Neurology_Adams

Neurology_Adams. Microscopically, there is widespread loss of nerve cells. Early in the disease this is most pronounced in layer II of the entorhinal cortex. In addition to marked neuronal loss in the hippocampus, adjacent parts of the medial temporal cortex—namely, the parahippocampal gyri and subiculum—are affected. The anterior nuclei of the thalamus, septal nuclei, and diagonal band of Broca, amygdala, and particular brainstem parts of the monoaminergic systems are also depleted. The cholinergic neurons of the nucleus basalis of Meynert (the substantia innominata) and locus ceruleus are also reduced in number, a finding that has aroused great interest because of its putative role of the former in memory function (see in the following text). In the cerebral cortex, the cell loss predominantly affects the large pyramidal neurons. Residual neurons are observed to have lost volume and ribonucleoprotein; their dendrites are diminished and crowd one another owing to the loss of synapses and neuropil.


Neurology_Adams

Neurology_Adams. the large pyramidal neurons. Residual neurons are observed to have lost volume and ribonucleoprotein; their dendrites are diminished and crowd one another owing to the loss of synapses and neuropil. Astrocytic hypertrophy (more than proliferation) is in evidence as a compensatory or reparative process, most prominent in layers III and V.


Neurology_Adams

Neurology_Adams. Three additional microscopic changes give this disease its distinctive character: (1) The presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, also in the form of loops, coils, or tangled masses (Alzheimer neurofibrillary changes or “tangles”) (Fig. 38-1). These strands are composed of a hyperphosphorylated form of the microtubular protein, tau, and appear as pairs of helical filaments when studied ultrastructurally. (2) Spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen with periodic acid-Schiff (PAS); the core of the aggregates is the protein amyloid, surrounded by degenerating nerve terminals (neuritic plaques) that stains with silver. Amyloid is also scattered throughout the cerebral cortex in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the


Neurology_Adams

Neurology_Adams. in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the plaques, so-called congophilic angiopathy. (3) Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus. This last change is least important in diagnosis but there is uncertainty regarding its nature; it had been thought to be simply a reactive process but recent studies suggest it reflects a defect in phagocytosis of degraded proteins.


Neurology_Adams

Neurology_Adams. Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the neurofibrillary tangles and quantitative neuronal loss, not the amyloid plaques, that correlate best with the severity of the dementia (Arriagada et al). If any part of the brain is disproportionately affected with these changes, it is the hippocampus, particularly the CA1 and CA2 zones (of Lorente de Nó) and the entorhinal cortex, subiculum, and amygdala. These parts have abundant connections with other parts of the temporal lobe cortex and dentate gyrus of the hippocampus and undoubtedly account for the amnesic component of the dementia. The associative regions of the parietal lobes are another favored site. Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum.


Neurology_Adams

Neurology_Adams. Experienced neuropathologists recognize a form of Alzheimer disease, particularly in older patients (beyond 75 years of age), in which there are senile plaques but few or no neuronal tangles (about 20 percent of 150 cases reported by Joachim et al). Increasingly, other pathologic changes are being appreciated in Alzheimer cases with fewer plaques and tangles than anticipated for the degree of dementia; Lewy bodies in particular are found by sophisticated techniques. Another problem for the neuropathologist is to distinguish between the normal-aged brain and that of Alzheimer disease. This accords with the difficulty in understanding the role of aging in this disease, as mentioned earlier. It is not unusual to find a scattering of senile plaques in individuals who were ostensibly mentally normal during life. Anderson and Hubbard studied 27 demented individuals aged 64 to 92 years and 20 age-matched nondemented controls. In the former, 3 to 38 percent of the hippocampal neurons


Neurology_Adams

Neurology_Adams. normal during life. Anderson and Hubbard studied 27 demented individuals aged 64 to 92 years and 20 age-matched nondemented controls. In the former, 3 to 38 percent of the hippocampal neurons contained neurofibrillary tangles; in all but 2 of the controls, the number of hippocampal neurons with tangles fell below 2.5 percent. Moreover, an increased number of tangles in the aged are associated with mild cognitive impairment and a higher likelihood of progression to Alzheimer disease.


Neurology_Adams

Neurology_Adams. Many demented individuals with clinical features of Alzheimer disease have sufficient neuronal loss and Lewy bodies in the cortex and substantia nigra to justify a diagnosis on histopathologic grounds of Parkinson disease (see further on). For example, Leverenz and Sumi found that 25 percent of their Alzheimer patients showed the pathologic (and clinical) changes of Parkinson disease, a much higher incidence than can be attributed to chance. Similarly, of 11 patients with progressive supranuclear palsy (also discussed further on) reported by Gearing and coworkers, 10 were demented and 5 had the neuropathologic features of Alzheimer disease. These mixed cases present problems not only of classification but also in understanding the neurobiology of these degenerative diseases. This subject is discussed further in the section on Parkinson disease.


Neurology_Adams

Neurology_Adams. It is of historical interest that Alzheimer was not the first to describe plaques, one of the hallmarks of the pathologic state. Miliary lesions (Herdchen) had been observed in senile brains by Blocq and Marinesco in 1892 and were named senile plaques by Simchowicz in 1910. In 1907, Alzheimer described the case of a 51-year-old woman who died after a 5-year illness characterized by progressive dementia. Throughout the cerebral cortex he found the characteristic plaques, but he also noted, thanks to the use of Bielschowsky’s newly devised silver impregnation method, a clumping and distortion of fibrils in the neuronal cytoplasm, the neurofibrillary change (tangles) that now, appropriately, carries Alzheimer’s name.


Neurology_Adams

Neurology_Adams. Analyses of the plaques and neuronal fibrillary changes have been undertaken in an attempt to elucidate the mechanism of Alzheimer disease, but so far, to little avail beyond implicating one or both in the accompanying neuronal degeneration. Several histologic techniques assist in this endeavor, including refined methods for silver impregnation that stain both amyloid and its main constituent (beta-amyloid protein [Aβ]); immunostaining using antibodies specific to such proteins as ubiquitin, neuronal tau protein, and β-amyloid protein; and visualization of β-pleated protein sheets using thioflavine S and in the past especially, Congo red with ultraviolet and polarized light. Tau (composed chemically of β2-transferrin) is a discrete cytoskeletal protein that promotes the assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and one


Neurology_Adams

Neurology_Adams. stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and one form of frontotemporal dementia (see further on), tau is hyperphosphorylated and aggregates, resulting in paired helical filaments that make up the neurofibrillary tangles. Electrophoretically, tau moves with the β2-globulins and functions as a transferrin, that is, it binds iron and delivers it to the cell. Its concentration can be measured in the CSF and serum, but this has not yet proven clearly to be useful as a diagnostic test or to offer understanding of the pathogenesis of the disease.


Neurology_Adams

Neurology_Adams. The Aβ (beta amyloid) protein is a small portion of a larger entity, the amyloid precursor protein (APP), which is normally bound to neuronal membranes. As shown schematically in Fig. 38-2, the Aβ protein is cleaved from APP by the action of proteases termed α, β, and γ secretase. One current hypothesis focuses on the manner in which APP is cleaved by these enzymes to give rise to different-length residues of Aβ. During normal cellular metabolism, APP is cleaved by either α or β secretase. The products of this reaction are then cleaved by the γ-secretase isoform of the enzyme. The sequential cleavage by α and then γ produces tiny fragments that are not toxic to neurons. However, cleavage by β and then γ results in a 40-amino-acid product, Aβ40, and a longer 42-amino-acid form. The latter Aβ42 form is toxic in several models of Alzheimer disease, and it has been proposed that the ratio of Aβ42 to Aβ40 is critical to the neuronal toxicity of amyloid.


Neurology_Adams

Neurology_Adams. Several pieces of evidence favor the view that elevation of the levels of Aβ42 leads to aggregation of amyloid and then to neuronal toxicity. This is currently the most often cited hypothesis for the genesis of the disease. It appears that the diffuse deposition of Aβ42 precedes the formation of better-defined neurofibrils and plaques.


Neurology_Adams

Neurology_Adams. The fact that the gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer disease and to the duplicated chromosome in Down syndrome, in which Alzheimer changes almost inevitably occur with aging (see further on), suggests that the overproduction of amyloid and all its Aβ residues are causative factors in the disease. Furthermore, the ratio of Aβ42 to Aβ40 is increased in Down syndrome. Another suggestive connection has been the finding that there are genetic defects in the genes encoding APP and in a pair of endosomal proteins termed presenilin 1 and 2 in some familial forms of Alzheimer disease. The presenilins are catalytic components of γ secretase, the enzyme that produces the Aβ42 fragment. Mutations of presenilin 1 and 2 also increase the relative levels of Aβ42. It should be noted that mutations of the APP and presenilin genes explain only a very small proportion of Alzheimer cases (Terry). Transgenic mice that express human


Neurology_Adams

Neurology_Adams. the relative levels of Aβ42. It should be noted that mutations of the APP and presenilin genes explain only a very small proportion of Alzheimer cases (Terry). Transgenic mice that express human Alzheimer disease-associated mutations in APP or presenilin genes develop plaques with Aβ42 but not neurofibrillary tangles. Many of the relationships and mechanisms depicted in Fig. 38-2 are derived from the understanding of genetic forms of Alzheimer disease; the extent to which they will be implicated in the native disease is unknown. However, some form of disruption in these mechanisms is likely to be involved.


Neurology_Adams

Neurology_Adams. There is still uncertainty regarding a direct relationship of amyloid deposition to the loss of neurons and brain atrophy in Alzheimer disease. Alternatively, soluble oligomers of Aβ amyloid may be the toxic agents, whereas the emphasis until now has been on the effects of visible assemblies of insoluble amyloid fibrils. Similarly, TDP-43, the product of inadequate functioning of the progranulin gene, is also deposited in neurons and may play a substantial role in the severity of expression of Alzheimer disease; this protein has been implicated in the pathogenesis of frontotemporal dementia and motor neuron disease, both discussed later in the chapter. Others have questioned the amyloid hypothesis and pointed to the imprecise relationship between amyloid deposition and neuronal loss, even suggesting that aggregated amyloid is in some way a protective mechanism of cells. It seems most likely that amyloid alone is not solely responsible for Alzheimer disease, particularly in cases of


Neurology_Adams

Neurology_Adams. suggesting that aggregated amyloid is in some way a protective mechanism of cells. It seems most likely that amyloid alone is not solely responsible for Alzheimer disease, particularly in cases of late-life onset. Amyloid may accelerate degeneration of neurons and once dementia is established, there may be little additional accumulation of amyloid.


Neurology_Adams

Neurology_Adams. The importance of neurofibrillary tangles has also been a matter of intense investigation, and the manner in which amyloid deposition relates to tangle formation is unclear. Unexplained also is prominent senile plaque formation in some cases and neurofibrillary tangles in others. One prevalent view is that the tangles are a secondary phenomenon. However, PET studies, such as the one by Wang and colleagues, indicate that tau deposition in the inferior temporal and parietal cortices, more clearly than amyloid, differentiate normal older individuals from those with mild cognitive impairment or Alzheimer disease and that tau is more closely aligned with temporal lobe cortical atrophy. This accords with neuropathology studies that show diffuse amyloid deposition throughout the cortex and more focal tau deposition that corresponds to cognitive ability in these states.


Neurology_Adams

Neurology_Adams. In their review, Hardy and Selkoe, authoritative investigators in this field, pointed out that “Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis.”


Neurology_Adams

Neurology_Adams. In recent years, some of the subcellular mechanisms that are deranged by the presence of intracellular or extracellular amyloid have been elucidated. The finding of a reduced number and enlargement of synapses in affected cortex early in the disease by DeKosky and Scheff and others could be interpreted as either the first sign of neuronal death or the result of the neuronal loss. Amyloid deposition would then be a later, secondary phenomenon. One hypothesis is that Alzheimer disease is a disorder of synaptic failure, as summarized by Querfurth and LaFerla. They summarize some of the subcellular derangements that may connect amyloid or tau deposition to neuronal cell loss; these include abnormal calcium regulation, inflammation, insulin signaling, cholesterol metabolism and aberrant cell-cycle reentry. These are complex and uncertain connections but they are among the most promising findings in this field of research.


Neurology_Adams

Neurology_Adams. It was long ago established that Alzheimer disease, contrary to views prevalent at that time, is not caused by any of the usual types of arteriosclerosis. On the other hand, several studies have indicated that the presence of cerebral infarctions, small or large, and of nondescript ischemic white matter disease accelerates the deposition of amyloid and the development of neurofibrillary tangles in the brains of Alzheimer patients (see further on); the mechanism of these interactions is not understood. Not surprisingly, cerebrovascular disease also exaggerates the rate of progression and degree of dementia. How this relates to the entity of arteriosclerotic, multiinfarct, or vascular dementia is not entirely clear. Without doubt, as discussed in Chap. 33, multiple cerebral strokes cause increasing deficits that cumulatively qualify as a dementia. At least some of the focal lesions that contribute to the cognitive syndrome can be identified clinically and there is a stepwise decline in


Neurology_Adams

Neurology_Adams. deficits that cumulatively qualify as a dementia. At least some of the focal lesions that contribute to the cognitive syndrome can be identified clinically and there is a stepwise decline in function that corresponds to strokes. Admittedly, this type of vascular dementia may be more difficult to recognize when a number of the infarcts are of the relatively silent lacunar type or affect cerebral white matter diffusely; the mental capacities of such patients may then appear to fail in a gradual and continuous fashion, similarly to Alzheimer disease. Usually, a pseudobulbar state or deterioration in gait eventually accompanies the dementia of vascular disease. The subcortical white matter change of Binswanger disease causes similar diagnostic problems. We are inclined toward the view expressed in Chap. 20 and summarized in the commentary by Jagust that there is an undefined, and perhaps synergistic, interaction between strokes and progressive mental decline in patients with Alzheimer


Neurology_Adams

Neurology_Adams. in Chap. 20 and summarized in the commentary by Jagust that there is an undefined, and perhaps synergistic, interaction between strokes and progressive mental decline in patients with Alzheimer disease. Most often, in our experience, it is the degenerative condition of Alzheimer that explains the dementia. A similar relationship between Alzheimer disease and previous head injuries is tentative but has led to speculation that several types of brain injuries are conducive to the development of neurofibrillary tangles and amyloid deposition, as if they were part of a reparative response.


Neurology_Adams

Neurology_Adams. No relationship to premorbid personality traits earlier in life has been established, but an intriguing finding from what has become known as the “nun study” and several similar studies suggests that poorer linguistic capability early in life corresponded to the development of Alzheimer disease with aging (Snowden et al, 1996). In this study, the autobiographies of 93 nuns, written in their twenties, were rated for linguistic and ideational complexity. Of 14 sisters who died in late life, deterioration of cognitive function and neuropathologically proven Alzheimer disease occurred in 7 who had a low “idea density” in their writings and in none of 7 whose writings were cognitively more complex. Obviously this type of correlation is subject to several interpretations, but the general notion of “cognitive reserve” having either a protective property or simply hiding mental decline, has emerged from numerous other studies. Also, there has been a general perception, confirmed by a few


Neurology_Adams

Neurology_Adams. of “cognitive reserve” having either a protective property or simply hiding mental decline, has emerged from numerous other studies. Also, there has been a general perception, confirmed by a few studies such as the one by Verghese and colleagues, that an active mental life may reduce the severity of mental decline with aging, but firm conclusions about causation cannot be made from the available information.


Neurology_Adams

Neurology_Adams. Neurotransmitter abnormalities Considerable interest was created in the late 1970s by the finding of a marked reduction in choline acetyltransferase (ChAT) and acetylcholine in the hippocampus and neocortex of patients with Alzheimer disease. This loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert), from which the major portion of neocortical cholinergic terminals originate (Whitehouse et al, 1981). However, a 50 percent reduction in ChAT activity has been found in regions such as the caudate nucleus, which shows neither plaques nor tangles. The specificity of the nucleus basalis cholinergic changes has been questioned for other reasons as well. For one, Alzheimer brain also shows a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of amino acid transmitters, particularly of


Neurology_Adams

Neurology_Adams. a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of amino acid transmitters, particularly of glutamate, is also reduced in cortical and subcortical areas (Sasaki et al) and the concentration of several neuropeptide transmitters—notably substance P, somatostatin, and cholecystokinin are likewise low—but it has not been determined whether any of these biochemical abnormalities, including the cholinergic ones, are primary or secondary to heterogeneous neuronal loss. Nevertheless, the administration of cholinomimetics—either acetylcholine precursors (e.g., choline or lecithin), degradation inhibitors (e.g., physostigmine), or muscarinic agonists that act directly on postsynaptic receptors—have had a mild and unsustained therapeutic effect (see further under “Treatment”).


Neurology_Adams

Neurology_Adams. The role of aluminum in the genesis of neurofibrillary tangles, as was once proposed, has never been validated. It has been suggested that the use of estrogen by postmenopausal women or of antiinflammatory agents in men or women delayed the onset of the disease or reduced its occurrence, but neither of these have been corroborated by other studies.


Neurology_Adams

Neurology_Adams. Genetic aspects of Alzheimer disease (Table 38-1) Of some importance has been the aforementioned series of discoveries in patients with inherited forms of Alzheimer disease, of defective genes that code for errant APPs localized to chromosome 21 near the β-amyloid gene (St. George-Hyslop et al). As mentioned, this also provided an explanation for the Alzheimer changes that characterize the brains of practically all patients with the trisomy 21 defect (Down syndrome) who survive beyond their 20th year; they overproduce amyloid as a result of the triplication of the gene. But gene defects on chromosome 21 are responsible for only a small proportion of familial cases and a minuscule percentage of disease overall. Other kindreds with familial Alzheimer disease have been linked to rare dominant mutations of the presenilin genes on chromosome 14 (presenilin 1; Sherrington et al), accounting in some series for up to 50 percent of familial cases, and on chromosome 1 (presenilin 2), which may


Neurology_Adams

Neurology_Adams. mutations of the presenilin genes on chromosome 14 (presenilin 1; Sherrington et al), accounting in some series for up to 50 percent of familial cases, and on chromosome 1 (presenilin 2), which may account for many of the remaining ones (Levy-Lahad et al). These are summarized in Table 38-1. The age of onset of the disease in these familial forms, as in the Down cases, is earlier than that in sporadic forms. These cohorts of patients have provided great insight into long duration between the appearance of amyloid in the brain, approximately a decade, and the onset of clinical disease, and they suggest the potential use of imaging of chemical biomarkers for the prodromal phase of the disease (The Dominantly Inherited Alzheimer Network; DIAN, see Bateman et al).


Neurology_Adams

Neurology_Adams. It has been clear that an excess or aberrant amyloid alone is an incomplete explanation for the disease. Certain sequence variants in normal genes confer an increased risk of the disease. The one first discovered was Apo E, a regulator of lipid metabolism that has an affinity for Aβ in Alzheimer plaques, has been found to modify the risk of acquiring Alzheimer disease. Of the several isoforms of Apo E, the presence of E4 (and its corresponding allele e4 on chromosome 19) is associated with a tripling of the risk of developing sporadic Alzheimer disease (Roses; Strittmatter et al; Polvikoski et al). This is the same allele that contributes to an elevated low-density lipoprotein fraction in the serum. Possession of two e4 alleles virtually assures the development of disease in those who survive to their eighties. The e4 allele also modifies the age of onset of some of the familial forms of the disease. In contrast, the e2 allele is underrepresented among Alzheimer patients. For these


Neurology_Adams

Neurology_Adams. to their eighties. The e4 allele also modifies the age of onset of some of the familial forms of the disease. In contrast, the e2 allele is underrepresented among Alzheimer patients. For these reasons it has been proposed that Apo E, by interacting with APP or tau protein in some way, modifies the formation of plaques. Indeed, possession of the e4 allele correlates with increased deposition of Aβ in the brain (McNamara). As pointed out by Hardy, Apo E appears to act at a point in the pathogenesis that is after the various genetic mutations have influenced the cellular pathology that ostensibly causes Alzheimer disease. However, these relationships do not invariably connect an allele to the disease in a particular individual. In other words, the e4 allele does not act as a mendelian trait but as a susceptibility (risk) factor. It follows that many, if not most, individuals who develop Alzheimer disease do not have the risk allele. Moreover, many individuals with the e4 allele live into


Neurology_Adams

Neurology_Adams. as a susceptibility (risk) factor. It follows that many, if not most, individuals who develop Alzheimer disease do not have the risk allele. Moreover, many individuals with the e4 allele live into their seventies and eighties without developing Alzheimer disease. All that can be stated with certainty is that, on average, the presence of the e4 allele accelerates the appearance of Alzheimer disease by about 5 years.


Neurology_Adams

Neurology_Adams. Another polymorphism, located in TREM2, is quite rare in comparison to the aforementioned Apo E variants but confers an equivalent risk of Alzheimer disease that has been shown in several populations in (Guerreiro et al and Jonsson et al). In sporadic Alzheimer disease, the TREM2 polymorphism that is implicated in Alzheimer disease putatively causes inadequate phagocytic clearance of amyloid. Another rare modifying gene has been found in familial cases at the UBQLN1 (ubiquilin 1) site, coding for a protein that interacts with PS1 and PS2 and participates in proteasomal degradation.


Neurology_Adams

Neurology_Adams. Studies with CT and MRI are useful, but not definitive ancillary tests (Fig. 38-3). In patients with advanced Alzheimer disease, the lateral and third ventricles are enlarged to about twice the normal size and the cerebral sulci are proportionately widened, both as a result of cerebral atrophy. Coronal MRI of the medial temporal lobes shows a disproportionate atrophy of the hippocampi and a corresponding enlargement of the temporal horns of the lateral ventricles. Early in the disease, however, the changes do not exceed those found in many mentally intact old persons. For this reason, one cannot rely solely on imaging procedures for diagnosis and CT and MRI are most valuable in excluding alternative causes of dementia such as brain tumor, subdural hematoma, cerebral infarction, and hydrocephalus. The EEG undergoes mild diffuse slowing, but only late in the course of the illness; it is useful again, in the exclusion of alternative causes of mental decline that manifest themselves in


Neurology_Adams

Neurology_Adams. The EEG undergoes mild diffuse slowing, but only late in the course of the illness; it is useful again, in the exclusion of alternative causes of mental decline that manifest themselves in seizure activity or changes typical of metabolic encephalopathy. The CSF is also normal, although occasionally the total protein concentration is slightly elevated. Using the constellation of clinical data, cerebral imaging in the context of the age of the patient and time course of the disease, the diagnosis of dementia of Alzheimer type is made correctly in 85 to 90 percent of cases.


Neurology_Adams

Neurology_Adams. Of some value have been studies of cerebral blood flow (single-photon emission computed tomography [SPECT]) and metabolism (positron emission tomography [PET]), which early in the illness often, but not always, show diminished activity in the parietal association regions of the cortex and in the medial temporal lobes. In most cases, when such changes are evident, the diagnosis was already obvious on clinical grounds. Newer PET ligand agents that bind to amyloid, such as “Pittsburgh compound” and tau-ligands are more sensitive in identifying and observing the course of Alzheimer disease. Their main utility may be in detecting changes before brain atrophy is evident and in identifying patients who have the earliest changes of Alzheimer disease, whose disease course may be amenable to alteration by medications. They are currently used as biomarkers in therapeutic trials of various agents that reduce or remove brain amyloid.


Neurology_Adams

Neurology_Adams. Neuropsychologic tests in the typical case show disproportionate deterioration in memory and verbal access skills. Testing is particularly useful when there is a serial decline in ability. Certain aspects of attention and executive function in Alzheimer disease that also show changes in Alzheimer disease were reviewed by Perry and Hodges. The use of these examinations is described in Chap. 20. Beyond PET and related imaging studies there are no established biologic markers of Alzheimer disease with the possible exception of the ratio of tau to Aβ 42 (tau-amyloid ratio) in the cerebrospinal fluid (the ratio is low in Alzheimer disease). This test is used in some clinics and in clinical trials (Maddalena et al). Schoonenboom and colleagues have shown that the incorporation of CSF phosphorylated tau (p-tau) with the typical CSF amyloid/tau ratio may provide additional specificity in distinguishing Alzheimer from other dementing diseases.


Neurology_Adams

Neurology_Adams. Differential Diagnosis of Alzheimer Disease (See Also Table 20-3) Formerly, when virtually all forms of dementia were untreatable, there was little advantage to either the patient or the family in ascertaining the cause of the cerebral disease. There are now adequate treatments for a number of diseases and conditions that cause cognitive decline, putting a premium on proper diagnosis.


Neurology_Adams

Neurology_Adams. The currently potentially treatable forms of dementia are those caused by normal-pressure hydrocephalus; chronic subdural hematoma; the dementia of HIV paraneoplastic and related autoimmune encephalitis; nutritional deficiencies (thiamine—Wernicke-Korsakoff syndrome, Marchiafava-Bignami disease, pellagra, vitamin B12 deficiency); chronic intoxication (e.g., alcohol, sedatives); multiple cerebral infarctions; certain endocrine and metabolic disorders (myxedema, Hashimoto encephalopathy), neurosyphilis and other chronic meningitides, Cushing disease, chronic hepatic encephalopathy; frontal and temporal lobe tumors; vascular dementia, cerebral vasculitis; sarcoidosis; progressive multifocal leukoencephalopathy (PML), Whipple disease; multiple sclerosis; and sometimes neglected, the pseudodementia of depression. Exclusion of most of these diseases is readily accomplished by careful history, sequential clinical evaluations, and testing of blood and CSF, CT, MRI, and neuropsychologic


Neurology_Adams

Neurology_Adams. of depression. Exclusion of most of these diseases is readily accomplished by careful history, sequential clinical evaluations, and testing of blood and CSF, CT, MRI, and neuropsychologic testing. We have incorporated the results of metabolic brain imaging (both FDG-PET and amyloid-ligand imaging) as well as CSF amyloid-tau ratio into practice when feasible.


Neurology_Adams

Neurology_Adams. In exceptional situations, brain biopsy may be justified in the diagnosis of dementia, almost limited to rapidly progressive cases. A perspective, albeit from a sample in the past that cannot be generalized to practice, has been given by Warren and colleagues of 90 consecutive brain biopsies performed between 1989 and 2003 for the evaluation of dementia. More than half provided a diagnosis, mostly Alzheimer, Creutzfeldt-Jakob disease, and inflammatory disorders. However, reasonable assurances must be given to the neurosurgeon that prion disease is unlikely.


Neurology_Adams

Neurology_Adams. A special problem in differential diagnosis is the distinction between a late-life depression and a dementia, especially when some degree of both is present. Observation over several weeks or more, and the patient’s demeanor, makes the distinction clearer. Multiinfarct dementia may be difficult to separate from Alzheimer dementia, as discussed further on. The dementia of normal-pressure hydrocephalus may also be confused with Alzheimer dementia (see Chap. 29). The problem of distinguishing Alzheimer disease from a more “benign” form of memory decline associated with aging comes up frequently in practice, as discussed further on. These treatable conditions are discussed in Chaps. 20, 29, and 33, and the important topic of depression is addressed in Chap. 48.


Neurology_Adams

Neurology_Adams. Often we have been confident on clinical grounds that a patient had Alzheimer disease, only to have revealed at autopsy that progressive supranuclear palsy, Lewy-body disease, Pick disease, another non-Alzheimer degeneration of the frontal lobes, or cortical-basal-ganglionic degeneration was the cause. All are discussed later in this chapter. There is no evidence that any of the formerly proposed therapies for Alzheimer disease—cerebral vasodilators, stimulants, l-dopa, massive doses of vitamins B, C, and E, gingko biloba, hyperbaric oxygen, intravenous immunoglobulin, and many others—have any salutary effect. Trials of oral physostigmine, choline, and lecithin have yielded mostly negative or uninterpretable results.


Neurology_Adams

Neurology_Adams. The effect of the currently used cholinergic precursors and agonists and acetylcholinesterase inhibitors, such as donepezil, is modest. With regard to the latter group of drugs, several large trials have demonstrated a slight prolongation of the patient’s ability to sustain an independent life, but such evidence generally requires that the medications be taken for 6 to 12 months. For example, a meta-analysis of the drugs collectively demonstrated a mean improvement of 2 to 3 points on the 70-point Alzheimer Disease Assessment Scale and a slight delay in progression. Despite some trials that have failed to demonstrate benefit (c.f., AD 2000 Collaborative Group), the balance of evidence probably favors the use of these medications in practice, but only in mildly or moderately affected patients.


Neurology_Adams

Neurology_Adams. Side effects of the aforementioned class of drugs may include nausea and less often, vomiting. The families of our patients report from time to time that the medication caused insomnia or increased confusion. It is worth mentioning that when the acetylcholine receptor antagonist succinylcholine is used prior to general anesthesia, its effects may be prolonged in patients taking the above drugs. The use of trazodone, haloperidol, thioridazine, risperidone, and related drugs may suppress some of the aberrant behavior and hallucinations when these are problems, making life more comfortable for both patient and family, but several trials suggest that their general application causes more problems than it solves and they must often be discontinued in response to adverse effects. The randomized trial conducted by Schneider and coworkers found that olanzapine, quetiapine, and risperidone for the treatment of psychosis, aggression, or agitation with Alzheimer disease were approximately as


Neurology_Adams

Neurology_Adams. trial conducted by Schneider and coworkers found that olanzapine, quetiapine, and risperidone for the treatment of psychosis, aggression, or agitation with Alzheimer disease were approximately as good as placebo in relieving these symptoms, but largely because the drugs were not tolerated. Olanzapine was slightly preferable in those who continued taking the medication. The clinician is left with little recourse but to use this class of medications or haloperidol to control unmanageable behavior. Small doses of diazepines, such as lorazepam, are useful when sleep is severely disturbed, but they often increase confusion as well.


Neurology_Adams

Neurology_Adams. The N-methyl-d-aspartate (NMDA) glutaminergic antagonists, specifically memantine (20 mg daily), have also been tried. In a study of memantine by Reisberg and colleagues of 252 patients (187 of whom completed the trial), there were better results on a few scales that reflected functional behavior compared to the use of placebo, but there was no change in 3 main measures of cognitive performance. Because the side effects were ostensibly minor, this drug has been approved for use in late-stage Alzheimer disease and in conjunction with cholinergic drugs. Nevertheless, hallucinations or agitation may occur and require discontinuation. The combination of memantine and donepezil in moderately to severely affected patients offered no benefit over either drug alone (Howard et al). The effects of these drugs in later stages of the disease are, in any case, minimal.


Neurology_Adams

Neurology_Adams. A series of trials using a small molecule inhibitors of the enzyme γ-secretase (Doody et al, 2013), or of an inhibitor of β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1, see Egan et al), or of a monoclonal antibody directed at soluble forms of amyloid (solanezumab; see Doody et al, 2014) have failed to demonstrate clear benefit in even early stages of Alzheimer disease. The presumption is being explored that amyloid is deposited well before the onset of clinical symptoms and such agents might be useful if started in the presymptomatic stages of disease but there have also been several failed trials at this stage of disease. This is one goal of studies in dominantly inherited forms of the disease, in which presymptomatic patients can be treated.


Neurology_Adams

Neurology_Adams. A series of animal experiments that demonstrated the possibility of removal of plaques by immunization against amyloid has led to human studies with a similar vaccination. One trial was stopped because of the occurrence of an immune encephalitis in a small number of patients, but in autopsy material there were indications that this approach may have had the desired effect of reducing amyloid deposition (Orgogozo et al). Revised vaccines are being formulated for further testing of this approach.


Neurology_Adams

Neurology_Adams. Given the state of therapeutics for Alzheimer disease, always important is the general management of the demented patient, which should proceed along the lines outlined in Chap. 20, keeping in mind that the physician’s counsel is often the family’s main resource for important medical and social decisions. As pointed out in a monograph that summarized the deliberations of a commission on the state of dementia care in Europe (Winblad et al), the care of affected patients “does not fit easily into typical health care delivery systems.” It is clear that community, family, and medical resources are difficult to coordinate and that end of life and competency decisions are fragmented. Considering the magnitude of the problem, this is a serious societal fault.


Neurology_Adams

Neurology_Adams. As indicated earlier, the histologic changes of Alzheimer disease have a number of interesting associations. Amyloid plaques and tangle deposition are far more common in the brains of patients with Parkinson disease (20 to 30 percent) than in the brains of age-matched controls (Hakim and Mathieson). These findings partly explain the high incidence of dementia in patients with Parkinson disease (see further on). As also mentioned, with the advance of Alzheimer disease, extrapyramidal features may emerge. In such cases, Burns and colleagues found changes in the substantia nigra including accumulation of synuclein and tau representative of Lewy bodies. Another association between the 2 diseases is apparent in the Guamanian Parkinson–dementia complex, which is also discussed below. In this entity, the symptoms of dementia and parkinsonism are related to neurofibrillary changes in the cerebral cortex and substantia nigra, respectively; senile plaques and Lewy bodies are unusual findings.


Neurology_Adams

Neurology_Adams. the symptoms of dementia and parkinsonism are related to neurofibrillary changes in the cerebral cortex and substantia nigra, respectively; senile plaques and Lewy bodies are unusual findings. What can be deduced from the crossover syndromes is that multiple degenerative changes can occur in these diseases and give rise to heterogeneity in clinical presentation.


Neurology_Adams

Neurology_Adams. The finding of neurofibrillary tangles (and to a lesser extent of plaques) in boxers (“punch-drunk” syndrome, or dementia pugilistica) and in the similar condition, chronic traumatic encephalopathy, is another interesting ramification of the Alzheimer disease process in that trauma appears to be able to elicit one of the core features of the disease as discussed in Chap. 34. Some cases of primary progressive aphasia (see further on) have Alzheimer change and amyloid plaque deposition as the primary pathologic change. There are other unusual and meaningful associations, such as dementia with motor neuron disease or the cases of familial dementia with spastic paraplegia reported by Worster-Drought and by van Bogaert and their associates (see later in this chapter). Here, neurofibrillary change is the most prominent feature whereas amyloid plaques are negligible in number or absent.


Neurology_Adams

Neurology_Adams. Another provocative connection is the already mentioned interrelationship between cerebrovascular disease and Alzheimer disease. This is a complex area that at one time, considered the 2 processes to be intimately related and later, was rejected, only to now be resurrected with clearer focus, as discussed Chap 33. Lobar Atrophies (Frontotemporal Degeneration [FTD], Primary Progressive Aphasia, Posterior Cortical Atrophy)


Neurology_Adams

Neurology_Adams. This broad category of disease has evolved and the nosology is confusing because type of selective atrophy of a cerebral lobe may be caused by several different histopathologic changes. The notion of lobar atrophy was introduced in 1892 when Arnold Pick of Prague described a special form of cerebral degeneration in which the atrophy was circumscribed (most often in the frontal or temporal lobes), with involvement of both gray and white matter; hence the term he applied was lobar rather than cortical sclerosis. In 1911, Alzheimer presented the first careful study of the microscopic changes, followed by even more complete analyses of the pathologic changes by the prominent neuropathologists of the age. The pathologic change associated may be any one of several types: Pick inclusion bodies, neurofibrillary tangles, other inclusions, or with no characteristic changes except for neuronal loss. Contrariwise, gliosis and mild spongiform changes in the superficial layers of cortex, and even


Neurology_Adams

Neurology_Adams. neurofibrillary tangles, other inclusions, or with no characteristic changes except for neuronal loss. Contrariwise, gliosis and mild spongiform changes in the superficial layers of cortex, and even typical plaque and tangle pathology, have all been associated with syndromes of gross atrophy of the frontal or temporal lobes. What has emerged since the work of Pick and of Alzheimer is that the lobar atrophies have diverse clinical and pathologic profiles.


Neurology_Adams

Neurology_Adams. In contrast to Alzheimer disease, in which the atrophy is relatively diffuse, the pathologic change in lobar atrophy is circumscribed and often asymmetrical. The parietal lobes are involved less frequently than the frontal and temporal lobes. The affected gyri become paper thin, resembling, in the advanced stages, the kernel of a dried walnut. The cut surface reveals not only a marked narrowing of the cortical ribbon but a grayish appearance and reduced volume of the underlying white matter. The corpus callosum and anterior commissure share in the atrophy but almost certainly as secondary phenomena. The overlying pia-arachnoid is often thickened, and the ventricles are enlarged. The preand postcentral, superior temporal, and occipital convolutions are relatively unaffected and stand out in striking contrast to the wasted parts.


Neurology_Adams

Neurology_Adams. The more common frontotemporal degenerations (FTDs) (to which Pick’s name was originally attached) may display any one of several pathologic changes and reflect different genetic causes but deposition of tau is probably the underlying pathology in most cases. For example, the behavioral or the aphasic variants of FTD, which are described below, may be the result of the deposition most often of tau, but also of progranulin, amyloid, or synuclein. It is not clear to us if the term “Pick disease” is worth retaining to denote a unique process aside from the unusual type that is due to deposition of argyrophilic intracytoplasmic inclusions (Pick bodies) and diffusely staining ballooned neurons (Pick cells). In other respects, it is simply one of the large group of FTDs. It is the lobar atrophy and marked changes in the underlying white matter that provide the unifying elements of this group of diseases.


Neurology_Adams

Neurology_Adams. The descriptive terms frontotemporal lobar atrophy and frontotemporal dementia are used by neurologists and neuropathologists to refer to a clinical syndrome that is associated with degeneration of the frontal and temporal lobes. Some of the clinical aspects of frontotemporal dementia were discussed in Chap. 20, but broadly speaking, there are 2 main types: a behavioral variant and a language (aphasic) variant, the latter being divided into semantic dementia, progressive nonfluent aphasia, and a logopenic variant, all described below.


Neurology_Adams

Neurology_Adams. In some writings on this subject, the term frontotemporal dementia has come to be used in a highly restricted sense, being assigned to cases that show only tau-staining material in neurons. Many of the cases are sporadic, but the inherited varieties of the behavioral variant of the disorder noted below may explain up to 40 percent and are linked to any of several genes, mainly related to tau (e.g., microtubule associated protein [MAPT], progranulin [GRN] both on chromosome 17) supports its distinction as a separate entity; it is in these cases that the intraneural deposition of tau is most striking, in both the frontotemporal cortex and the substantia nigra. These mutations alter the proportions of different isoforms of this protein and lead both to tau accumulation and its hyperphosphorylation. Indeed, many cases of frontotemporal dementia are associated with tau gene mutations. However, abnormal aggregates of tau have been identified in practically all neurodegenerative atrophies


Neurology_Adams

Neurology_Adams. Indeed, many cases of frontotemporal dementia are associated with tau gene mutations. However, abnormal aggregates of tau have been identified in practically all neurodegenerative atrophies and, of course, form the main constituent of the paired helical filaments (neurofibrillary tangles) of Alzheimer disease, and in progressive supranuclear palsy where they are abundant, although of slightly different structure. From the observations of workers such as Neary and of Neary and colleagues, pure tau-reactive cases outnumber Pick disease when the latter is strictly defined by the cortical white matter degeneration and Pick inclusions. Finally, the aphasic variants of FTD are as, or more often, associated with Alzheimer changes, making the category difficult to navigate.


Neurology_Adams

Neurology_Adams. Behavioral variant FTD Patients under consideration with behavioral changes present with personality and related abnormalities that include apathy, disinhibition, perseveration, poor judgment and limited ability for abstraction, loss of empathy, bizarre affect, eating disorders, and a general disengagement. Insight is almost always impaired and some subjects become euphoric or display repetitive compulsive behaviors. An initial diagnosis of depression has been common. Other psychiatric symptoms such as sociopathic and disinhibited behavior with aspects of hyperorality and hyperphagia may predominate late in the illness. Utilization behavior (the compulsive use of implements and tools put before the patient) is also displayed in advanced cases.


Neurology_Adams

Neurology_Adams. CT, MRI, and functional imaging demonstrate a disproportionate atrophy and hypofunction in the frontal lobes, usually asymmetric. A proportion of patients with this type of frontotemporal dementia have parkinsonian features. A form of motor neuron disease is also linked to frontotemporal dementia in a small number of cases. This is particularly the case in the Guamanian (now called western Pacific) variety and in the heredofamilial frontotemporal atrophy linked to a mutation in TAU on chromosome 17. Nonetheless, a frontotemporal dementia identical to that of the tau-reactive cases has been observed in others without any tau or synuclein staining of neurons.


Neurology_Adams

Neurology_Adams. Nonetheless, a frontotemporal dementia identical to that of the tau-reactive cases has been observed in others without any tau or synuclein staining of neurons. Primary progressive aphasias (PPA) Focal disturbances, particularly aphasia and apraxia, occur early and prominently in certain patients with lobar degenerations, indicating a lesion in the left frontal or temporal lobes. Viewed from another perspective, a prominent language disorder has been described in almost two-thirds of all patients with temporal lobe atrophy.


Neurology_Adams

Neurology_Adams. Several types of this disturbance have been delineated. In the first, progressive nonfluent aphasia, the patient initially speaks less and has word-finding difficulty (anomia), but language structure is intact (Mesulam, 1982); later, he may forget and misuse words and soon fails to understand much of what is heard or read. Sentences are short and telegraphed. Later, dysarthria and apraxia become apparent and finally, the patient is virtually mute, seemingly without impulse to speak, and with an inability to form words (Snowden et al, 1992).


Neurology_Adams

Neurology_Adams. A second type, semantic dementia (aphasia), is characterized by early difficulty naming items, people, and words, followed by verbal perseveration, but fluency is retained. There is considerable difficulty in generating lists of words of a given category, such as animals. These individuals are quite aware that they are having trouble finding words. Eventually the patient loses not just the use of names of people and objects, but also their meaning, or the conceptual knowledge of the word. Some may develop severe prosopagnosia, especially if the atrophy is predominantly right sided. Memory for day-to-day events is preserved. A third type has been proposed, logopenic aphasia, that shares most aspects of nonfluent aphasia but in which the meaning of words is retained.


Neurology_Adams

Neurology_Adams. A third type has been proposed, logopenic aphasia, that shares most aspects of nonfluent aphasia but in which the meaning of words is retained. According to Mesulam (2003), who has studied the condition extensively, 60 percent of these cases show no characteristic pathologic change, 20 percent have Pick bodies, and a similar proportion show the typical changes of Alzheimer disease in the affected cortical region. A clear familial tendency has not been found. Chapter 22 can be consulted for details of the aphasic disorders.


Neurology_Adams

Neurology_Adams. Posterior cortical atrophy This regional variant of lobar degeneration has been slightly less frequent than primary progressive aphasia in our practices. The fundamental feature is the progressive loss of the ability to interpret and use visual information. The result is progressive and ultimately severe visuospatial difficulty with a relative preservation of memory. Prosopagnosia, achromatopsia, and dyslexia emerge, or, there may be difficulty with depth perception, reaching for objects and an inordinate sensitivity to bright light. Patients under our care have initially had a vague sense of visual disorientation followed over months by difficulty in seeing or recognizing objects in front of them. Many have alexia with agraphia while others have acalculia or the other elements of the Gerstmann syndrome. Several eventually become cortically blind. The syndrome is essentially that of an apperceptive visual disturbance that includes fragments of the Balint and the Gerstmann syndromes.


Neurology_Adams

Neurology_Adams. syndrome. Several eventually become cortically blind. The syndrome is essentially that of an apperceptive visual disturbance that includes fragments of the Balint and the Gerstmann syndromes. The average age of onset is about 60 years. The most common pathologic change in most reports has been characteristic of Alzheimer disease.


Neurology_Adams

Neurology_Adams. Lewy Body Dementia (Diffuse Lewy Body Disease, DLB)


Neurology_Adams

Neurology_Adams. Next to Alzheimer disease, diffuse Lewy body disease, or Lewy body dementia, has been the most frequent pathologic diagnosis established in many series of globally demented patients. Reports of this condition have increased steadily since the original communication by Okazaki and colleagues in 1961 (see review by Kosaka). The disease is defined by the diffuse involvement of cortical neurons with Lewy body inclusions and by an absence or inconspicuous number of neurofibrillary tangles and amyloid plaques. To some extent, increased recognition of this disorder is a result of improved histologic techniques, particularly the ability to detect ubiquitin and synuclein, main components of the Lewy body, by immunostaining. With this improved detection, has come a better definition of the clinical syndrome and its distinctions from Alzheimer and other dementias. Because the Lewy bodies in cortical neurons are not surrounded by a distinct halo, as they are in the substantia nigra in cases of


Neurology_Adams

Neurology_Adams. syndrome and its distinctions from Alzheimer and other dementias. Because the Lewy bodies in cortical neurons are not surrounded by a distinct halo, as they are in the substantia nigra in cases of Parkinson disease (see further on for discussion and photomicrograph of a typical Lewy body) they were not readily appreciated. Aggreagated α-synuclein is the main component of the Lewy body an observation that will prove important in understanding both Parkinson disease and Lewy-body dementia.


Neurology_Adams

Neurology_Adams. The disease in its typical form is marked by parkinsonian features, dementia, and a tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder (described below and in Chap. 18). Diagnostic criteria have been offered by a working group, requiring 2 of 3 of the following: a parkinsonian syndrome (usually symmetric), fluctuations in behavior and cognition, and recurrent hallucinations (McKeith et al). The latest recursion of this group’s criteria emphasizes the presence of the REM sleep behavior disorder and severe neuroleptic sensitivity.


Neurology_Adams

Neurology_Adams. Over the years there has been an appreciation of the dimensions of the disease. In an analysis of 34 cases of diffuse Lewy body disease, acquired when the syndrome was being defined, Burkhardt and colleagues found that the most characteristic syndrome was one of progressive dementia in an elderly patient with the additional late onset of parkinsonism in many cases. In Lennox’s summary of 75 cases, parkinsonism, particularly with limb and axial rigidity, was a prominent feature in 90 percent once the illness was fully developed, and almost half had tremor of the parkinsonian type (this is somewhat different from other series). Byrne and associates, as have many others, pointed out that episodic confusion, hallucinations, and paranoid delusions were features of Lewy body dementia; such psychotic aspects are generally uncharacteristic of Alzheimer and lobar dementias and only then, in advanced stages. In Lennox’s review, one-third of patients had these swings in behavior, but as the


Neurology_Adams

Neurology_Adams. psychotic aspects are generally uncharacteristic of Alzheimer and lobar dementias and only then, in advanced stages. In Lennox’s review, one-third of patients had these swings in behavior, but as the illness advanced, amnesia, dyscalculia, visuospatial disorientation, aphasia, and apraxia differed little from those of Alzheimer disease. In the cases reported by Fearnley and coworkers, there was a supranuclear gaze palsy simulating that of progressive supranuclear palsy. These overlapping clinical features make diagnosis difficult unless the specific feature of episodic hallucinations is evident. Difficulty in diagnosis also arises because the parkinsonian disorder may be either mild or prominent and may occur as an early or a late manifestation.


Neurology_Adams

Neurology_Adams. The parkinsonian features can respond favorably to l-dopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations that would be uncharacteristic of early Parkinson disease (Hely et al); in others, the response to l-dopa is inconsistent or inapparent. Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating multiple system atrophy-P (striatonigral degeneration, or Shy-Drager syndrome [see further on]). Many authors have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome.


Neurology_Adams

Neurology_Adams. In our experience with Lewy body disease, the parkinsonian symptoms have been more prominent than they are in progressive supranuclear palsy, and the most characteristic feature besides the movement disorder and a slowly advancing dementia has been a vacuous, anxious state with intermittent psychotic or delirious behavior. The burden on family and other caregivers for this disease have impressed us as being unusually high.


Neurology_Adams

Neurology_Adams. With regard to diagnostic testing, SPECT scans with radiolabeled dopamine transporter or dopamine receptor tracers show reductions in lenticular nuclei and caudate (striatal) activity, usually asymmetrically, compared to controls, as also seen with Parkinson’s disease but unlike Alzheimer disease. Increased avidity with FDG PET in these same structures is also an abnormal and characteristic finding in both Lewy body and Parkinson diseases. With radiolabeled dopamine ligands, PET in Lewy body disease shows reduced avidity in these regions. Therefore, these studies can be used to distinguish Lewy body (and


Neurology_Adams

Neurology_Adams. Parkinson’s disease) from normal individuals and those with other dementias, including Alzheimer disease but are not used to distinguish the two parkinsonian disorders from each other. There has been increased interest in detecting phosphorylated alpha-synuclein in the small (presumably autonomic) nerves in the skin and it has been found that this test can distinguish Lewy body from other dementias (Donadio et al). Whether it differentiates this from Parkinson disease is not clear.


Neurology_Adams

Neurology_Adams. Treatment This has proved to be difficult, both in managing motor symptoms as mentioned above and more so, in treating psychosis. If orthostatic hypotension or wide swings in blood pressure supervene, the picture becomes even more complicated. For the blood pressure changes, midodrine is often prescribed; we have had less success with mineralocorticoids. At least one randomized trial has described benefit from the anticholinesterase inhibitor, rivastigmine, in reducing delusions, hallucinations, and anxiety (McKeith and colleagues, 2000). Pimavanserin, a selective serotonin 5-HT2A inverse agonist used to treat psychosis in Parkinson disease, has shown some modest benefit for psychosis and hallucinations in a trial in Lewy body dementia without worsening motor symptoms (see Cummings et al). Antipsychotic drugs such as quetiapine and clozapine are also used but are limited by their risks and side effects.


Neurology_Adams

Neurology_Adams. This obscure entity has been connected with a late-life dementia in which behavioral disturbances precede memory difficulty. Whether the finding of argyrophilic grains in the medical temporal lobe, different from tau-laden neurofibrillary tangles and from the glial inclusions (putatively a defining feature of multiple system atrophy), constitutes a specific entity is not clear to the authors. The finding overlaps with the deposition of other materials that are more closely associated with dementing diseases such as phosphorylated tau and Lewy bodies. Probst and Tolnay remarked that these small argyrophilic inclusions are not found in nondemented individuals. It is unlikely that the condition can be identified in life; if it is a genuine entity, it must be rare. The interested reader may consult the review by Ferrer.


Neurology_Adams

Neurology_Adams. There have been infrequent case reports of dominantly inherited, adult-onset dementia with a fulminant evolution suggestive of encephalopathy and the special feature of seizures. The distinctive feature has been the presence at autopsy of large eosinophilic, PAS-positive intraneuronal inclusions that contain aggregates of neuroserpin, thus the initial description of “familial encephalopathy with neuronal inclusion bodies.” The serpins are a family of protease inhibitors that include neuroserpin, a protein expressed exclusively in neurons, and α1-antitrypsin. The neuronal inclusions are densest in the deep layers of the cortex and in the substantia nigra. Missense mutations in the gene encoding neuroserpin have been identified as the cause. This entity is reviewed by Lomas and Carrell.


Neurology_Adams

Neurology_Adams. This disease, distinguished by the triad of dominant inheritance, choreoathetosis, and dementia, commemorates the name of George Huntington, a medical practitioner of Pomeroy, Ohio. In 1872, his paper, read before the Meigs and Mason Academy of Medicine and published later that year in the Medical and Surgical Reporter of Philadelphia, gave a succinct and graphic account of the disease that was based on observations of patients that his father and grandfather had made in the course of their practice in East Hampton, Long Island. Reports of this disease had appeared previously (see DeJong for historical background) but they lacked the completeness of


Neurology_Adams

Neurology_Adams. Huntington’s description. In 1915, Davenport was able to show that practically all the patients with this disease in the eastern United States could be traced to about 6 individuals who had emigrated in 1630 from the tiny East Anglian village of Bures, in Suffolk, England. One remarkable family was traced for 300 years through 12 generations, in each of which the disease had expressed itself.


Neurology_Adams

Neurology_Adams. To quote Huntington, the rule has been that “When either or both of the parents have shown manifestations of the disease, one or more of the offspring invariably suffer of the disease, if they live to adult life. But if by any chance these children go through life without it, the thread is broken and the grandchildren and great grandchildren of the original shakers may rest assured that they are free from disease.” Vessie in a review of 962 patients with Huntington chorea, found only 5 who had descended from unaffected parents. Possibly, in these 5 patients, a parent had the trait, in very mild form, or parentage was in question, because spontaneous mutations are rare.


Neurology_Adams

Neurology_Adams. In university hospital centers, this is a regularly observed type of hereditary nervous system diseases and the main cause of progressive chorea at most ages. Its overall frequency is estimated at 4 to 5 per million, and 30 to 70 per million among whites of northern European ancestry. The usual age of onset is in the fourth and fifth decades, but 3 to 5 percent begin before the 15th year and some even in childhood, where it takes on special form. In approximately 30 percent, symptoms become apparent after 50 years. The progression of the disease is generally slower in older patients for reasons noted below. Once begun, the disease progresses relentlessly, until only a restricted existence is possible and a medical disease terminates life.


Neurology_Adams

Neurology_Adams. Exhaustive genealogic documentation many years ago established the cause to be an autosomal dominant gene with complete penetrance. Koller and Davenport made the observation that young patients usually inherit the disease from their fathers and older patients from their mothers. It has been observed beginning at almost the same age in identical twins.


Neurology_Adams

Neurology_Adams. The first important achievement in respect to the biologic understanding of Huntington disease was the discovery by Gusella and colleagues of a marker linked to what is now termed the huntingtin gene (also termed HTT) and localized to the short arm of chromosome 4. Subsequently, these investigators and others identified the mutation as an excessively long repeat of the trinucleotide CAG within the gene, the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs. The result of the expansion is the accumulation of abnormal protein also termed huntingtin. At the Huntington gene locus there are normally 11 to 34 (median: 19) consecutive repetitions of the CAG triplet, each coding for glutamine. Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree, or limited to the below-mentioned “senile chorea.”


Neurology_Adams

Neurology_Adams. coding for glutamine. Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree, or limited to the below-mentioned “senile chorea.” Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough. The rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so infrequent that few clinicians will encounter it (Margolis et al).


Neurology_Adams

Neurology_Adams. These discoveries have made possible the development of a genetic test for the measurement of the repeat length that confirms the diagnosis in symptomatic patients and allows screening of asymptomatic individuals. Because there is no treatment for the disease, testing raises certain ethical considerations that must be resolved before its utilization.


Neurology_Adams

Neurology_Adams. The mental disorder assumes several subtle forms long before the more obvious deterioration of cognitive functions becomes evident. In approximately half the cases, slight but annoying alterations of personality are the first to appear. Patients begin to find fault with everything, to complain constantly, and to nag other members of the family; they may be suspicious, irritable, impulsive, eccentric, untidy, or excessively religious, or they may exhibit a false sense of superiority. Poor self-control may be reflected in outbursts of temper, fits of despondency, slovenliness, alcoholism, or sexual promiscuity. Disturbances of mood, particularly depression, are common (almost half of the patients in some series) and may constitute the most prominent symptoms early in the disease. Invariably, sooner or later, the intellect begins to fail globally. The patient becomes less communicative and socially withdrawn. The emotional disturbances and changes in personality may reach such


Neurology_Adams

Neurology_Adams. Invariably, sooner or later, the intellect begins to fail globally. The patient becomes less communicative and socially withdrawn. The emotional disturbances and changes in personality may reach such proportions as to constitute a virtual psychosis with persecutory delusions or hallucinations.


Neurology_Adams

Neurology_Adams. Diminished work performance, inability to manage household responsibilities, and disturbances of sleep may prompt medical consultation. There is difficulty in maintaining attention and concentration and in assimilating new material. Mental flexibility lessens. Simultaneously, there is loss of fine manual skills (see further on). The performance parts of the Wechsler Adult Intelligence Scale show greater loss than the verbal parts. Memory is relatively spared. This gradual dilapidation of intellectual function has been characterized as a “subcortical dementia,” that is elements of aphasia, agnosia, and apraxia are observed only rarely and memory loss is not profound. Often the process is so slow, particularly in cases of late onset, that a fair degree of intellectual capacity seems to be retained for many years.


Neurology_Adams

Neurology_Adams. The abnormality of movement is subtle at first and most evident in the hands and face; often the patient is merely considered to be fidgety, restless, or “nervous.” Slowness of movement of the fingers and hands, a reduced rate of finger tapping, and difficulty in performing a sequence of hand movements are early signs. Gradually these abnormalities become more pronounced until the entire musculature is implicated with chorea. The frequency of blinking is increased (the opposite of parkinsonism), and voluntary protrusion of the tongue, like other attempts at sustained posture, is constantly interrupted by unwanted darting movements. In the advanced stage of the disease the patient is seldom still for more than a few seconds. The choreic movements are slower than the brusque jerks and postural lapses of Sydenham chorea, and they involve many more muscles. They tend to recur in stereotyped patterns yet are not as stereotyped as tics. In advanced cases, they acquire an athetoid or


Neurology_Adams

Neurology_Adams. postural lapses of Sydenham chorea, and they involve many more muscles. They tend to recur in stereotyped patterns yet are not as stereotyped as tics. In advanced cases, they acquire an athetoid or dystonic quality. Muscle tone is usually decreased until late in the illness, when there may also be some degree of rigidity, tremor, and bradykinesia, elements suggestive of Parkinson disease. Parkinsonism with rigidity characterizes the Westphal or “rigid” variant, which is more common with a childhood onset, or the HDL2 genetic variant noted earlier. Tendon reflexes are exaggerated in one-third of patients, but only a few have Babinski signs. Voluntary movements are initiated and executed more slowly than normal, but there is no weakness and no ataxia, although speech, which becomes dysarthric and explosive because of incoordination between tongue and diaphragm, may convey the impression of a cerebellar disorder. Inability to hold the tongue protruded is characteristic. In late-onset


Neurology_Adams

Neurology_Adams. and explosive because of incoordination between tongue and diaphragm, may convey the impression of a cerebellar disorder. Inability to hold the tongue protruded is characteristic. In late-onset cases there may be an almost constant rapid movement of the tongue and mouth, simulating the tardive dyskinesia that follows the use of neuroleptic drugs. These disorders of movement that characterize Huntington chorea are described more fully in Chap. 4.


Neurology_Adams

Neurology_Adams. Oculomotor function is subtly affected in most patients (Leigh et al; Lasker et al). Particularly characteristic are impaired initiation and slowness of both pursuit and volitional saccadic movements and an inability to make a volitional saccade without movement of the head. Excessive distractibility may be noticed during attempted ocular fixation. The patient feels compelled to glance at extraneous stimuli even when specifically instructed to ignore them. Upward gaze is often impaired as the illness progresses.


Neurology_Adams

Neurology_Adams. As Wilson stated, the relation of the choreic to the mental symptoms “abides by no general rule.” Most often the mental symptoms precede the chorea but they may accompany or follow it, sometimes by many years. Once the movement disorder is fully established, there is nearly always some degree of cognitive abnormality. Exceptional cases have been reported in which the movement disorder existed for 10 to 30 years without mental changes (Britton et al); this would be most characteristic of patients with fewer CAG repeats. More typically, after 10 to 15 years of symptoms, most patients deteriorate to a vegetative state, unable to stand or walk and eating little; in this late stage, a mild amyotrophy may appear. Noteworthy is the high suicide rate, as pointed out by Huntington himself (see also Schoenfeld et al). Because there is a higher-than-normal incidence of head trauma, chronic subdural hematoma is another common finding at autopsy.


Neurology_Adams

Neurology_Adams. The first signs of the disease may appear in childhood, before puberty (even younger than the age of 4 years), and several series of such early-onset cases have been described (Farrer and Conneally; van Dijk et al). Mental deterioration at this early age is more often accompanied by cerebellar ataxia, behavior problems, seizures, bradykinesia, rigidity, and dystonia than by chorea (Byers et al). However, this rigid form of the disease (Westphal variant) also occurs occasionally in adults as mentioned above, in some cases because of HDL2. Functional decline is much faster in children than it is in adults (Young et al).


Neurology_Adams

Neurology_Adams. The dementia is generally more severe in cases of early onset and with correspondingly longer repeat lengths (15 to 40 years of age) than in those of later onset (55 to 60 years of age). In adult patients with early onset, the emotional disturbance tends to be more prominent initially and precedes the chorea and intellectual loss by years; with older age of onset, choreiform features are more often the initial components; in the middle years, dementia and chorea have their onset at nearly the same age. At the other extreme of age, the first features may become evident in the eighties, with orofacial or other dyskinesias that are mistakenly attributed to an exposure to neuroleptic drugs or called “senile chorea” (see Chap. 4).


Neurology_Adams

Neurology_Adams. Gross atrophy bilaterally of the head of the caudate nucleus and putamen is the characteristic abnormality, usually accompanied by a moderate degree of gyral atrophy in the frontal and temporal regions. The caudate atrophy alters the configuration of the frontal horns of the lateral ventricles in that the inferolateral borders do not show the usual bulge formed by the head of the caudate nucleus. In addition, the ventricles are diffusely enlarged (Fig. 38-4); in CT scans, the bicaudate-to-cranial ratio is increased, which corroborates the clinical diagnosis in the moderately advanced case.


Neurology_Adams

Neurology_Adams. The early articles of Alzheimer and Dunlap and the more recent one of Vonsattel and DiFiglia contain the most authoritative descriptions of the microscopic changes. The latter authors have graded the disease into early, moderately advanced, and far advanced stages. In 5 early but genetically verified cases, no striatal lesion was found, which suggests that the first clinical manifestations are based on a biochemical or infrastructural change. This view is supported by the observation that Huntington patients studied with PET show a characteristic decrease in glucose metabolism in the caudate nuclei, which precedes the volumetric loss of tissue (Hayden et al). The striatal degeneration begins in the medial part of the caudate nucleus and spreads, tending to spare the nucleus accumbens. Of the 6 cell types in the striatum (a differentiation based on size, dendritic arborizations, spines, and axon trajectories), the smaller neurons are affected before the larger ones. Loss of dendrites


Neurology_Adams

Neurology_Adams. the 6 cell types in the striatum (a differentiation based on size, dendritic arborizations, spines, and axon trajectories), the smaller neurons are affected before the larger ones. Loss of dendrites of the small spiny neurons has been an early finding, while the large cells are relatively preserved and exhibit no special alterations.


Neurology_Adams

Neurology_Adams. The anterior parts of the putamen and caudate are more affected than the posterior parts. Some observers have noted changes in the globus pallidus, subthalamic nucleus, red nucleus, cerebellum, and in the pars reticulata of the substantia nigra. In the cerebral cortex, there is slight neuronal loss in layers 3, 5, and 6, with replacement gliosis. Cases are reported with typical striatal lesions but normal cortices in which only chorea had been present during late life. Several neuropathologists have observed marked cell loss and gliosis in the subthalamic nuclei in Huntington-affected children or young adults with chorea and behavior disorders. However, Hadzi and colleagues have determined that the pathologic changes in the striatum and the cortex evolve differently and have separate relationships to the CAG repeat length.


Neurology_Adams

Neurology_Adams. Genetics and mechanism of disease As mentioned above, there is a general relationship between the number of CAG repeats and the age of onset of symptoms. It has been found that it is the longer sequence on either of the 2 alleles that determines the age of onset, the size of the expansion of the normal allele exerting no influence (Lee et al, 2012). Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence.


Neurology_Adams

Neurology_Adams. From the molecular perspective, the pathogenesis of this disease is a direct, but still poorly understood, consequence of the aforementioned expansion of the polyglutamine region of huntingtin. It has been shown that the mutant huntingtin protein aggregates in the nuclei of neurons. Moreover, the protein accumulates preferentially in cells of the striatum and parts of the cortex affected in Huntington disease. Evidence, particularly that given by Wetz (cited in the review by Bates), suggests that these aggregates may be toxic to neurons, either directly or in their protofibrillary (unaggregated) form. The situation is, however, likely to be more complex, as the bulk of huntingtin deposition is found in cortical neurons, whereas the neuronal loss is predominantly striatal. One theory supports the concept that the polyglutamine complex renders certain cell types unduly sensitive to glutamate-mediated excitotoxicity. Two mechanisms have been proposed based on an interruption of protein


Neurology_Adams

Neurology_Adams. the concept that the polyglutamine complex renders certain cell types unduly sensitive to glutamate-mediated excitotoxicity. Two mechanisms have been proposed based on an interruption of protein transcription by the binding of mutant huntingtin to transcription proteins or that mitochondrial dysfunction occurs directly or through the same transcriptional mechanism, as summarized by Greenamyre. Because polyglutamine expansions are implicated in several neurodegenerative diseases (reviewed in corresponding sections of this chapter), treatments that block their effects on cellular function may be broadly effective in several degenerative diseases.


Neurology_Adams

Neurology_Adams. A category of disorders, termed “phenocopies” of Huntington disease but without an excessive number of trinucleotide repeats in the HD gene, has been found to be due to hexanucleotide repeats within C9orf 72, the same gene implicated in some cases of ALS. The clinical features included chorea and mental deterioration but also many other features such as myoclonus. In a cohort of 514 such patients reported by Hensman Moss et al, 2 percent of cases had the C9orf 72 expansion.


Neurology_Adams

Neurology_Adams. Once the disease has been observed in its fully developed form, its recognition requires no great clinical acumen. The main difficulty arises in patients who lack a family history but who display progressive chorea, emotional disturbance, and dementia. This problem has been largely overcome since the mutation was identified. It is now possible to confirm or exclude the diagnosis by analysis of DNA from a blood sample. The presence of 36 of CAG repeats confers a risk of developing clinical manifestations at some time. Those with 36 to 40 repeats may not manifest the disease, particularly if the patient does not live long enough to express the illness. Most individuals with 40 or more repeats will demonstrate the disorder in middle life. Therefore, the length of the repeat segment indicates the likelihood of developing clinical manifestations, and the likely age of onset. However, from large multigenerational kindreds in Venezuela, it has been estimated that approximately 40 percent of


Neurology_Adams

Neurology_Adams. the likelihood of developing clinical manifestations, and the likely age of onset. However, from large multigenerational kindreds in Venezuela, it has been estimated that approximately 40 percent of the variability in age of onset is accounted for by genetic factors other than the triplet length and by environmental aspects (see Wexler et al).


Neurology_Adams

Neurology_Adams. Chorea that begins in late life with only mild or questionable intellectual impairment and without a family history of similar disease is a source of diagnostic difficulty. A few cases are the result of the earlier mentioned HDL2 mutation and others derive from alternative degenerative conditions discussed below. Referring to the problem as “senile chorea” does not solve the problem. Indeed, senile chorea has many causes. We have seen it appear with infections, hyperglycemia, drug therapy, strokes, and thyrotoxicosis, only to disappear after a few weeks. A few times we have been confronted with the problem of an older patient who displays orolingual dyskinesias that are most characteristic of exposure to neuroleptic drugs but in whom there was no such history of exposures; testing usually disclosed Huntington disease.


Neurology_Adams

Neurology_Adams. Chorea in early adult life always raises the question of a late form of Sydenham chorea, of lupus erythematosus with antiphospholipid antibodies, or of cocaine use, but neither familial occurrence nor mental deterioration is part of these processes. A “benign inherited chorea,” transmitted as an autosomal dominant trait without prolongation of a triplet sequence, has been traced to chromosome 14q. It is differentiated from Huntington disease by onset before age 5 years, progressing little, and having no associated mental deterioration (Breedveld et al). Other progressive neurologic disorders inherited as autosomal dominant traits and beginning in adolescence or adult life (e.g., polymyoclonus with or without ataxia, acanthocytosis with progressive chorea, and dentatorubropallidoluysian degeneration) can closely mimic Huntington disease, as described further on; sometimes only the genetic and pathologic findings settle the matter. A midlife progressive chorea without dementia (after


Neurology_Adams

Neurology_Adams. degeneration) can closely mimic Huntington disease, as described further on; sometimes only the genetic and pathologic findings settle the matter. A midlife progressive chorea without dementia (after more than 25 years of followup) that does not display the Huntington genotype has been reported. In at least one family in which this clinical picture is dominantly inherited, the fundamental defect is a mutation in the gene encoding the light chain of ferritin (Curtis). Affected individuals have axonal changes in the pallidum with swollen, ubiquitinand tau- positive aggregates; serum ferritin levels may be depressed. The implication of this mutation is that perturbations of iron metabolism may be toxic to neurons, a feature that also characterizes Hallervorden-Spatz disease, now called PANK disease, mentioned below.


Neurology_Adams

Neurology_Adams. Dentatorubropallidoluysian atrophy (DRPLA), sometimes mistaken clinically for Huntington chorea, was described in European families by Warner and associates and is discussed further on. The extrapyramidal manifestations include chorea, myoclonus, and rigidity. Adult-onset chorea and dementia has been described with propionic acidemia; propionic acid is elevated in the plasma, urine, and CSF. This disorder must be added to other metabolic diseases described in Chap. 36 as causes of childhood chorea and dyskinesia—such as glutaric acidemia, keratin sulfaturia, calcification of basal ganglia, phenylketonuria, and PANK disease.


Neurology_Adams

Neurology_Adams. Other problems in differential diagnosis include prion disease, Wilson disease (see Chap. 36), acquired hepatocerebral degeneration (see Chap. 39), paraneoplastic chorea (see Chap. 30), and most often and especially, tardive dyskinesia (see Chap. 41). Many drugs in addition to the toxic effects of l-dopa and antipsychotic medications occasionally cause chorea (amphetamines, cocaine, tricyclic antidepressants, lithium, isoniazid, linezolid). The hyperglycemic–hyperosmolar state is known for producing a variety of generalized or local movement disorders, prominent among them being chorea.


Neurology_Adams

Neurology_Adams. The dopamine antagonist haloperidol, in daily doses of 2 to 10 mg, is effective partially in suppressing the movement disorder. Because of the danger of superimposing tardive dyskinesia on the chronic disorder, the chorea should be treated only if it is functionally disabling, using the smallest possible dosages. Haloperidol may also help alleviate abnormalities of behavior or emotional lability, but it does not alter the progress of the disease. The authors have not been impressed with the therapeutic effectiveness of other currently available drugs. Levodopa and other dopamine agonists make the chorea worse and, in the rigid form of the disease, evoke chorea. Drugs that deplete dopamine or block dopamine receptors—such as reserpine, clozapine, and particularly tetrabenazine, which is an inhibitor of vesicular monoamine oxidase transporter 2 (VMAT2) and has been validated in a controlled study (Huntington Study Group)—suppress the chorea to some degree, but their side effects


Neurology_Adams

Neurology_Adams. is an inhibitor of vesicular monoamine oxidase transporter 2 (VMAT2) and has been validated in a controlled study (Huntington Study Group)—suppress the chorea to some degree, but their side effects (drowsiness, akathisia, and tardive dyskinesia) usually outweigh their desired effects. Deutetrabenazine is a newer VMAT2 inhibitor, which has been approved for use in HD. Both tetrabenazine and deutrabenazine are contraindicated in patients with active suicidality or inadequately treated depression. The juvenile (rigid) form of the disease is probably best treated with antiparkinsonian drugs. Preliminary studies of the transplantation of fetal ganglionic tissue into the striatum have achieved mixed results. The psychologic and social consequences of the disease require supportive therapy, and genetic counseling is essential. Antidepression drugs are widely implemented because of the high incidence of depression and suicidality but their efficacy is not clear. Huntington disease pursues a


Neurology_Adams

Neurology_Adams. genetic counseling is essential. Antidepression drugs are widely implemented because of the high incidence of depression and suicidality but their efficacy is not clear. Huntington disease pursues a steadily progressive course and death occurs as mentioned, on average 15 to 20 years after onset, sometimes much earlier or later.


Neurology_Adams

Neurology_Adams. Novel therapeutic agents in the form of antisense oligonucleotides are currently being tested. These agents are introduced intrathecally and bind to huntingtin mRNA in the central nervous system. In early stage in-human safety and tolerability studies lead to dose-dependent reduction in huntingtin mRNA and protein. This approach is comparable to what has been accomplished in spinal muscular atrophy (discussed later in this chapter).


Neurology_Adams

Neurology_Adams. Occasionally, the authors have encountered families in which several members developed a spastic paraparesis and a gradual failure of intellectual function during the middle adult years. The patient’s mental horizon narrowed gradually, and the capacity for high-level thinking diminished; in addition, the examination showed exaggerated tendon reflexes, clonus, and Babinski signs. In one such family, the illness had occurred in 2 generations; in another, 3 brothers in a single generation were afflicted. Skre described 2 recessive types of hereditary spastic paraplegia in Norway, 1 with onset in childhood, the other with onset in adult life. In contrast to the dominant form (see further on), the recessive types displayed evidence of more widespread involvement of the nervous system, including dementia, cerebellar ataxia, and epilepsy. Also, Cross and McKusick have observed a recessive type of paraplegia accompanied by dementia beginning in adolescence. They named it the Mast syndrome,


Neurology_Adams

Neurology_Adams. dementia, cerebellar ataxia, and epilepsy. Also, Cross and McKusick have observed a recessive type of paraplegia accompanied by dementia beginning in adolescence. They named it the Mast syndrome, after the afflicted family.


Neurology_Adams

Neurology_Adams. Worster-Drought and others reported the pathologic findings in 2 cases of this type. In addition to plaques and neurofibrillary changes, there was demyelination of the subcortical white matter and corpus callosum and a “patchy but gross swelling of the arterioles,” which gave the staining reactions for amyloid (“Scholz’s perivascular plaques”). van Bogaert and associates published an account of similar cases that showed the characteristic pathologic features of Alzheimer disease.


Neurology_Adams

Neurology_Adams. Another interesting association of familial spastic paraplegia is with progressive cerebellar ataxia. Fully one-third of the cases that we have seen with such a spastic weakness were also ataxic and would fall into the category of spinocerebellar degenerations. Yet another variant of this group of diseases has been described by Farmer and colleagues; the inheritance in their cases was autosomal dominant, and the main clinical features were deafness and dizziness, ataxia, chorea, seizures, and dementia, evolving in that order. Postmortem examinations of 2 patients disclosed calcification in the globus pallidus, neuronal loss in the dentate nuclei, and destruction of myelinated fibers in the centrum semiovale.


Neurology_Adams

Neurology_Adams. Under this title, Robitaille and colleagues have described a progressive neurologic disease in adults characterized clinically by spasticity, chorea, dementia, and a predominantly sensory polyneuropathy that is reviewed in more detail in Chap. 39. Structures that closely resembled Lafora bodies and corpora amylacea were found in large numbers in both central and peripheral neural processes (mainly in axons) and also in astrocytes. These basophilic PAS-positive structures were composed of glucose polymers (polyglucosans) and were readily demonstrated in sural nerve biopsies and therefore probably best termed polyglucosan bodies. Some of these structures were also found in the heart and liver.


Neurology_Adams

Neurology_Adams. More recently, Rifal and associates reviewed the findings in 25 cases of this disease—one observed by them and 24 reported previously. The dementia was relatively mild, consisting of impairment of retentive memory, dysnomia, dyscalculia, and sometimes nonfluent aphasia and deficits of “visual integration”; this was overshadowed by rigidity and spasticity of the limbs and the peripheral nerve disorder. Bladder dysfunction has been an early sign in many patients including a middle-aged woman under our care who had only diffuse white matter changes in the cerebral MRI and a moderate sensory neuropathy. Nerve conduction velocities were diminished and the leg muscles were denervated. Moderate degrees of generalized cerebral atrophy, multifocal areas of white matter rarefaction, and degeneration of the corticospinal system, disclosed by MRI. Some cases simulate motor neuron disease. The finding of polyglucosan axonal inclusion in biopsied nerves confirms the diagnosis. The disease has


Neurology_Adams

Neurology_Adams. of the corticospinal system, disclosed by MRI. Some cases simulate motor neuron disease. The finding of polyglucosan axonal inclusion in biopsied nerves confirms the diagnosis. The disease has sometimes been misinterpreted as adrenoleukodystrophy. The disorder appears to be a glycogenosis that is allied with Anderson disease, as discussed in Chaps. 37 and 43.


Neurology_Adams

Neurology_Adams. Adult forms of metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, and neuronal ceroid lipofuscinosis (Kufs disease) may be present with a similar clinical picture of progressive dementia (see Chap. 36) as may Whipple disease (Chap. 31) or the Wernicke-Korsakoff disease (Chaps. 20 and 41). Quite rare instances of the same syndrome with adult onset have proved to be caused by phenylketonuria or other aminoacidopathies (see Chap. 36).


Neurology_Adams

Neurology_Adams. This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it was characterized by “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” Strangely, his essay contained no reference to rigidity or to slowness of movement and it stressed unduly the reduction in muscular power. The same criticism can be leveled against the term paralysis agitans, which appeared for the first time in 1841 in Marshall Hall’s textbook Diseases and Derangements of the Nervous System and has fallen out of use, but was such a common term in the literature that it is mentioned here.


Neurology_Adams

Neurology_Adams. The natural history of the disease is of interest. As a rule, it begins between 45 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age, and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, “rigid personality,” and so on, were among many factors that had been suggested over the years as predisposing to the disease but there is no evidence to support any such claims. Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in African Americans is lower than in whites. There may be an increased incidence in rural compared to urban areas, attributed tentatively and not consistently, to exposure to pesticides. In Asians, the incidence is one-third to one-half that in whites. The disease is frequent in North America, where there are approximately 1 million affected patients, constituting about 1


Neurology_Adams

Neurology_Adams. pesticides. In Asians, the incidence is one-third to one-half that in whites. The disease is frequent in North America, where there are approximately 1 million affected patients, constituting about 1 percent of the population over the age of 65 years. The incidence in European countries where vital statistics are kept, is similar. A possible relationship to repeated cerebral trauma and to the “punch-drunk” syndrome (dementia pugilistica; chronic traumatic encephalopathy) has been particularly problematic and is unresolved despite several celebrated cases (Lees); certainly most cases do not have this exposure. A protective effect of smoking and coffee drinking has emerged in some epidemiologic studies but the magnitude of effect is marginal.


Neurology_Adams

Neurology_Adams. A tetrad of hypoand bradykinesia, resting tremor, postural instability, and rigidity are the core features of Parkinson disease. These are evident as an expressionless face, poverty and slowness of voluntary movement, “resting” tremor, stooped posture, axial instability, rigidity, and festinating gait. Much can still be gained from perusal of the often-cited study by Hoehn and Yahr, published in 1967 before the widespread use of l-dopa. Table 38-2 is reproduced from that paper although more extensive grading scales such as the Unified Parkinson Disease Rating Scale (UPDRS) are in frequent use. Because of the common use of the latter instrument in clinical trials, it is appropriate for the clinician to be familiar with its broad outlines. This complex scale encompasses subsections on motor and mental function and activities of daily living, and gives a summed score ranging from 0 to 176 with higher numbers denoting more severe disease manifestations.


Neurology_Adams

Neurology_Adams. One of the most interesting clinical aspects of the disease is the lack of concordance across symptoms—a tremor predominant form with few other symptoms is well known and even hypokinesia (a lack of shifting of natural postures and a tendency to stay still) and bradykinesia (slowness of commended or intended movement) in some cases seem to be somewhat dissociated. The manifestations of basal ganglionic disease are fully described in Chap. 4, and only certain diagnostic problems and variations of the clinical picture need be considered here.