Disclosure
Background: In 1907, Alois Alzheimer described the first case of Alzheimer disease (AD). From its status as a rare disease, AD has evolved into one of the most common diseases in the aging population, and it ranks as the fourth most common cause of death. AD is a progressive neurodegenerative disorder characterized by the gradual onset of dementia. The pathological hallmarks of the disease are Abeta amyloid plaques, neurofibrillary tangles (NFTs), and reactive gliosis. Current diagnosis of AD is made by means of clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation is based on nonspecific features such as atrophy, a late feature in the progression of the disease. Therefore, developing new approaches for early and specific recognition at the prodromal stages of AD is of crucial importance. An appropriate cure and effective therapies to halt or slow disease progression are still lacking. A number of in vivo neuroimaging techniques, which can be used to reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise in future. With time and improvements in technology, these imaging techniques might yield acceptable neuroimaging biomarkers of AD. Although present therapy involves enhancers of cholinergic function, disease-modifying agents may be available in the future. Emphasis is being placed on detecting the presymptomatic phase of the disease, which may be termed mild cognitive impairment (MCI). Neuroimaging is also used to exclude other causes of dementia, such as normal-pressure hydrocephalus, brain tumors, subdural hematoma, and multiple infarction. Pathophysiology: The pathophysiology and etiology of AD are unknown. AD has been inconsistently associated with traumatic head injury, low educational achievement, depression, advanced parental age at the time of birth, smoking, and Down syndrome in a first-degree relative. In some observational studies, the use of estrogen-replacement therapy in postmenopausal women and the regular use of anti-inflammatory agents in both men and women have been associated with lowered risks of AD. On biochemical analysis, the most consistent change in patients with AD is a 50-90% reduction of the activity of choline acetyl transferase in the cerebral cortex and hippocampus. Amyloid has a major role in familial AD, but the link between amyloid deposition, tangle formation, and neuronal death is unknown. The amyloid cascade hypothesis proposes that histopathologic abnormalities of senile plaques (SPs), NFTs, and neuronal loss are all secondary to amyloid deposition. The extent to which sporadic disease may be related directly to abnormal amyloid metabolism is yet unknown. Pathology of ADGross pathology In AD, the brain usually shows gross atrophy, most prominently involving the cortex surrounding the sylvian fissure and hippocampal formations. Diffuse ventriculomegaly is most prominent, involving the temporal horns. Severity of dementia is not correlated with the degree of atrophy. Findings in the cerebellum and brainstem are typically unremarkable. Microscopic pathology Histologic features include NFTs and neuritic plaques (NPs). Other findings include granulovacuolar degeneration, Hirano bodies, and amyloid angiopathy. Synaptic loss is the best pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost (Coleman, 2004). NPs are seen throughout the depth of the neocortex, especially the temporal and parietal regions and less so in frontal regions. Abundance of NP in the neocortex is not strongly correlated with the severity of dementia. At present, Ab1-40 or Ab1-42 molecules are thought to be the central pathologic molecules in AD. Persons homozygous for the APOE*E4 allele have more Ab deposition than do those with other genotypes. Mutations in the PS1 and PS2 genes lead to overexpression of Ab1-42. Neurofibrillary tangles NFTs are intraneuronal inclusions that contain hyperphosphorylated tau protein. The regional specificity of NFTs differs from that of NPs. The NFT count is strongly associated with the severity of disease. NFTs are most prominent in the neocortex and in the hippocampal, perihippocampal, and entorhinal regions. Tau protein Tau undergoes phosphorylation at several sites along its length. In NFTs, tau is excessively phosphorylated, leading to the aggregation of tau molecules into paired helical filaments and then to the insoluble NFTs. Histologic diagnosis of AD The most widely used neuropathologic diagnostic criteria for AD, the Khachaturian criteria, are based exclusively on numbers of NPs found in the neocortex. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathologic criteria are based on the Khachaturian criteria. According to Braak and Braak (1991), as the disease progresses, 6 stages can be distinguished on the basis of the distribution of NFTs: stages I–II (transentorhinal), III–IV (limbic) and V–VI (neocortical). The evolution of these pathologic stages takes several decades, and clinically manifested dementia appears in the late limbic–neocortical stages. Kovacs et al (2001) studied the pathology of the cortical olfactory centers LOF and PAC in relation to the damage of the olfactory bulb in AD and determined the structures with earliest NFT formation compared with Braak staging using immunohistochemistry and quantitative densitometry. The olfactory bulbs were damaged in early stages of AD, even earlier than the entorhinal cortex was. This finding supports the fact that olfactory dysfunction in AD mainly results from the damage of the olfactory bulb and the medial temporal lobe. These findings further support the view that olfactory tests might be useful preclinical markers in AD, as the olfactory bulb is involved in early Braak stages. CERAD neuropathology criteria use the presence and density of neuritic SPs to establish the diagnosis of AD (Mirra, 1991). Regions that must be examined include middle frontal gyrus, superior and middle temporal gyri, inferior parietal lobule, hippocampus, entorhinal cortex, and midbrain including the substantia nigra. The final diagnosis is based on observations from the neocortical areas sampled. The semiquantitative measure (sparse, moderate, or severe) of neuritic SP in the most severely affected neocortical region is combined with the subject's age to yield an age-related plaque score. This score is then integrated with the clinical information for the diagnosis of definite, probable, or possible AD. The National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria provide 3 levels of diagnosis: probable, possible, and definite AD. Probable AD is dementia established by means of clinical examination and documented and confirmed with neuropsychological tests. Deficits affect 2 or more areas of cognition. Patients have progressive impairment in intellect, memory, and other cognitive functions with normal consciousness. The first symptom occurs after the age of 40 years and before 90 years. No evidence of clinically significant systemic and other brain diseases explain the progressive deficit. With possible AD, the onset, clinical presentation (single progressive deficit without identifiable cause), or course are considered atypical. As an alternative, a second systemic or brain disorder is present and sufficient to produce dementia, but it is not considered to be the cause in the particular case. Most cases of possible AD eventually turn out to be probable cases. Definite AD is possible or probable AD with histologic confirmation on biopsy or autopsy. Criteria for the diagnosis of AD from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), includes memory impairment with 1 or more of the following features: aphasia, apraxia, agnosia, or disturbance in executive functioning. These cognitive deficits can cause clinically significant impairment in social and occupational functioning that represents a notable decline from a previous level of functioning. The course is gradual in onset with a progressive decline. No other neurologic, psychiatric, systemic or substance-induced conditions known to cause cognitive deficits explain the decline, and they do not occur exclusively during the course of delirium. A follow-up consensus conference elaborated on the initial criteria by citing a role for NFTs in the diagnosis of AD by using the Braak staging system. The 1997 criteria state that the likelihood of AD is high when NP is frequently abundant according to CERAD criteria and when the NFT pathology is Braak stages V or VI. The likelihood of AD is intermediate when the NP burden is moderate according to the CERAD criteria and when the NFT pathology is Braak stages III or IV. Other pathologic findings in ADGranulovacuolar degeneration Granulovacuolar degeneration occurs in the same distribution as NFTs. Hirano bodies are rod-shaped eosinophilic intracellular bodies found in the dendrites of hippocampal CA1 region neurons. They contain tau and actin. Amyloid angiopathy Amyloid angiopathy commonly involves small-to-medium vessels, usually those in the leptomeninges and superficial cortex. On histology, the media of the vessel wall is thickened and hyalinized as a result of the amyloid deposition. The ApoE genotype is associated with increased amounts of vascular amyloid. Amyloid cascade hypothesis Data from studies of missense mutations in 3 genes known to cause autosomal dominant forms of early-onset AD strongly support the amyloid cascade hypothesis of AD. The genes include the gene for amyloid precursor protein located on chromosome 21 and the genes for presenilin 1 and presenilin 2 located on chromosomes 14 and 1, respectively. ApoE genotype associated with AD risk The APOE*E2 allele may be protective, and the APOE*E4 allele is associated with increased risk, though its precise role remains unclear. Neurotransmitter and neuropeptide abnormalities In AD, deficits in choline acetyltransferase is the key feature in the neocortex and hippocampus. These deficits, in turn, involve the cholinergic pathway neurons in the nucleus basalis, septum, and diagonal band, resulting in cellular dysfunction, NFT formation, and eventual cell death over time. Frequency:
Mortality/Morbidity: In general, an inexorable decline of functions occurs in patients with AD, though considerable variations and rarely plateaus are noted.
Sex: Female sex is a surprisingly controversial risk factor. Women are consistently overrepresented in clinical series of AD, mostly because they live longer than men. Age: The incidence of AD is strongly related to age. Data from most studies suggest that the incidence of the disease continues to increase even in extreme old age (Andersen, 1999; Hebert, 1995). Each year, AD develops in almost 1 in every 10 people older than 85 years. A meta-analysis of 23 published studies showed that the age-specific incidences of dementia and AD rose exponentially through age 90 years (Jorm, 1987). The average incidence rate for AD across studies for persons aged 70-74 years is 0.51%, increasing to 3.9% in persons aged 85-89 years (Petersen, 2001). Clinical Details: Manifestations of AD evolve from the earlier signs of memory impairment to severe cognitive loss with progression to complete incapacity and death. At first, information that patients newly acquire is impaired, whereas memory for remote events remains relatively unimpaired. With progression of disease, deficits in language, abstract reasoning, and executive functions can be elicited. Language disturbance is reportedly most prominent in patients with early onset, in contrast to silent memory disturbance with visuospatial problems in patients with late onset. Neuropsychiatric symptoms can be observed and include mood disturbances (especially depression), delusions and hallucinations, personality changes, and behavior disorders. Except for the mental state evaluation, neurologic examination usually demonstrates normal findings. Extrapyramidal features are relatively common in advanced AD and include rigidity, bradykinesia, shuffling gait, and postural changes. Preferred Examination: Laboratory testing Routine laboratory test results are normal. CSF is normal, though the protein count may be slightly increased. Ubiquitin and tau levels in the CSF have been reported to be raised in AD. For sporadic or familial late-onset AD, the E4 polymorphism of the gene for apolipoprotein E (ApoE) has been associated with a high risk of the disease. However, it does not provide sufficient sensitivity or specificity for diagnosis, and its use is not recommended. Neuroimaging studies MRI can be considered the preferred neuroimaging examination because it allows for accurate measurement of 3-dimensional volumes of brain structures, especially the size of the hippocampus and related regions. As widely believed, neuroimaging is generally useful in excluding reversible causes of dementia syndrome, such as normal-pressure hydrocephalus, brain tumors, and subdural hematoma and in excluding other likely causes of dementia, such as cerebrovascular disease. The most recent practice parameters for the diagnosis and evaluation of dementia, as published by the American Academy of Neurology (AAN), consider structural brain imaging optimal (Petersen, 2001). Nonenhanced CT and MRI are the appropriate imaging methods (Doody, 2001). The AAN suggests that neuroimaging may be most useful in patients with dementia characterized by a young age of onset or an unusual course. Limitations of Techniques: Routine laboratory test results are normal in AD. CSF results are normal, though a slight increase in protein count may be noted. Ubiquitin and tau levels in CSF are reportedly raised in AD. For sporadic or familial late-onset AD, E4 polymorphism of the gene for ApoE has been associated with a high risk of the disease. However, it does not provide sufficient sensitivity or specificity for diagnosis, and its use is not recommended.
Parkinson disease
Findings: Overall atrophy Initial criteria for CT diagnosis of AD includes diffuse cerebral atrophy with enlargement of the cortical sulci and increased size of the ventricles. A multitude of studies have shown that cerebral atrophy is significantly greater in patients with AD than in patients who are aging without AD. This concept was soon challenged because cerebral atrophy can be present in elderly and healthy subjects, and some patients with dementia may have no cerebral atrophy, at least in early stages. The extent of cerebral atrophy was determined by using linear measurements, in particular bifrontal and bicaudate diameters and the diameters of the third and lateral ventricles. Various measurements were adjusted according to the diameter of the skull to account for normal variation. To complement this modification, volumetric studies of the ventricles were done. Despite these efforts, it is still difficult to distinguish findings in a healthy elderly patient and those in a patient with dementia. In addition, a review of serial CT scans obtained over several months was not clinically useful in the primary diagnosis of the disease. Rate of change of brain atrophy Changes in the rate of progression of atrophy can be a useful tool (Jagust, 1987). Longitudinal changes in brain size are associated with longitudinal progression of cognitive loss (Bird, 1986). Enlargement of the third and lateral ventricles is greater in patients with AD than in control subjects (Luxenberg, 1987). Changes in brain structure Diffuse cerebral atrophy with widened sulci and dilatation of the lateral ventricles can be observed. Disproportionate atrophy of the medial temporal lobe, particularly of the volume of the hippocampal formations (<50%), can be seen. Dilatation of the perihippocampal fissure is a useful radiologic marker for initial diagnosis of AD, with a predictive accuracy of 91% (Ferris, 1980). The hippocampal fissure is surrounded laterally by the hippocampus, superiorly by the dentate gyrus, and inferiorly by the subiculum. These structures are all involved in the early development of AD and explains the enlargement in the early stages. At the medial aspect, the fissure communicates with the ambient cistern, and its enlargement on CT scans is often seen as hippocampal lucency or hypoattenuation in the temporal area medial to the temporal horn. White-matter attenuation is not a feature of AD. The temporal horns of the lateral ventricles can be enlarged. Prominence of the choroid and hippocampal fissures and enlargement of the sylvian fissure may be noted. Degree of Confidence: CT indices of hippocampal atrophy are highly associated with AD, but the specificity is not well established. Use of a nonquantitative rating scale showed a sensitivity of 81% and a specificity of 67% in differentiating 21 patients with AD with moderate dementia from 21 age-matched control subjects (Scheltens, 1992). Hippocampal volumes in a sample of similar size permitted correct classification of 85% of control subjects (Jack, 1992). |
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Findings: Many studies have shown that cerebral atrophy is significantly greater in patients with AD than in persons without AD. The variability of atrophy in the normal aging process makes it difficult to use MRI as a definitive diagnostic technique. Fox and colleagues (1996) used a potentially clinically applicable automated technique to subtract MRIs obtained an average of 1 year apart. They observed a significant difference in the rates of change in patients with AD compared with control subjects. With MRI, sensitivity and specificity were approximately 90% for predicting the decline in dementia. Early MRI studies to evaluate the size of the hippocampus in patients with AD relative to control subjects showed large reductions in hippocampal volumes (approximately 50%) and high sensitivity and specificity for classification (Kesslak, 1991). Over time, enlargement of the temporal horns and the third and lateral ventricles was noted in patients with AD compared with control subjects. On structural MRI, atrophy of the entorhinal cortex is already present in MCI. In the autosomal dominant forms of AD, the rate of atrophy of the medial temporal structures differentiates affected individuals from control subjects as early as 3 years before the clinical onset of cognitive impairment. The accelerated annual rate of brain atrophy is a surrogate tool for evaluating new therapies in small samples that saves time and resources. MRI measurements of the hippocampus, amygdala, cingulate gyrus, head of the caudate nucleus, temporal horn, lateral ventricles, third ventricle, and basal forebrain yield a prediction rate of 77% for conversion to AD from questionable AD (Killiany, 2000 and 2002). Recent functional MRI techniques can be used to measure cerebral perfusion. Dynamic susceptibility contrast (DSC) MRI consists of the passage of a concentrated bolus of a paramagnetic contrast agent that sufficiently distorts the local magnetic field to cause a transient loss of signal with pulse sequences, especially T2-weighted sequences. The passage of contrast material is imaged over time by means of sequential rapid imaging of the same section. In animal studies, the rate of change of signal intensity over time gives a measure directly proportional to cerebral blood volume. Studies in humans have shown a correlation between PET and DSC MRI results, between cerebral blood volumes measured with DSC MRI and perfusion on SPECT. Studies have been performed by using MRI with echo-planar imaging and signal targeting with attenuation radiofrequency (EPISTAR) in patients with AD. Focal areas of hypoperfusion were in the posterior temporoparietooccipital regions. Ratios of signal intensity in parietooccipital and temporooccipital areas to signal intensity on whole section signal intensity were significantly lower in the patients with AD than in others. The parietooccipital ratios were not correlated with the severity of dementia, as measured by using the Blessed Dementia Scale Information Memory Concentration subset. With functional MRI (fMRI), structural imaging can be done by using the same imaging plane, field of view, and section thickness. Activational fMRI studies have included blood oxygenation level–dependent (BOLD) imaging, which uses changes in the level of oxygenated hemoglobin in capillary beds to depict areas of regional brain activation. In AD, fMRI activation in hippocampal and prefrontal regions are decreased. On functional MRI, paradigms activate a larger area of parietotemporal association cortex in persons at high risk for AD than in others, whereas the entorhinal cortex activation is relatively low in MCI. The techniques are reasonably sensitive and specific in differentiating AD from changes due to normal aging, and recent studies with pathologic confirmation show good sensitivity and specificity in differentiating AD from other dementias. These techniques can also be used to detect abnormalities in asymptomatic or presymptomatic individuals, and may help in predicting the decline to dementia. Degree of Confidence: MRI findings of hippocampal atrophy are highly associated with AD, but the specificity is not well established (Scheltens, 1992). In patients with AD and moderate dementia, hippocampal volumes permitted correct classification in 85% (Jack, 1992). In patients with AD and mild dementia, sensitivity and specificity were 77% and 80%, respectively (Jack, 1997). Hippocampal volume was the best discriminator, though a number of medical temporal-lobe structures were studied, including the amygdala and the parahippocampal gyrus. Both hippocampal and entorhinal cortical atrophy are features of frontotemporal dementia, but they do not appear to be as profound as atrophy in AD (Frisoni, 1999). False Positives/Negatives: Hippocampal atrophy appears to be a feature of vascular disease (multi-infarct dementia) and Parkinson disease, even in patients with Parkinson disease without dementia. Both hippocampal and entorhinal cortical atrophy are features of frontotemporal dementia, but they do not appear to be as profound as the atrophy in AD.
Findings: Single photon emission CT Single photon emission CT (SPECT) uses direct photon-emitting isotopes rather than radioisotopes. SPECT isotopes have an average half-life of 6-12 hours. SPECT instrumentation is highly variable; therefore, use of a SPECT scanner with poor resolution can result in poor clinical performance. Positron emission tomographic (PET) scanners use tracers that measure regional glucose metabolism (rCMRglc). SPECT imaging is most commonly used for blood-flow measurement. Early SPECT studies of blood flow replicated findings of functional reductions in the posterior temporal and parietal cortex (Jagust, 1987; Johnson, 1987; DeKosky, 1990). The severity of temporoparietal hypofunction has been correlated with the severity of dementia in a number of studies. Reductions of blood flow and oxygen use can be found in the temporal and parietal neocortex in patients with AD and moderate-to-severe symptoms (Frackowiak, 1981). Early reductions of glucose metabolism are seen in the posterior cingulate cortex. SPECT is uncommonly used to assess AD. SPECT has utility in the diagnostic assessment of AD if standardized and semiquantitative techniques are used. Trollor et al (2005) examined 18 subjects with early AD and 10 healthy elderly control subjects with high-resolution SPECT during their performance of a simple word-discrimination task. SPECT images were coregistered with individual MRIs, allowing for the delineation of predetermined neuroanatomical regions of interest (ROI). They observed a gradation of regional cerebral blood flow (rCBF) values in both groups, with the lowest values in the hippocampus and the highest in the striatum, thalamus, and cerebellum. Compared with healthy control subjects, patients with AD had low relative rCBF in parietal and prefrontal cortices. Analysis of individual ROI demonstrated bilateral reduction of rCBF in the prefrontal poles and posterior temporal and anterior parietal cortex, with unilateral reduction of rCBF in the left dorsolateral prefrontal cortex, right posterior parietal cortex, and left cingulate body. They found no significant differences in hippocampal, occipital or basal ganglia rCBF. Discriminant function analysis indicated that rCBF in the prefrontal polar regions permitted the best classification (Trollor, 2005). In class II studies, the sensitivity of SPECT was lower than that of the clinical diagnosis (Knopman, 2001). Sensitivity increased as the severity of dementia worsened, but the pretest probability of AD also increased (van Gool, 1995). The added value of SPECT was greatest for a positive test among patients with mild dementia in whom the diagnosis of AD was substantially doubted (Johnson, 1990). In this situation, a positive SPECT result would have increased the posttest probability of AD by 30%, whereas a negative test result would have increased the likelihood of no AD by only 10% (Claus, 1994). Positron emission tomography PET is a powerful imaging technique that enables in vivo examination of brain functions. It allows for noninvasive quantification of cerebral blood flow, metabolism, and receptor binding. It helps to improve our understanding of disease pathogenesis, to aid with diagnosis, and to monitor disease progression and response to treatment. PET involves introduction of a radioactive tracer into the human body, usually with an intravenous injection. A tracer is essentially a biologic compound of interest that is labeled with a positron-emitting isotope, such as carbon-11, fluorin-18, or oxygen-15. These isotopes are used because they have relatively short half-lives (minutes to <2 h), allowing the tracers to reach equilibrium in the body without exposing the subjects to prolonged radiation. The 2 most common physiologic process measurements performed by using PET scan include glucose with [18F] fluoro-2-deoxyglucose (FDG) and cerebral blood flow by using water (Scheltens, 1992). FDG PET has been used extensively to study AD, and it is evolving into an effective tool for early diagnosis and differentiation of AD from other types of dementia. FDG PET has been used to detect subjects at risk for AD even before the onset of symptoms (Silverman, 2001). Patients with AD have characteristic temporoparietal glucose hypometabolism, and the degree of hypometabolism is correlated with the severity of dementia (Salmon, 2002). With progression of disease, frontal involvement may be evident. Glucose hypometabolism in AD is likely to be due to a combination of neuronal cell loss and decreased synaptic activity (Maziotta, 1992). In AD, FDG PET has a sensitivity of 94% and a specificity of 73%. It could also be used to correctly predict a progressive course of dementia with 91% sensitivity and a nonprogressive course with a specificity of 75% (Salmon, 1996). Individuals at high risk for AD (asymptomatic carriers of the APOE*E4 allele) had a pattern of glucose hypometabolism similar to that of patients with AD. After a mean follow-up of 2 years, the cortical metabolic abnormality continued to decline despite preservation of cognitive performance (Small, 1995; Reiman, 1996). Entorhinal cortex hypometabolism on FDG PET seen in control subjects is of predictive value of progression to MCI or even AD (Small, 2000; Reiman, 2001). The identification of asymptomatic individuals at risk will have an enormous role in the treatment strategy for AD (de Lean, 2001). On PET or SPECT, mild AD may be more difficult to detect than moderate or severe disease. Temporal and parietal glucose hypometabolism is widely seen on PET images in patients with AD. Despite the technical differences, results from both PET and SPECT are comparable, though data suggest that PET is more sensitive than SPECT (Messa, 1994). In patients with AD, PET performed with ligand PK11195 labeled with carbon-11, or (R)-[11C] PK11195, showed increased binding in the entorhinal, temporoparietal, and cingulate cortices. This finding corresponded to the postmortem distribution of AD pathology (Alsen 2002). Efforts to develop a specific ligand for beta-amyloid plaques may further enhance the sensitivity of PET for early diagnosis of AD and provide a biologic marker of disease progression (Alsen, 2002). Degree of Confidence: Without surprise, clinically validated SPECT studies showing differences between patients with AD and control subjects reveal high sensitivities and specificities of 80-90% (Claus, 1994). Investigators compared patients from a dementia clinic with a community sample of control subjects using quantitative SPECT in which AD was defined as temporal-lobe perfusion more than 2 standard deviations below control values. The authors reported 63% sensitivity and 87% specificity. Holman and colleagues (1992) found that bilateral temporoparietal hypoperfusion had a positive predictive value of 82% for AD. Using inhaled xenon-133 and injected technetium-99m hexamethylpropyleneamine oxime, researchers reported a sensitivity of 76% and a specificity of 73% with a positive predictive value of 92% and a negative predictive value of 57% (Bonte, 1997). These studies may assist in the early and late diagnosis of AD and the differential diagnosis of dementias.
Findings: Angiography is not useful in the detection of AD.
Intervention: At present, no intervention is possible. Medical/Legal Pitfalls:
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