake, malabsorption syndromes, or chronic systemic illnesses. The dementia associated with pellagra is manifested by apathy, confabulation, psychomotor slowing, irritability, and memory impairment. Cogwheel rigidity and frontal release signs (sucking and grasping signs) are seen in acute niacin deficiency.

b. Treatment

Consumption of a diet with adequate niacin is a standard treatment, although niacin supplements may be necessary for several days in severe cases. Most symptoms resolve gradually over several weeks after initiating treatment.

C. Toxic Conditions

There are numerous substances known to be toxic to the central nervous system, and exposure to such substances continues to increase as technology advances. Many industrial pollutants in the air and water, pesticides, herbicides, food additives, and household supplies such as cleaners, paints, and organic solvents have been reported to produce potentially toxic effects on the central nervous system. Although many of these substances require a prolonged, continuous exposure to be harmful, the long-term effects of a number of chemicals are not known. In addition, medications can produce toxicity if they are overused or if alterations in the individual’s metabolism prevent toxic by-products from being adequately cleared from the body. The elderly are particularly susceptible to toxic effects of drugs, due to greater variability in metabolic rates, decreased body mass, and lower drug-binding protein levels. Thus, close monitoring for toxicity and modification of drug dosages are often necessary in older persons. Finally, drugs of abuse have frequently been associated with dementia, and the neurotoxic effects of alcohol reflect perhaps the most common dementia associated with substance abuse.

1. Occupational and Environmental Toxic Exposure

a. Clinical Features

A number of metals may interfere with cellular metabolism, producing dementia after prolonged or accumulated exposure. Lead, inorganic and organic mercury, manganese, arsenic, thallium, tin, bismuth, nickel, and cadmium have all been associated with dementia syndromes. Organic solvents can enter the body through inhalation or skin contact. They are often used in various cleaning supplies and include carbon tetrachloride, trichloroethane, trichloroethylene, methyl chloride, and ethylene glycol. These substances may produce irritability, depression, impaired concentration, memory deficits, and peripheral neuropathy. Organochlorine insecticides may produce anxiety and irritability, but dementia syndromes are somewhat rarer. In contrast, prolonged or continuous exposure to organophosphate insecticides may produce memory impairment, sleep disturbance, distractibility and anxiety.

b. Treatment/Prevention

The use of protective clothing and devices may be effective in eliminating or minimizing exposure to these hazardous toxic substances, thereby preventing intoxication.

2. Toxic Effects of Medications

a. Clinical Features

Medications frequently have side effects that may produce dementia following prolonged use. Tricyclic antidepressants have anticholinergic properties that may exacerbate memory impairment in vulnerable persons, and their use in the elderly must be carefully monitored. Lithium has also been associated with a dementia syndrome manifested by disorientation, impaired attention and concentration, and comprehension deficits. A high-frequency tremor is often associated with lithium use as well. Benzodiazepines (e.g., diazepam, lorazepam, and alprazolam) are associated with impairment in memory functioning that is characterized by an inability to learn new information. Neuroleptic medications (e.g., haloperidol and the phenothiazines) may also produce chronic confusional states and dementia syndromes following long term use. Use of benzodiazepines and neuroleptics are also associated with increased risk of falling and hip fracture in the elderly. Some dementia syndromes have occasionally been associated with antihypertensive medications such as alpha-methyldopa and propanolol presumably through disruption of catecholaminergic synaptic functioning. Recent studies of anticonvulsants suggest that the barbiturates have the greatest impact on cognitive functioning, while anticonvulsants such as phenytoin, carbamazepine, and valproic acid do not commonly produce major cognitive effects at therapeutic serum levels. Dementia syndromes have also been associated with several drugs used in chemotherapy for cancer.

3. Toxic Effects of Drugs of Abuse

a. Clinical Features

Chronic polydrug abuse has been associated with dementia syndromes, particularly when barbiturates and analgesics are combined. Intravenous drug use using unsterile needles may produce multi-infarct dementia through bacterial endocarditis, although spread of HIV through sharing needles constitutes a much greater risk. An irreversible parkinsonian syndrome was produced in a small group of intravenous drug users who injected themselves with the compound MPTP (described in Degenerative Dementias~Parkinson’s Disease). Intentional solvent inhalation (e.g., “glue sniffing”) is also associated with significant central nervous system effects resuiting in motor and cranial nerve abnormalities and dementia.

Alcohol is the most common substance associated with abuse and consequently has been widely studied. At least three mechanisms are thought to underlie cognitive deficits in alcohol abuse: thiamine deficiency through dietary neglect (described in the section on vitamin deficiencies), hepatic dysfunction through cirrhosis (described in the section on systemic illnesses–hepatic disease), and direct neurotoxic effects of alcohol on the central nervous system. Alcoholic dementia accounts for approximately 7% of dementias among patients evaluated for cognitive decline, and it tends to be seen in older patients after a number of years of abuse. According to Cummings and Benson, daily alcohol intake of 150 ml of absolute alcohol constitutes the definition of excessive alcohol use, which corresponds to two bottles of wine, seven pints of beer, or one-half bottle of distilled spirits. Neuropsychological deficits are seen in the following cognitive domains: memory, visuospatial functioning, abstract reasoning, and verbal fluency. Disorientation, circumstantiality, perseveration, psychomotor slowing and impaired attentional deployment are also typical. CT and MRI scans show cerebral atrophy manifested by enlarged lateral ventricles and widening of the cortical sulci. Atrophy of the cerebellar vermis is also commonly seen. Abnormal EEG slowing is also common in this patient group. Atrophy of the white matter and of the cerebral cortex have been reported at autopsy, together with atrophy of the mammillary bodies, dorsomedial nucleus of the thalamus, the mammilothalamic tract, and the cerebellar vermis.

b. Treatment

Abstinence from alcohol, together with improved dietary nutrition, results in at least partial reversal of many cognitive deficits, with recovery being dependent both on the chronicity of abuse and on the length of abstinence. However, it is rare for an alcoholic to return to their baseline level of cognitive functioning.

V. Dementia Due to Other Causes

A. Hydrocephalus

1. Clinical Features

Although this condition is not a common cause of dementia, it can be effectively treated if discovered early. An accumulation of cerebrospinal fluid (CSF) in the brain leads to enlargement of the ventricles. The nature of this CSF accumulation is unclear, but possible causes include excessive CSF secretion from the choroid plexus (e.g., choroid plexus papilloma), obstruction of CSF outflow from the ventricles to the cerebral subarachnoid space (e.g., obstructive noncommunicating hydrocephalus), or obstruction of the CSF flow from the subarachnoid space to the saggital sinus region (e.g., obstructive communicating hydrocephalus). Intracranial pressure can be normal or high in any of these conditions. The clinical triad of gait disturbance, cognitive impairment, and urinary incontinence are commonly associated with communicating hydrocephalus. The cognitive impairment is manifested by disorientation, memory impairment, psychomotor slowing, poor abstract reasoning, and bradyphrenia.

2. Treatment

Communicating hydrocephalus may be treated by placement of a shunt tube to divert CSF from intracranial spaces to an extracranial site. Maintaining patency of the shunt tube can be problematic and may require shunt replacement. Nonobstructive hydrocephalus (e.g., hydrocephalus ex vacuo) refers to ventricular enlargement due to cerebral atrophy typically due to degenerative conditions, and is not amenable to surgical intervention.

B. Head Trauma

1. Closed Head Injury

a. Clinical Features

Severe closed head injury may produce a posttraumatic dementia. The cognitive deficits may be due to a variety of mechanisms, including diffuse axonal injury, subdural or intracerebral hematoma, and cerebral contusions. The range of deficits following head injury is dependent on the location of cerebral damage and on the severity and mechanism of the trauma. Degree and duration of coma have been shown to correlate with functional outcome. Following loss of consciousness, a period of posttraumatic confusion and disorientation typically ensues, which may last days to weeks. Delirium, agitation, irritability, apathy, or withdrawal may be seen during this period. The duration of posttraumatic and retrograde amnesia duration are sometimes useful prognostic indicators, with longer amnestic periods associated with poorer outcomes. The duration of posttraumatic amnesia refers to the period between the injury and the resumption of continuous memory. The duration of retrograde amnesia refers to the period between the accident and the first clear memory prior to the accident. Longer durations of posttraumatic amnesia have been found to correlate with poorer cognitive outcomes in some studies. Other indices of severity, such as oculocephalic disturbances, are also prognostic of return to work and cognitive recovery. Minor head injury with no or minimal (less than 20 minutes) loss of consciousness, no focal neurologic deficits, and no positive neuroradiologic findings typically does not result in significant cognitive sequelae longer than three months postinjury in persons with no pre-injury history of head trauma, neuropsychiatric disturbance, or drug or alcohol abuse.

b. Treatment

Rehabilitation programs are frequently helpful in developing strategies to compensate for cognitive and motor deficits.

2. Dementia Pugilistica

a. Clinical Features

Repeated minor head blows, such as those that occur in boxing, result in the condition known as dementia pugilistica. Degeneration of the substantia nigra, neuronal loss in the cortex and cerebellum, neurofibrillary tangle formation and diffuse deposition of beta-amyloid plaques are seen at autopsy. Initial clinical features include mild coordination difficulty and affective dyscontrol, followed by apraxia, aphasia, agnosia, apathy, blunted affect and focal neurologic signs. End stages of the disease are characterized by global cognitive deterioration and the development of parkinsonism.

b. Treatment

Anti-parkinsonian medications may be helpful in treating the movement abnormalities, although this condition is considered to be progressive.

C. Tumors

1. Clinical Features

Depending on their location and extent, tumors can cause only discrete cognitive deficits, or they may produce global cognitive impairment characteristic of a dementia syndrome. Tumors in the thalamus, hypothalamus, or frontal or temporal cortex are more often associated with dementia. As noted above, chemotherapy can sometimes be associated with development of dementia independent of the tumor.

2. Treatment

The clinical course of patients with tumors is highly variable, depending on the pathology of the tumor and its location. However, with improved imaging methods, treatment can frequently be initiated early, thereby improving prognosis.

D. Psychiatric Conditions

1. Depression

a. Clinical Features

Severely depressed individuals may manifest impaired attention and concentration, disorientation, and memory deficits, which may frequently be difficult to differentiate from a dementia. In addition, a “dementia syndrome of depression” has been recognized. Some reports have suggested that individuals with this syndrome may exhibit greater cortical volume loss, greater anxiety, and more frequent delusions relative to depressed patients without cognitive impairment. Difficulty abstracting and grasping the meaning of situations, increased response latency, and impaired attention, concentration, and recall but relatively preserved recognition memory are common neuropsychological features. The memory deficit associated with depression is thought to be related to fluctuations in attention and concentration and is less severe than that seen in Alzheimer’s disease. Aphasia, apraxia, and inability to name objects are generally not present. The etiology of depression and the dementia syndrome of depression remains elusive, but it is relatively clear that multiple neurotransmitter systems are involved. Disturbed functioning of nigrostriatal and frontal-limbic connections may also be involved in producing variable alertness and attention.

b. Treatment

Cognitive deficits associated with depression are highly treatable with conventional antidepressant pharmacotherapy, or with electroconvulsive therapy in the case of pharmacologic nonresponse. Cognitively oriented psychotherapy has also been a highly effective treatment for depression. Antidepressants with potent anticholinergic properties should be avoided, as these medications may potentially exacerbate the severity of memory impairment.

2. Schizophrenia

a. Clinical Features

Schizophrenia (dementia praecox) affects approximately 1% of the general population. Initial presentation is that of psychosis, which generally begins in adolescence or young adulthood. Clinical features include “positive” symptoms such as delusions, hallucinations, and formal thought disorder, and “negative” symptoms such as apathy, blunted affect, and anhedonia. Negative symptoms tend to emerge later in the disorder and are associated with dementia (“deficit syndrome”). Exacerbations and remissions of psychotic features characterize the course of the illness. Cognitive deficits are more common during exacerbations of the disease and include difficulty with abstract reasoning, memory impairment, disorientation, perseveration, impaired judgment, and tangentiality. The mechanism of cognitive decline in schizophrenia has not been determined. Ventricular enlargement and sulcal widening on CT and MRI scans correlate with the severity of cognitive impairment, raising the possibility that neuronal loss may account for the dementia. However, disordered monoamine function has also been proposed to underlie the cognitive deficits in schizophrenia.

b. Treatment

Treatment with the phenothiazines, butyrophenones, and thioxanthenes has been used to reduce the positive symptoms. Negative symptoms tend to be unaffected by these three classes of medications, although clozapine has shown some promise.

Bibliography:

  1. Cummings, J. L., & Benson, D. F. (1992). Dementia: A clinical approach (2nd ed.). Boston: Butterworth-Heinemann.
  2. Heilman, K. M., & Valenstein, E. ( 1993). Clinical neuropsychology (3rd ed.). New York: Oxford.
  3. Kolb, B., & Whishaw, I. Q. (1990). Fundamentals of human neuropsychology (3rd ed.). New York: W. H. Freeman.
  4. Mann, D. M. A., Neary, D., & Testa, H. (1994). Color atlas and text of adult dementias. London: Mosby-Wolfe.
  5. Roberts, G. W., Leigh, P. N., & Weinberger, D. R. (1993). Neuropsychiatric disorders. London: Mosby-Wolfe.

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