The neurodegenerative syndromes are cognitive loss syndromes of later life characterized by slowly progressive clinical change, aggregation of abnormally metabolized chaperone proteins in brain and neurons, the accretion of abnormal protein-aceous material in intercellular spaces, and cell death by apoptosis. The archetypal neurodegenerative dementia is AD—the dementia with clinical features that defines a clinical model against which all other cognitive loss syndromes are measured. The National Institute of Neurological and Communicative Disorders and Stroke criteria for AD are:
• Dementia present (a progressive cognitive loss syndrome of sufficient severity to cause impairment of social or vocational function).
• Onset between the ages of 40 and 90 years.
• Deficits in 2 or more cognitive areas.
• Progression of deficits for more than 6 months.
• Consciousness undisturbed.
• Absence of a better medical explanation for the syndrome.
In AD, memory failure almost always is the first cognitive domain affected; personality features and neuromotor functions are generally retained until later in the disease course. A variety of noncognitive neuropsychiatric features inevitably accompany the syndrome; these include apathy, agitation, atypical psychotic features, depression-like syndromes, and stereotypical behavioral disorders.
The neuropathological mechanisms that underlie AD are multiple and include the accumulation of abnormally phosphorylated t proteins within neurons (tangles), the accumulation of 42 amino acid amyloid fragments within the neuropil (plaques), vasculopathic changes within blood vessels, small strokes, and neuronal death.
Perhaps the starkest evidence that genetic factors play a role in AD came from recent studies that showed an association between point mutations in any of 3 gene loci (amyloid precursor protein gene, presenilin 1, presenilin 2) and autosomal dominant inherited AD, which was clinically and pathologically identical to nongenetic AD, except for a younger age at onset. For late-onset AD, the most common form of the disorder, it has proved more difficult to find the genetic loci. There is a risk locus at the apolipoprotein gene on chromosome 19. Secondary genes are known to exist as well, but it has proved difficult to find these outside delimited populations. Total genome screen studies, even of large cohorts of patients with AD, show only the chromosome 19 risk.
Environmental (nongenetic) risk factors are known to account for perhaps 50% of the clinical variance of AD expression. There is ongoing research to identify these nongenetic risk factors, since they may hold the key to treatment or prevention. Not all environmental risk factors are known. Some of the ones that are suspected include low education, hormone replacement therapy, use of drugs such as statins and NSAIDs, metabolic syndrome, all vascular risk factors, closed head injury, lack of physical fitness, and alcohol(Drug information on alcohol) consumption.
Treatments are now available for AD, which are of modest but definite benefit. In the Cognitive Disorders Program at the Cleveland Clinic, we try to implement a 4-domain treatment regimen for persons with early AD: (1) risk factor management with cholesterol reduction, glucose control, blood pressure control, smoking cessation; (2) physical fitness through aerobic exercise 3 times a week, as tolerated; (3) cognitive fitness using individualized cognitive rehabilitation; and (4) cognition-enhancing medications, including a cholinesterase inhibitor, donepezil(Drug information on donepezil) 10 mg daily, rivastigmine(Drug information on rivastigmine) 3 to 6 mg 2 times a day, or galantamine(Drug information on galantamine) 8 mg 2 or 3 times a day (sustained-release galantamine is now available). In addition, memantine(Drug information on memantine) 10 mg is FDA-approved for moderate to severe AD. Most patients experience a transient stabilization of symptoms for 6 to 18 months, followed by resumed progression of the disease in most cases, which clearly shows the need for better treatments for AD.
The non-AD neurodegenerative disorders fall into 2 broad categories: the frontotemporal syndromes and the parkinsonian syndromes. In general, the frontotemporal syndromes are characterized by behavior changes that affect language and personality, and the parkinsonian syndromes are characterized by dementia in the presence of abnormal motor function. The correlation between clinical diagnoses and pathological findings, however, may not yet be high in the non-AD syndromes.4
The frontotemporal spectrum disorders (frontotemporal lobar degeneration [FTLD], and others) are characterized by progressive changes in social behavioral, personality, motor function, and speech/language function.5 The list of clinical syndromes encompassed by this category of disorders spans most of neuropsychiatry and is growing (Table 2).
The symptoms of the FTLD disorders range from subtle mood and cognitive changes through movement disorders to the motor neuron diseases. Patients may present with social disinhibition, apathy, deficits in executive functions, involuntary emotional expression (pseudobulbar affect disorder), neck stiffness, progressive aphasia, falls, alien hand syndromes, atypical parkinsonism, weakness, and fasciculations.
The cognitive loss syndrome in these disorders spares memory, as compared with the AD-like disorders. A retrospective validation study of clinical criteria for various frontotemporal syndromes suggests that 5 features make the strongest contribution to separating the patients with FTLD from those with AD: presence of social conduct disorder, hyperorality, akinesia, absence of amnesia, and absence of a perceptual disorder.6
The neuropathological diagnosis of these disorders is also difficult. Most of them are disorders of chaperone protein aggregation: t, a-synuclein, and ubiquitin. In general, AD is a disorder of t aggregation and amyloid aggregation; the parkinsonian syndromes are disorders of abnormal a-synuclein aggregation, and the FTLD syndromes are disorders of ubiquitin and/or t aggregation. However, the present molecular genetic distinctions among the neurodegenerative disorders are not “clean” because the frontotemporal disorders share a good deal of t pathology with AD, and the parkinsonian syndromes share substantial tangle and plaque pathology with AD. Also, the FTLD syndromes overlap clinically with the motor neuron disorders and possibly with some of the severe psychiatric disorders, such as schizophrenia.
Investigators are trying to develop a molecular genetic classification scheme for these frontotemporal disorders (Figure). In general, the onset of the frontotemporal syndromes occurs at a younger age than occurrence of AD syndromes, and frontotemporal syndromes progress faster. Neurochemically, the acetylcholine system seems to be intact in the FTLD syndromes. Thus, cholinesterase inhibitors are not considered useful. Serotonin and dopamine(Drug information on dopamine) neurotransmitter systems show reduced levels of function and turnover in these, so pharmacological up-regulation of these neurotransmitters should be tried, depending on the clinical features.7