Progressive Aphasia

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NONFLUENT APHASIA. The degenerative focus centers on anterior perisylvian language cortices (Broca's area). Neuropathology of progressive aphasia has included (1) nonspecific degenerative changes, including increased neuronal lipofuscin, y neuronal loss, astrocytosis, and peri- neuronal microvacuolation in superficial laminae with or without occasional amyloid plaques y ; (2) nonspecific degenerative changes with focal accumulations of achromatic




Major Topography

Main Pathology

Cognitive Signs

Other Early Neurological Signs



Dominant frontal operculum


Nonfluent aphasia

Dysarthria, reflex asymmetry, memory loss


Dominant temporal


Fluent aphasia


Dominant anterior temporal



Acalculia, apraxia, other parietal signs, memory loss


Dominant perisylvian


All aspects of speech disturbed

Abulia and other frontal lobe signs, memory loss

Memory loss, dysarthria, acalculia, apraxia



Asymmetrical bilateral P-T-O



Alexia, memory loss


Asymmetrical parietofrontal



Hemiakinetic-rigid syndrome, psychomotor slowing


Asymmetrical P-F and P-O


Asimultanagnosia and apraxia

Memory loss, aphasia, and any of the above



Asymmetrical bilateral prefrontal

Pick's, nonspecific

Abulia, disinhibition

Memory loss, anomia, anosognosia



Nonspecific (PLS)

Psychomotor slowing

Spasticity, dysarthria


Asymmetrical bilateral precentral gyrus

Asymmetrical bilateral frontal


Spastic-dementia syndrome




Bilateral mesial temporal


Memory loss


Right inferior temporal (bilateral?)



Memory loss, alexia


Bilateral anterior temporal


Anomia, amnesia, abulia

Psychomotor slowing, anosognosia

CBGD, Corticobasal ganglionic degeneration; PLS, primary lateral sclerosis; P, parietal; T, temporal; F, frontal; O, occipital. Adapted from Caselli RJ Focal and asymmetric cortical degeneration syndromes. The Neurologist 1995;1:1-19.

Figure 12-5 Photomicrograph of frontal cortex demonstrating nonspecific histology. Note the neuronal loss and gliosis, with spongiosis involving the superficial cortical Hematoxylin and eosin; 25*; courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)

neurons[44] ; and (3) unusual combinations of Pick/Alzheimer y and Alzheimer/Pick/Lewy body disease type pathology in one family (without Pick bodies). y The hippocampal formation is involved by the asymmetrical degeneration, but the nucleus basalis is spared. y Additionally, pigmented brain stem nuclei may be affected.y

FLUENT APHASIA. The degenerative focus is more posteriorly placed, including Wernicke's area, although usually the entire left temporal lobe appears atrophic. Neuropathology is similar to that of nonfluent aphasia, including nonspecific degenerative changes with moderate spongiosus of superficial cortical layers and involvement of the amygdala,y but some patients have been found to have AD.y

ANOMIC APHASIA. The responsible degenerative focus is in the left anterior temporal lobe. Neuropathologically, Pick's disease may cause generalized atrophy that is more severe in the left hemisphere, particularly the left anterior temporal lobe and insula, with sparing of the nucleus basalis of Meynert. y

MIXED APHASIA. Again, the degenerative focus appears to involve the left perisylvian cortices, particularly the left temporal lobe diffusely. Neuropathological findings include nonspecific degenerative changes with focal spongiosus of superficial cortical layers y and AD.y

Progressive Frontal Lobe Dementias (FLDs) and Frontotemporal Dementia (FTDs) Syndromes (Pick's Disease). Arnold Pick originally introduced the concept of a lobar atrophy with relevant progressive focal symptoms in his description of a patient with progressive aphasic dementia, who at autopsy had, in addition to generalized cortical atrophy, focally accentuated atrophy of the left temporal lobe. The specific histological findings were later appreciated by Alzheimer in 1911, who observed distinctive intraneuronal inclusions, which were termed "Pick bodies." Swollen, ballooned, and poorly staining (chromatolytic) neurons were subsequently called "Pick cells."

Over the following decades, most investigators have included three pathological varieties of Pick's disease: lobar atrophy with swollen chromatolytic neurons (SCN) and Pick bodies (Pick's disease Type A), lobar atrophy with SCN but not Pick bodies (Pick's disease Type B), and lobar atrophy without SCN or Pick bodies (Pick's disease Type C, or nonspecific degeneration). y Whether the findings in Pick's disease Types B and C are indeed variants of Pick's disease or different disease processes is debated.

The cardinal pathological changes in Pick's disease Type A are lobar atrophy with corresponding neuronal loss that is most apparent in the first three cortical layers (

Fig 33-6 ). The maximally involved cortical gyri are very thin, and they are often described as walnut or knife-edge in appearance. When the temporal lobe atrophy is focally accentuated, the posterior one-third of the superior temporal gyrus appears relatively preserved. Marked caudate and hippocampal atrophy are also typical findings. Variable degrees of co-existing subcortical gliosis and degeneration of other subcortical nuclei can occur as well, although the basal forebrain tends to be spared. Pick bodies are argentophilic, eosinophilic, rounded cytoplasmic masses that appear densely black on silver stains ( .Fig, 33-7 ). They are

Figure 12-6 Pick's disease. Note the circumscribed frontotemporal cortical atrophy with relative sparing of the posterior one third of the superior temporal gyrus. The marked gyral thinning is often described as walnut or knife-edged in app(Courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)

Figure 12-7 Photomicrograph of frontal cortex in classic Pick's disease (Pick's type A). The argentophilic, rounded cytoplasmic masses are Pick bodies, which are principally composed of 8 to 20 nm straight fila(Bielsshowsky silver stain; 200*; courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)

composed of 10- to 20-nm straight filaments that share antigenic properties with neurofilaments. Pick bodies tend to predominate in the most severely atrophic cortical regions and in the hippocampi. Pick cells also immunostain positively to neurofilaments, but they are not regarded diagnostic of Pick's disease because similar-appearing cells have been observed in several other disorders. The nucleus basalis is spared or only mildly affected in both Pick's disease and in FLD. y

Pick's disease usually involves the frontal and anterior temporal lobes, but rare cases with preferential parietal lobe atrophy have also been described. Therefore, patients with Pick's pathology have exhibited the FLD and FTD syndromes, progressive aphasia syndrome, y and progressive perceptual-motor syndrome (corticobasal ganglionic degeneration [CBGD]). y There are a few kindreds with autosomal dominant Pick's disease, but no chromosome has been identified by genetic analysis to date.

Progressive Spasticity (Primary Lateral Sclerosis). Neuropathologically, there is highly circumscribed atrophy of the precentral gyrus with loss of Betz cells, decreased numbers of pyramidal neurons, and laminar gliosis in the external and internal pyramidal cell cortical layers. y No lower motor neuron abnormalities are typically found in hypoglossal or spinal gray nuclei, and the substantia nigra is generally unaffected. y

Progressive Perceptual-Motor Syndromes VISUAL. To date, neuropathological studies of patients with dorsal visual syndromes have generally shown senile plaques and neurofibrillary tangles, which is typical of AD. The topographic distribution, however, differs from that seen in Alzheimer's dementia, with heaviest involvement of primary and association visual cortices in the occipital lobes and, to a slightly lesser degree, in the parietal lobes. y The nucleus basalis is involved in these cases. y Other pathologies include nonspecific degenerative changes (gliosis, neuronal loss, and vacuolation of superficial cortices), y and Creutzfeldt-Jakob disease (Haidenhain variant). y To date, there are no published pathological studies of patients with progressive ventral visual cortical disorders.

MOTOR. To date, most patients reported with this syndrome have had CBGD with neuronal achromasia or nonspecific degenerative changes (see section on CBGD). Other histological patterns have included Pick's disease, y AD with involvement of the nucleus basalis,y and PSP.y There is generalized but asymmetrical atrophy with the most severe focal degeneration generally occurring in superomedial frontoparietal regions, primary motor cortex, and parietal convexity cortex, but other cortical regions, including Wernicke's area, sometimes can be severely involved as well. The substantia nigra is also involved, but the nucleus basalis is spared in the absence of AD.W]

MIXED. Pathological findings include CBGD and AD. Progressive Bitemporal Syndromes PROGRESSIVE AMNESIA. See Alzheimer's Disease. PROGRESSIVE PROSOPAGNOSIA. See Progressive Visual Syndromes.

PROGRESSIVE BITEMPORAL NEUROPSYCHIATRIC SYNDROMES. On a clinical basis, patients with progressive bitemporal neuropsychiatry syndromes probably have either Pick's disease or AD, but neuropathological study is lacking.

Epidemiology and Risk Factors. There are no incidence and prevalence studies of this group of disorders, but clinical experience (at a tertiary care referral center) suggests that they are, as a group, perhaps a tenth as common as AD. Genetic factors may play a role, but the data are scant.

Clinical Features and Associated Disorders. There are four broad categories of ACDS, each of which can be further subdivided, and topographical and pathological correlations could be made for each (see Iable33.:2 ).

In most cases, there are three properties of the atrophy topography that are radiologically discernible: (1) there is a lateralized major atrophic focus; (2) there is a contralateral area of focal atrophy that is less severe than the primary focus, the homologous cortices; and (3) there is milder generalized atrophy. Metabolic abnormalities reflect this pattern as well. y

Several types of ACDS are associated with amyotrophic lateral sclerosis (ALS), including progressive aphasia, y frontal lobe syndromes including Pick's diseasey and nonspecific frontal lobe degeneration, y and bitemporal syndromes. y In such cases, longevity is determined by the ALS component, and in the case of progressive aphasia with ALS, the disease course appears particularly rapid. y Occasional patients with apparent primary lateral sclerosis (PLS) may have mild lower motor neuron abnormalities, and they appear to have a slower course than typical ALS. Patients with a bitemporal or frontotemporal syndrome and ALS may have a more severe neuropsychiatric syndrome with features of Kluver-Bucy syndromey compared with those without ALS. Finally, subtypes of ACDS may overlap in the same patient, such as progressive aphasia and a progressive perceptual-motor syndrome.

Progressive Aphasia. Although original credit should probably go to Arnold Pick for correlating lobar atrophy with aphasic dementia, y Mesulam's 1982 report of progressive aphasiay essentially refocused modern neurology on the relationship of focal cortical degeneration to a progressive cortical syndrome. Because most patients are left- hemisphere dominant for language, most patients have left- sided asymmetrical atrophy. However, occasional patients are found who are left handed and who have right-hemisphere asymmetrical atrophy accompanying progressive aphasia. Cognitive deficits other than those directly attributable to language may also occur, especially memory impairment and constructional apraxia.

Nonfluent progressive aphasia generally reflects anterior perisylvian cortical degeneration (Fig. 33-8 (Figure Not Available) ). It should be readily distinguished from typical AD. Speech is effortful, halting, and sometimes dysarthric. Naming ability is marked by phonemic paraphasic errors (for example, "calicopter" for helicopter), repetition is generally severely impaired, and although writing sometimes is easier than speaking, it is also usually abnormal. Aural and reading comprehension are less impaired in mild to moderate stages but deteriorate in most patients with disease progression. Some patients have orofacial apraxia but not gestural or limb apraxia. Verbal memory tests are difficult to administer, but verbal memory is typically impaired.

Fluent aphasia involves degeneration of temporal and posterior perisylvian cortices. Contiguous involvement of neighboring cortices may complicate the clinical picture, making it difficult to distinguish a focal left temporoparietal syndrome (with aphasia, amnesia, apraxia, and acalculia) from a so-called diffuse cognitive disorder, or Alzheimer's dementia. The nonlanguage impairments, however, are much less disabling than the language impairment in progressive fluent aphasia.

Fluency, articulation, and prosody are normal, but comprehension and naming are impaired. Sentence repetition appears to be impaired less consistently. Ihe characteristic naming errors are semantic paraphasias, but phonemic paraphasias occur as well. Typically, a patient may recognize and describe the object or action they cannot name (e.g., "something that flies" for a helicopter), or give a generic descriptor. Spelling errors are frequent.

Anomic aphasia involves degeneration of anterior temporal cortices. Patients are fluent, comprehend well, and can repeat, read, and write with minimal difficulty. However, their speech lacks semantic precision. They substitute generic terms for specific words (e.g., "machine" for computer), and make semantic paraphasias (e.g., "staple" for paper clip). Anomia is a common feature of both AD and Pick's disease, but verbal memory is usually impaired even in the absence of dementia.

Mixed progressive aphasia is a more nonspecific pattern

Figure 12-8 (Figure Not Available) Progressive nonfluent aphasia. MRtop) and SPECI (bottom) showing left frontal opercular atrophy(Reprinted from Caselli RJ, Jack CR Jr: Asymmetric cortical degenerative syndromes: A proposed clinical classification. Arch Neurol 1992;49:770-780. By permission of Little, Brown and Company [Inc.].)

involving degeneration of left temporal and perisylvian cortices. Patients with this condition have impairment of all aspects of language, making classification into a single taxonomic category impossible. They are nonfluent, with impaired comprehension, naming, repetition, writing, and reading.

Progressive Perceptual-Motor Syndromes. Although most patients have a mixed sensory-motor syndrome (including visual or somatosensory systems, or both), there are a few patients who have a pure sensory (typically visual) or pure motor syndrome (typically a hemiakinetic rigid syndrome). Progressive spasticity is considered under Asymmetrical Cortical Degeneration Syndromes.

Progressive visual syndromes involve degeneration of parieto-occipital or parieto-temporal visual association cortices, or both. Visual association cortices can be broadly divided into dorsal (occipitoparietal) and ventral (occipitotemporal) pathways, and disorders of visual association cortices reflect this dichotomy. The occipitoparietal pathway is more concerned with localizing an object in space (where), and the occipitotemporal pathway is more concerned with object identification (what). Two broad types of complex visual disturbance have been described with ACDS. The more commonly reported is progressive asimultanagnosia, reflecting dysfunction of the dorsal cortical visual pathway. Patients cannot integrate the numerous components of an ordinarily complex scene into a coherent whole. When viewing a street scene, for example, they might describe a car or a person or a lamppost, but overlook the fact that it is an inner city rush hour. Occasional associated problems that also reflect posterior parietal and temporal involvement include alexia, acalculia, right-left disorientation, and mild deficits of memory and language (fluent aphasia). Eventually, patients may be found to have inferior quadrantanopia, although typically visual field testing produces inconsistent responses.

The second type of complex visual disorder resulting from ACD is visual agnosia, of which there are fewer reported examples. y , y Visual agnosia results from dysfunction of the ventral cortical visual pathway. Some patients have been described with progressive prosopagnosia, which is a failure to recognize familiar faces. y Rarely, patients may describe progressive atopographagnosia, the inability to recognize familiar places. In later stages, both ventral and dorsal visual pathways become involved, and a more globally encompassing visual agnosia results, as illustrated best by Oliver Sacks' Professor P. y

Progressive Motor Syndromes (see also CBGD). Two major clinical characteristics, both slowly progressive in onset, make this disorder distinctive and easily recognized. The first are lateralized somatic deficits, including hemi-spasticity, hemiparesis, hemisensory impairment (usually in the form of astereognosis or tactile agnosia with less consistent impairment of more basic somatosensory modalities), and myoclonic jerks. Some patients may have a hemirigid or hemidystonic syndrome with tremor. The second is severe and disabling apraxia, including limb apraxia (inability to use the limb in a meaningful way, such as to use a comb), gestural apraxia (inability to pantomime or imitate symbolic movements), dressing apraxia, constructional apraxia, and apraxic agraphia. If the lateralized limb defects reflect dominant hemispheric dysfunction, then a mild fluent aphasia may be present that is milder than that seen in progressive fluent aphasia. When the lateralized limb defects reflect nondominant hemisphere dysfunction, it is uncommon (but possible) for a hemineglect syndrome to result.

Additional clinical abnormalities may include acalculia, psychomotor slowing, aphasia, and supranuclear oculomotor disturbances. Although patients with severe apraxia, psychomotor slowing, and mild aphasia may appear demented according to neuropsychological testing, they are usually rational, insightful, and upset by their condition. In late stages, patients can barely move or speak despite preserved consciousness.

Many patients have both a sensorimotor and a visuospatial disorder, combining features of both of the above- mentioned groups (Fig. 33-9 (Figure Not Available) ). Progressive Frontal Lobe and Frontotemporal Syndromes.

The three main frontal lobe syndromes are a progressive neuropsychiatric syndrome (frontal and frontotemporal dementia), a progressive spastic syndrome, and a mixture of these two.

The progressive neuropsychiatric syndrome is the best-known

Figure 12-9 (Figure Not Available) Progressive perceptual-motor syndrome. MRop) and SPECT (bottom) showing right greater than left parietal atrophyReprinted from Caselli RJ, Jack CR Jr: Asymmetric cortical degenerative syndromes: A proposed clinical classification. Arch Neurol 1992;49:770-780. By permission of Little, Brown and Company [Inc.].)

example of this group and has been referred to as frontal lobe or frontotemporal dementia (Fig. 33-10 (Figure Not Available) ). Pick's disease is prominently represented in this group. More recently, Bruny and GustafsonWi described a similar clinical syndrome in the absence of Pick bodies. Although the clinical picture is characteristic, many clinicians have difficulty distinguishing these patients from those with Alzheimer-type dementia. Another common misdiagnosis is depression. Ihe errors made by these patients tend to be omissions rather than commissions, and the term that describes this condition is abulia. They fail to change their clothes, to brush their teeth, to pursue their former interests, and to initiate many activities that constitute a normal day. Just as they fail to start something new, they may fail to stop what they are doing and perseveratively fixate, in a seemingly idiosyncratic fashion, on some particular activity, such as going to the bathroom, sorting through their wallet, or watching television. Some patients have greater disinhibition and emotional lability, crying at the least provocation, or laughing loud and long. They may complain that they are hungry yet be unmoved to fix themselves a snack. Some may perseveratively want to eat over and over. Memory and language (especially naming) are typically impaired. Despite their sometimes reduced temporal latency in responding to the examiner (they may start answering a question before the physician has finished asking it), their answers are brief, and often consist of "I don't know." Patients with FLD may stick close to their caregiver and generally cause fewer disruptions than patients with AD, particularly in mild to moderate stages (although there are notable exceptions).

Associated clinical abnormalities reflect dysfunction of other frontal lobe functions including spasticity and nonfluent aphasia. Because Pick's disease has a predilection for the temporal as well as the frontal lobe, some patients also develop signs referable to the temporal lobe, particularly anomia.

Ihe syndrome of progressive spasticity has been termed PLS, and historically, the nosological focus has been on its relationship to ALS (see Ch§pt§L3.6. ) rather than other frontal lobe degenerations. PLS reflects degeneration of the precentral gyrus and primary motor cortex. y Cognitive impairment is minimal but can include emotional lability, mild frontal lobe-related cognitive deficits, and mild memory impairment. y

Some patients present early in their course with a combination of both spasticity and FLD/FID. y Conceivably, these patients have Pick's disease because Pick's disease produces spasticity late in the course of the illness, but patients with aD have also been reported to present (rarely) with progressive spasticity.

Progressive Bitemporal Syndromes. Ihe three syndromes in this category are progressive amnesia, progressive prosopagnosia, and progressive neuropsychiatric syndrome. Progressive amnesia is discussed in the section on AD, and progressive prosopagnosia is discussed in the section on progressive visual syndromes because this entity overlaps both categories of ACDS. Patients with a progressive neuropsychiatric syndrome due to bitemporal degeneration (Fig. 33-11 (Figure Not Available) ) have severe anomia and amnesia, relative indifference to their condition, and mild perseverative behaviors that are shared with patients in the frontal lobe group. Psychomotor speed is normal or only mildly impaired. Neuroimaging shows bilateral severe anterior temporal atrophy and hypoperfusion with relative sparing of the frontal lobes.

Differential Diagnosis. The two broad categories to consider are nondegenerative structural focal brain lesions, such as a slowly growing tumor and other degenerative conditions. Regarding the first, a slowly progressive neurological syndrome that can be reasonably localized could be neoplastic, whether malignant or benign. Rarely, high- grade arterial stenoses cause stuttering infarction mimicking a slowly progressive degenerative cortical syndrome,

Figure 12-10 (Figure Not Available) Progressive frontotemporal dementia. M(top) and SPECT (bottom) showing right greater than left frontal and anterior temporal atrophy in a patient with autopsy-documented Pick's dise(Reprinted from CaselliRJ, Jack CR Jr: Asymmetric cortical degenerative syndromes: a proposed clinical classification. Arch Neurol 1992;49:770-780. By permission of Little, Brown and Company [Inc.].)

Figure 12-11 (Figure Not Available) Progressive bitemporal neuropsychiatric syndrome: M(top) and SPECT (bottom), showing right greater than left anterior temporal atroph(From Caselli RJ: Focal and asymmetric cortical degeneration syndromes. The Neurologist 1995;1:1-19.)

but this is very uncommon. Other pathological processes that could occur focally, including infection or abscess and demyelinating or vasculitic conditions, should also be considered. Other degenerative illnesses include Creutzfeldt-Jakob disease in rapidly progressive cases and the wide variety of degenerative pathologies discussed earlier. For example, a patient suspected of CBGD may have AD at autopsy. Among the frontal lobe, aphasic, and bitemporal varieties of ACDS, an association with ALS must also be considered.

Evaluation. The most important diagnostic test is adequate structural neuroimaging. MRI is preferable to CT, but either will generally suffice to evaluate the possibility of a tumor. In addition to excluding nondegenerative structural abnormalities, a magnetic resonance angiographic (MRA) study could be included, if available, to search for a potentially relevant high-grade arterial stenosis. Patients with ACDS usually, but not invariably, have radiologically discernible focal atrophy in the symptomatic region. It is often subtle and of insufficient severity to permit blinded diagnosis of ACDS. However, in a patient with progressive anomic aphasia for example, focal left anterior temporal atrophy should be considered important not only because of the absence of a tumor but because it shows the responsible lesion to be an atrophic one, presumably degenerative. Formal neuropsychological assessment can be helpful to assess quality and severity of cognitive impairment to a greater extent and usually demonstrates a pattern that is not typical for Alzheimer's dementia. It is also useful for monitoring disease progression. Other laboratory studies are less helpful because of the apparent focal nature of the ACDS. Metabolic encephalopathies do not usually cause the syndrome of slowly progressive aphasia, which is difficult to confuse with a diffuse encephalopathy. Nonetheless, it is still reasonable to make certain that basic laboratory data is normal, as was discussed for AD.

Management. Considerations similar to those discussed for AD are applicable here with minor additions. First, patients with ACDS are usually aware of their limitations and are not likely to get themselves in trouble unwittingly by wandering, refusing medications, and so forth. They require nursing home placement less often if a caregiver exists. Physical therapy is important for patients with CBGD and PLS, especially because of the complications resulting from altered muscle tone and gait unsteadiness. Occupational therapy is particularly important for ACDS patients with apraxia and spatial disorders to assist with dressing, eating, and other activities of daily living. Speech therapy is appropriate to consider for progressive aphasia not only because of the aphasia but in later stages of nonfluent aphasia in particular, because of dysphagia as well. Late-stage complications are similar for AD but perhaps are most severe for CBGD. In this condition, because all avenues of communication are lost, including speech and praxis, and because muscle tone contorts them into painful dystonic postures with contracture formation, there remains relative preservation of insight, perhaps compounding their suffering further. Trials of carbidopa and levodopa (Sinemet) in CBGD should be considered, even though it is usually of minimal efficacy at best. In patients with CBGD with severe myoclonus, small doses of clonazepam can also be considered. Finally, in cases with severe dystonic posturing, especially hand closure, selective botulinum toxin injection can be considered to accomplish limited goals, such as allowing the hand to be opened for maintenance of skin hygiene and to retard contracture formation.

Prognosis and Future Perspectives. All of the ACDSs are progressive and follow a similar time course to AD. Most patients have a more generalized cortical degenerative process that becomes more significant in later stages, but occasionally patients have a highly focal process with minimal evidence of generalized decline, even at the time of their death. Prognosis is better in the group with the

highly focal process. Otherwise, ACDS of all types, like AD and other degenerative brain diseases, results in death after relentless progression. ALS-Dementia Complex

Pathogenesis and Pathophysiology. The nosological distinction among frontotemporal lobe dementia (FTD), FTD with motor neuron disease (MND), and classic MND has been debated, with some arguing that FTD with MND is a distinct disorder and others suggesting each represents a phenotype along a continuum of the same disease.y The histological findings do not clarify nosology because in the majority of cases, they are nonspecific: neuronal loss, gliosis, and microvacuolation or spongiform changes predominantly affecting the superficial cortical layers and subcortical white matter. Degeneration is usually greatest in frontotemporal regions and, less commonly, in perisylvian language cortices. The nucleus basalis of Meynert appears normal, as do cortical levels of choline acetyltransferase and somatostatin.^] Variable degrees of degeneration also occur in the amygdala, hippocampus, thalamus, caudate nucleus, and substantia nigra.

Epidemiology and Risk Factors. Dementia rarely occurs in patients with ALS, although known associations include the Parkinson-ALS-dementia complex of Guam, which occurs in the indigenous Chamorro population y ; familial ALSy ; and sporadic cases from both Eastern y and Westerny , y , y , y populations. Pathogenesis in most patients is uncertain, and histopathological features are generally nonspecific.

Clinical Features and Associated Disorders. Frontal lobe or frontotemporal dementia is the most common dementia pattern, followed by aphasic dementia. Clinical descriptions in the literature, however, have varied and include unqualified dementia, y dementia of the Alzheimer type, Pick's disease, y and dementia with Kluver-Bucy syndrome,y in addition to frontotemporaly and aphasic dementia. y Bulbar symptoms have been consistently prominent.

For some years, an association with Creutzfeldt-Jakob disease was suspected, but this is no longer thought to be the case. y

Differential Diagnosis. Certain types of the ALS-dementia complex may be rapidly progressive, with anarthria within 1 year and death within 2 years. Given the severity, rapid progression, and sometimes paucity of limb abnormalities, Creutzfeldt-Jakob disease should be considered. In rapidly progressive cases, carcinomatous meningitis can also cause encephalopathy and polyradiculopathy, which might be mistaken for ALS-dementia complex, so CSF evaluation can be useful. Head and neck tumors, particularly carcinoma of the posterior tongue with CNS metastases can cause severe dysarthria and mental status changes, and they should not be overlooked particularly when dysarthria is the main finding. Finally, neuromuscular weakness due to ALS, myasthenia gravis, acid maltase deficiency, myotonic dystrophy, and any other disease of sufficient severity to compromise ventilatory capacity may lead to a hypoxic encephalopathy that, in the absence of a corroborating history, might be mistaken for ALS-dementia complex, so arterial blood gases should be considered in some cases.

Evaluation. Both the nature of the neuromuscular disorder and the cognitive disorder must be established. EMG is important for the neuromuscular disorder and an essential diagnostic step but may not be conclusive, especially in bulbar cases. Further evaluation of the ALS aspect of this disorder is considered in the section on ALS but may include acetylcholine receptor antibody and creatine phosphokinase among other tests. Regarding the cognitive disturbance, formal mental status assessment is the first step, and if there is any doubt, formal neuropsychological assessment focusing particularly on frontal lobe and language function should be performed. Evaluation of the dementia should then proceed with similar considerations, as discussed for AD, with particular attention to neuroimaging. In this context, MRI is preferable to CT because imaging of lower brain stem structures in particular is better accomplished by MRI. In selected circumstances, as discussed earlier, additional consideration should be given to EEG, CSF examination, consultation with an otolaryngologist, and arterial blood gas evaluation.

Management. Treatment considerations overlap those for ALS (see the section on ALS). Caregiving for the demented patient is discussed under AD. This is a particularly difficult condition because of the combination of neuromuscular and cognitive problems that confront the patient.

Prognosis and Future Perspectives. As with other neurodegenerative diseases, progression is inevitable and generally more rapid than in AD, with death occurring within 3 to 5 years in typical cases. Unlike uncomplicated ALS, in which the mind is preserved, causing some individuals to opt for feeding tubes, external ventilatory support, and other life-sustaining measures, ALS-dementia complex also produces severe intellectual decline, making justification of such measures difficult.

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