Sci. Aging Knowl. Environ., 2 April 2003
Vol. 2003, Issue 13, p. dn1
[DOI: 10.1126/sageke.2003.13.dn1]

NEURODEGENERATIVE DISEASE CASE STUDIES

Frontotemporal Dementia

Lawrence S. Honig, Karen Bell, and Steven S. Chin

The authors are at Columbia University College of Physicians and Surgeons, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Gertrude H. Sergievsky Center, and the Departments of Neurology and Pathology, New York, NY 10032, USA. E-mail: lh456{at}columbia.edu (L.S.H.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/13/dn1

Key Words: frontotemporal dementia • frontal lobe • temporal lobe • tau

Abstract: In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with frontotemporal dementia (FTD). FTD most often presents with either a change in personality or behavior, such as social withdrawal, increased gregariousness, disinhibition, or obsessive behaviors; or with impairment of language function. Memory difficulties are common, but usually are less prominent than these other symptoms in the early stages of the disease. Frequently, psychiatric diagnoses are initially the primary consideration. Cases may be either familial or sporadic. In this familial case, an autopsy was ultimately performed and revealed findings characteristic of FTD, with grossly evident focal brain degeneration in the frontal and temporal regions, microscopic signs of gliosis, and cellular abnormalities of the intracellular microtubule-associated protein tau.

Introduction Back to Top

Mr. Q. presented to a neurologist at age 47, because his family had noticed changes in his personality over several months. He had become much less concerned about the details of his business. He seemed to have less ability to control his emotions. He was much more easily distracted, and seemed to have some new mild difficulties remembering recent events. Despite these changes, he carried out all his activities of daily living, and was rated by his family as "100% independent." The initial impression of the neurologist was that Mr. Q might have some possible cognitive change or psychosocial stressors, but no diagnosable brain disorder.

Over the next 3 years, he started to show further changes in personality. Formerly fastidious, he gave less attention to personal hygiene and dressing. Appetites were noticeably increased for salt- and sugar-containing foods, with constant consumption of sweets. He became more dependent on his wife and was unable to make decisions. For example, he had problems making a selection of meal items from a restaurant menu. He often was hyperemotional and exhibited mood swings, irritability, and frustration. He became insensitive to the feelings of others, although he also became overly generous with people and charities. He became less able to handle money, and his wife had to remove his credit card from his possession. He started sleeping excessively, about 10 hours per day. He displayed repetitive vocal mannerisms, such as repeating the phrase "ah hah!" He developed an obsession about driving several states away from his home for purchases, and showed increased forgetfulness, often misplacing his wallet. Despite these personality and cognitive changes, he was able to navigate without difficulty, with a well-maintained, excellent sense of direction. He was unable to continue to work, because of distraction and disorganization, but was still able to explain how to perform complicated jobs to his workmen. At this time, at age 50, he was rated "70% independent."

On the basis of these personality changes, he was diagnosed with frontal lobe dementia. Because there is no specific medication for this disorder, he was prescribed donepezil hydrochloride, a medication used for Alzheimer's disease (AD), and venlafaxine, for depression; these medications did not bring about a noticeable improvement in his symptoms. He continued to develop the following progressive personality changes. His judgment abilities became impaired. His sense of humor deteriorated. And, in addition to his penchant for sweets, he developed the habit of eating too quickly. He became increasingly agitated and restless and displayed a fear of water. At age 51, he displayed increasing language problems and became more socially withdrawn. He developed tooth-grinding (bruxism) and loss of control over his bladder (urinary incontinence). Restlessness, agitation, impatience, social withdrawal, obsessive TV watching, and sleep disruption continued to worsen. These symptoms were treated with the antipsychotic tranquilizing medication risperidone, as well as with the anti-anxiety medication lorazepam and the hypnotic sedative zolpidem. He became flirtatious and exhibited some sexually inappropriate behavior. He still was able to navigate well, with good map-reading ability and recall of directions. However, his disabilities increased and he died at age 55.

Medical History Back to Top

Prior illnesses were seemingly unrelated to his brain condition and included lumbar back disk disease, pneumonia, kidney stones, and peptic ulcers.

Social History Back to Top

Mr. Q. had completed high-school (education = 12 years) and was the owner-operator of a business. He had no history of tobacco smoking or excessive alcohol use.

Family History Back to Top

Several relatives had suffered early-onset dementia. One of his parents had a 10-year illness that developed shortly after age 50, with new, uncharacteristic, strange, obsessive habits that included constant whistling and the obsessive behavior of repeatedly sweeping floors. This condition progressed to memory difficulties and resulted in accidental death at age 60. Two siblings of Mr. Q. also developed early dementia at about age 50. One sibling had a 9-year illness, starting with symptoms of disinhibition and progressing to loss of communicative abilities [for example, superficial speech, repeating the phrases of others (echolalia)], memory problems, and seizures. Another sibling had several years of severe social withdrawal, was no longer able to perform activities of daily living, such as cooking and cleaning, and developed echolalia; the diagnosis was a frontal lobe neurodegenerative disorder (Pick's disease).

Neurological Examination Back to Top

Initial examination of Mr. Q. at age 47 was notable in that only mild mental status changes were evident. He was reasonably well-oriented, and correctly stated the date, but incorrectly stated the day, and was unable to specify on what floor of the building he was located. He also had some difficulty concentrating, and remembered only two of three objects verbally presented to him after a delay of 5 minutes. His Columbia modified mini-mental status examination (mMMS) score was 52/57. Subsequent examination at age 48 revealed little difference in his symptoms, nor marked change in his test results; his mMMS score was 53/57, essentially unchanged from the previous year. When he next visited the medical center, at age 50, examination did show interim changes that included increased difficulties in concentration, impairment of arithmetic abilities and spelling, and decreased short-term memory. He was able to remember one of three objects after a delay; his mMMS score had declined to 44/57. However, his orientation, speech, written and verbal comprehension, and abilities to repeat a spoken phrase and to write were still intact, as were his visuospatial abilities, including drawing (constructional praxis). Cranial nerve examination showed normal function of visual, visuomotor, and other cranial nerves. Motor examination showed new slight rigidity in the upper extremities, but was otherwise unremarkable. Results from sensory and reflex examinations were normal.

Laboratory Testing Back to Top

Blood tests were performed to examine blood cell counts, liver and kidney function, and vitamin B12 and thyroid hormone status and to look for serological evidence of past infection with syphilis. Results from all of these tests were within normal limits, although the B12 level was at the lower end of the normal range. Anatomical imaging using magnetic resonance imaging (MRI) at age 47 (Fig. 1, left column) showed only very slight brain atrophy (cerebral atrophy), such that minimal enlargement of the cerebral ventricles (fluid-filled cavities) was noticeable on the axial slices (Fig. 1, middle row). Repeat imaging at age 50 (Fig. 1, right column) revealed a dramatic change, in that the ventricles were markedly increased in size, as evident on sagittal view (top row), and were more prominent frontally, as evident on the axial view (middle row), and temporally (laterally) as evident on coronal section (bottom row). There is evident marked increase in volume of the brain sulci (the spaces between ridges) in the frontal region, as a result of a decrease in the size of the cortical gyri, which are the ridges themselves [most evident in sagittal (top) and axial (middle) sections in Fig. 1]. Functional imaging was performed using single photon emission computed tomography (SPECT) after injection of radiolabeled exametazime ([Tc-99m]hexylmethylpropyleneamine oxime, HMPAO), an agent whose brain distribution reflects brain blood flow. This procedure revealed moderately severe (somewhat asymmetric, left greater than right) hypoperfusion (decreased blood flow through the brain) in each frontal lobe and adjacent anterior parietal lobe, regions important for higher cognitive functions. The hypoperfusion of these regions was most evident in sagittal (top row) and axial (middle row) images; decreased perfusion was also evident in each temporal lobe [most easily seen on coronal (bottom row) images], regions important for memory (Fig. 2). Structures that did not exhibit decreased perfusion included the posterior parietal and occipital cortex (specific regions of the cerebral cortex that are important for visuospatial abilities, including drawing, visual reasoning, and navigation), deep nuclear structures, including the basal ganglia and thalami (which are important for movement and relaying sensory information, respectively), and the cerebellum (a part of the hindbrain that functions in motor function and balance).



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Fig. 1. Brain MRI. Selected sagittal (top row), axial (middle row), and coronal (bottom row) plane images of the brain obtained at age 47 (left column) and at age 51 (right column). Images are of 5-mm-thick brain sections and show fluid as black, since they were obtained with T1-weighting or FLAIR (fluid attenuated inversion recovery) sequence (right middle frame only). Minimal atrophy was evident at age 47, with slight ventricular enlargement compared to what is normal for that age. By age 51, there is a marked progression of atrophy, with significant shrinkage of brain volume. These tissue losses are reflected in the increased size of the fluid-filled lateral ventricles, most prominently in the frontal region (see axial slices, middle row), but also evident in the temporal region (see increased size of temporal horns in coronal slices, bottom row, short arrows). The fluid-filled sulci have become larger, reflecting brain loss that occurs with gyral narrowing, particularly in the frontal and temporal regions as seen in the sagittal and axial slices (long arrows). There is also some slight increased FLAIR signal periventricularly (right middle frame), consistent with some white matter change, likely secondary to the loss of gray matter.

 


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Fig. 2. Brain SPECT. Selected 5-mm slices in sagittal (top row), axial (middle row), and coronal (bottom row) planes, from a single photon emission computed tomography imaging study performed at age 51 using exametazime (Ceretec, HMPAO, see text). Quantitative measures of radiotracer uptake are coded in pseudocolor, as shown in the strip at the bottom, with black, green, and blue representing very low perfusion (blood flow) signal, and orange, gray and white representing higher blood flow. Normal brain shows a relatively homogeneous cortical perfusion pattern, for example, with "orange" throughout the superficial gray matter, and somewhat higher levels (for example, "white") in the deep nuclei, including basal ganglia and thalami, and the cerebellum. In this study, marked decreased relative perfusion is notable in the frontal regions (long arrows) and anteromesial temporal (short arrows) regions, indicating regions of decreased brain function, that are greater in extent than evident areas of severe atrophy detected by MRI.

 
Neuropsychological testing at age 47 showed overall average intellectual performance (IQ) on the Wechsler Adult Intelligence Scale (WAIS) for both verbal and nonverbal tests. Mild, isolated deficits were noted on tests of attention and concentration, including slowness on tasks requiring "executive function," a frontal lobe function. However, memory, a temporal lobe function, was intact, as were visuospatial abilities, which are generally parietal lobe functions. Tests for depression did not reveal marked signs of this condition. The interpretation of these borderline testing results was that his symptoms of emotionality and distractibility might derive from psychosocial stressors, including the illnesses of several family members, rather than from a neurodegenerative condition. However, at age 51, repeat neuropsychological testing showed significant decline from the prior evaluation. Language functions were particularly affected. On a test of ability to name objects, his previously intact performance had markedly declined. He had initially been able to name 56 of 60 pictured objects, but his performance had deteriorated, such that he could only name 25 of 60. Similarly, on tests of verbal fluency (ability to generate a large list of words of a particular type), he had previously performed within normal limits, but now exhibited severely impaired performance of "letter" and "category" fluency (results were at less than the first and fourth percentiles, respectively). Abilities to repeat a phrase and to comprehend written and spoken language were all preserved. Abstract reasoning and the ability to shift-set (change strategy on a test) had become severely impaired; marked perseveration (inappropriate repetition of his previous strategies) was evident. Tests of attention, concentration, and executive function showed impairment in these areas; he displayed both slow speed and difficulty in performance. Visuospatial abilities were still relatively normal, such that he exhibited average ability to manipulate visual material, relatively preserved drawing skills, and excellent matching and recognition of visual material. Memory testing showed only mild impairment (performance at 20th percentile) for recall of verbal material (word lists and content of stories) after a delay and similar modest impairment of memory for nonverbal material, such as visual drawings. This testing, which now showed a variety of severe deficits in frontal lobe function, with lesser deficits in temporal lobe functions, and relative sparing of mental functions relating to the parietal lob, was judged most consistent with a frontal lobe dementia. He was tested once again at age 52, to monitor the progression of his disorder. By that age, he had developed even more severe difficulties with naming and verbal fluency, and his performance in tests of memory had become significantly impaired, for verbal material more than for visual material. Tests of attention showed further decline, and drawing ability now showed some impairment.

Clinical Diagnosis Back to Top

This gentleman had insidious gradually progressive changes in mental capacity, starting at about age 47. These changes became more explicitly evident to family and physicians by age 51. There are a number of features of this disorder that make it dissimilar from the usual presentation of the most common dementia, AD. First, memory dysfunction was neither a major complaint nor a significant finding early in the course of the disease. This result would be quite unusual for an individual with AD, the most common neurodegenerative disorder, because it routinely affects memory systems as its earliest manifestation. Furthermore, there were marked early changes in behavior, which included distractibility, loss of interests (anhedonia), disinhibition, hyperemotionality, overeating (hyperphagia), unusual vocal mannerisms, and obsessiveness, all symptoms of frontal lobe and temporal lobe dysfunction that occur in frontotemporal dementia (FTD). In addition, comprehension of language and visuospatial abilities were not affected, even very late in the course of the disease; these superior temporal and parietal functions are usually very affected in AD. Second, the patient was unusually young. Although AD might present with symptoms as early as the third or fourth decade of life, it is quite uncommon for onset to occur in individuals under the age of 50. The population prevalence of AD at age 50 is <0.1%, compared to 2% at age 70 and 30 to 60% at age 90. Among persons presenting to a university dementia clinic, typically <1% of patients diagnosed with AD are under age 50. Finally, there is a striking family history of similar unusual early-onset dementing illnesses in his first-degree relatives (parent and siblings). Both AD and FTD might present as early-onset familial disorders, but the particular symptoms of the relatives, like those of the patient himself, are also characteristic of FTD. Thus, the clinical syndrome in this case shows symptoms distinct from those of AD. Other features of this case, including frontal atrophy and hypoperfusion revealed by neuroimaging and frontal dysfunction revealed by neuropsychological testing, are also supportive of a diagnosis of FTD, although neither is diagnostic by itself.

Neuropathological Examination Back to Top

Mr. Q. died at age 55, and an autopsy restricted to the brain resulted in a definitive diagnosis of FTD. On external examination, the brain was of low to average weight. However, there was marked shrinkage (atrophy) in the frontal lobe (with the exception of the precentral gyrus, or motor strip) and anterior and inferior portions of the temporal lobe (see Fig. 3). The gyri were notably thin and showed a granular appearance with tan discoloration. The intervening fluid-filled spaces (sulci) were enlarged. Gyri in the parietal lobes showed only mild alterations, and those of the occipital lobe appeared normal. There were no focal abnormalities that suggested strokes, tumors, or abscesses. There were no abnormalities of blood vessels and no signs of atherosclerosis. Thus, the gross examination of the entire brain was significant for an obvious pattern of disproportionate atrophy of frontal and temporal lobes.



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Fig. 3. Gross external view of the formalin-fixed right cerebral hemisphere. The overlying leptomeninges have been removed from most of the brain surface, except for a small portion over the parietal lobe and the occipital lobe (on the left). Marked shrinkage of gyri and widening of sulci are evident in the frontal (at right, long arrows) and temporal (at bottom, short arrow) lobes. The superior temporal gyrus exhibits marked atrophy of the anterior one-third portion, whereas the posterior two-thirds are normal in appearance.

 
Microscopic examination of brain sections from different cortical brain regions revealed specific neuropathologic findings in a regionally informative pattern. Particularly involved were middle frontal, superior, middle, and inferior temporal, inferior parietal, precentral, cingulate, insular, entorhinal, and trans-entorhinal cortices. Thus, the anterior regions of the brain were more affected than the posterior, parietal, and occipital portions, a pattern characteristic of FTD. The alterations included changes in neuron number and structure, as well as severe loss of neurons and the presence of ballooned neuronal cells (Fig. 4). Immunostaining for a phosphorylated form of the microtubule-associated protein tau (using monoclonal antibody AT8) showed diffuse abnormal intraneuronal cytoplasmic staining, sometimes referred to as "pretangles," within cortical and pyramidal neurons in the hippocampus (Fig. 5) and granular cell neurons of the dentate gyrus (gray matter under the hippocampus). There were also significant astroglial changes, including the presence of tau-positive "tuft-like" profiles in astrocytes in these regions (Fig. 6). Rarefaction (loss of density) of white matter was noted (Fig. 7), indicative of axonal loss consequent to neuronal cell loss. In the deep nuclei of the basal ganglia and basal forebrain, gliosis (increased astrocytic cell size and number) was also apparent, although the neurons themselves were relatively preserved. The thalamus was preserved, whereas the brainstem showed marked degeneration. The substantia nigra (Fig. 8) in the midbrain showed prominent neuronal cell loss, unaccompanied by cell inclusions such as Lewy bodies or neurofibrillary tangles. Similarly, in the pons, there was severe depletion of the pigmented neurons of the locus coeruleus. The cerebellum showed mild loss of Purkinje cells (neurons that conduct signals away from the cerebellum), a not uncommon change that is not specific for a particular disorder. There were no signs of Alzheimer's pathology in the brain, including either any amyloid deposition in the form of diffuse plaques or neuritic plaques, nor any classical neurofibrillary tangles. Thus, the microscopic sections showed regional significant loss of neurons and associated white matter, astroglial change, and immunohistochemical evidence of tau protein pathology.



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Fig. 4. Microscopic histological changes. A ballooned neuron (center of field, arrow) is noted against a background of rarefied neuropil (with decreased fiber content) and gliosis (increased presence of astrocytes) in this section of frontal neocortex stained with hematoxylin and eosin.

 


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Fig. 5. Neuronal tau protein changes. In this section of hippocampus, phosphorylated tau protein deposits are seen in the cytoplasm of many of the pyramidal neurons, as shown by the diffuse brown staining (long arrows) in their cytoplasm. In the normal-appearing neurons, the cytoplasm is pale blue (short arrows) as a result of the visualized counterstain, without superposed immunostain. This section was immunohistochemically stained with an antibody (AT8) directed against phosphorylated tau protein and visualized with immunoperoxidase methodology.

 


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Fig. 6. Astrocytic tau protein changes. Astrocytic cells also showed abnormal tau protein deposits. Immunohistochemical staining of the frontal neocortex for phosphorylated tau protein (AT8 antibody) revealed the presence of tau pathology in the cytoplasm of astrocytic cells. The three-dimensional arrangement of the tau protein-rich cell processes gives these astrocytes a so-called "tuft-like" appearance (arrows). This section was immunohistochemically stained with an antibody (AT8) directed against phosphorylated tau protein and visualized with immunoperoxidase methodology.

 


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Fig. 7. White matter changes. This low-magnification view of the cerebral white matter shows marked tissue rarefaction. There is a noticeable decrease in the density of oligodendrocytes, represented by the small, round, dark blue nucleated cells without discernible cytoplasm (long arrows). There are also increased numbers of astrocytic cells, represented by the slightly larger nucleated cells with distinctive pink cytoplasm with processes (short arrows). This section was stained with hematoxylin and eosin.

 


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Fig. 8. Brainstem changes. This low-magnification view of the brainstem shows the substantia nigra. The distinctive pigmented neurons (arrows) are much reduced in number compared to normal. There is also astrogliosis and background tissue rarefaction. This section was stained with hematoxylin and eosin.

 

Discussion Back to Top

The combination of symptoms and signs, and the results from auxiliary testing are all most compatible with a diagnosis of FTD. Two broad presentations of this disorder are recognized: one with behavioral involvement and personality change; and the other with prominent language involvement, which can be either a variety with progressive expressive aphasia (inability to speak) or one with progressive failure to comprehend (semantic dementia). The characteristics described in this report correspond to the behavioral presentation of FTD. There was a panoply of symptoms and signs that all were indicative of dysfunction of the frontal, and also temporal, lobes of the brain. Negative symptoms such as placidity, loss of interests, apathy, depression, abulia (decreased speech, movement, and decision-making), and anhedonia are all common symptoms that originate with frontal lobe dysfunction. Positive symptoms that include agitation, frustration, hyperemotionality, hypersexuality, hyperorality, and overeating may also be the consequence of frontal dysfunction. It is likely that such positive symptoms generally result from loss of frontally mediated "inhibiting" influences on behavior. For this reason, "disinhibition," or loss of usual social inhibitions, is often viewed as a hallmark sign of frontal lobe impairment. Obsessive, repetitive, and often bizarre behaviors are also seen as a consequence of dysfunction of the frontal and temporal lobes.

These consequences of bilateral frontal and temporal lobe injury have also been seen in rare cases of nondegenerative injuries in humans. In classic brain lesion experiments in primates, rhesus monkeys subjected to bilateral temporal lobe ablations were found to show a specific spectrum of symptoms, termed the "Klüver-Bucy" syndrome. This includes marked "oral tendencies," that is, excessive eating and inappropriate placement of nonfood objects in the mouth. Decreased emotional responses, but increased, inappropriate sexual activities, are prominent. Attentiveness is preserved, often with a tendency to pay excessive, obsessional attention to visual stimuli.

Neuropsychological testing can often suggest a "frontal" pattern of deficits. Language difficulties in the expressive domains, with decreased word generation, verbal perseveration (repetitiveness), and echolalia, may occur. Disturbances of executive function may be noted, with difficulty performing sequencing tasks. Performance on tests requiring "set-shifting," or responses to changed circumstances, also shows marked impairment. These signs of frontal lobe dysfunction can also be seen in a variety of conditions including, to a lesser degree, AD. However, in the appropriate clinical setting, such frontal neuropsychological dysfunction in the absence of more typically Alzheimer-like dysfunction of temporal regions (evident as verbal and nonverbal memory problems) and parietal regions (manifested as visuospatial dysfunction and navigational difficulties), makes FTD much more likely.

A number of clinical disorders primarily manifesting signs and symptoms of degeneration of the frontal, or frontal and temporal, lobes have been described. Various monikers for these syndromes have included Pick's disease, frontal lobe dementia, progressive subcortical gliosis, and others. These disorders are now broadly classified as FTD. Such disorders seem to have a common pathologic basis of abnormalities of tau protein deposition, such as in the above neuropathological description of this case. Some of these disorders are familial, and have an autosomal dominant pattern of inheritance, as is seemingly present in this case. However, the majority are nonfamilial, or sporadic. Of the individuals with inherited forms of the disease, a significant proportion have been found to have mutations in the tau gene, located on chromosome 17, either in exonic (coding) regions, or in intronic regions, which can affect the RNA-splicing pattern of tau transcripts and the relative prevalence of tau isoforms. Although some but not all FTD cases involve derangement of tau expression or deposition, there is still very limited understanding of the sequence of disease pathogenesis in these cases, as well as in those cases less obviously involving tau protein. Related to the insufficient knowledge of disease pathogenesis, at the present time there are no disease-specific treatments available for FTD. However, a spectrum of neuropsychiatric medications are very helpful in providing symptomatic benefits.


April 2, 2003

Abbreviations: Activities of daily living. Daily tasks such as bathing, eating, and dressing. Clinicians often assess activities of daily living to determine what kind of care a patient needs. • Aphasia. The inability to produce or comprehend spoken or written language due to brain lesions and not a result of faulty innervation of speech muscles, disorders of articulation, or mental retardation. Head trauma, stroke, Alzheimer's disease (AD), and infection can damage language areas of the brain--specifically, the left temporal lobe or nearby frontal lobe--and produce disturbances in language function. • Basal ganglia. Several large clusters of neurons located within the cerebral hemispheres made up of the putamen, caudate nucleus, and globus pallidus. The cells of this region are crucial to initiating and coordinating movement. Disorders associated with diseases of the basal ganglia include chorea, athetosis, hemiballism, and Parkinson's disease. • Brainstem. The portion of the brain immediately superior to the spinal cord, consisting of the pons, medulla, and midbrain. Collected here are neuronal circuits that control respiration, cardiovascular function, eye movement, equilibrium, and some stereotyped movements of the body. Many of the cranial nerves arise in the brainstem, and all of the nerve fibers running between the spinal cord and higher brain centers pass through this region. • Cerebral cortex. Thin mantle of gray matter covering the cerebral hemispheres, folded into ridges (gyri) and furrows (sulci). The cortex is involved in cognition, memory, consciousness, behavioral reactions, and speech. Deficits associated with lesions of the cerebral cortex depend on the specific area(s) affected. • Cerebellum. Portion of the brain that lies just below the posterior part of the cerebrum and behind the brainstem. Integrating information from the cerebrum and peripheral parts of the body, the cerebellum plays an essential role in coordinating voluntary movement, controlling muscle tone, and maintaining balance. Symptoms of cerebellar lesions include motor incoordination, tremors, disturbances of gait and balance, slurred speech, and nystagmus. • Dementia. The loss of cognitive and intellectual capacities characterized by deficits in memory, attention, orientation, language, judgment, motor and spatial skills, and altered emotional behavior and personality. Dementia is most commonly caused by neurodegenerative conditions in which neuronal cell function or integrity is progressively lost. • Diffuse plaques. Early-stage deposits of {beta}-amyloid protein in the brain. These plaques appear less dense than neuritic plaques and do not have associated neurites. These plaques consist primarily of {beta}-amyloid protein and have little associated detritus from nearby dead or dying neurons. • Frontal lobe. A region of the anterior cerebral hemisphere where the motor cortex, speech centers, and some association cortices are located. Damage to the frontal lobe may be marked by deficits in motor function, language use, memory, abstract and creative thinking, problem solving, concentration, judgment and impulse control, and changes in behavior and personality. • Gray matter. The portion of the brain and spinal cord that appears gray in unstained specimens. It is mostly composed of nerve cell bodies, dendrites, unmyelinated portions of axons, and glial cells, and it includes the cortex of the cerebrum and the cerebellum, as well as deeper brain structures such as the basal ganglia. • Gyrus. A convolution or ridge on the surface of the cerebrum, separated from other gyri by grooves or furrows known as sulci. • Hippocampus. Part of the limbic system located in the medial temporal lobe and important in memory formation. Hippocampal lesions lead to an inability to transfer contents of short-term memory to long-term memory (anterograde amnesia). • Hypoperfusion. Abnormally low blood flow through a tissue. In neurodegenerative disease, regionally decreased blood flow is usually not an indication of an obstruction of blood flow to that region, but rather an indication of impaired brain function in that region, with resultant decreased blood demand. • Lewy bodies. Intracytoplasmic inclusions originally identified within select subcortical and brainstem neurons of patients with Parkinson's disease. Lewy bodies were subsequently found to be more widespread in distribution in patients that exhibited a dementing neurodegenerative disorder. That disorder is now referred to as dementia with Lewy bodies. Lewy bodies contain many proteins, but three proteins are particularly abundant--alpha-synuclein, neurofilament, and ubiquitin. • Locus coeruleus. A collection of norepinephrine-rich neurons located in the lateral isthmus of the pons, with projections to the hypothalamus, cerebral cortex, amygdala, hippocampus, and thalamus. The locus coeruleus plays a role in alertness, observational skills, regulation of respiration, micturition, control of central nervous system blood vessels, and REM sleep. There is a marked decline of neurons here in patients with AD. • Magnetic resonance imaging. MRI is a diagnostic technique based on the physical principle of nuclear magnetic resonance. The body to be imaged is inserted into a magnetic field, causing the magnetic spin of the hydrogen nuclei to align with the magnet. Radio signals are used to transiently perturb this alignment. As the nuclei snap back to alignment, weak electromagnetic signals are produced. The use of additional spatial magnetic field gradients, and integration of multiple signals, allows computerized reconstruction of an image of the tissue. MRI provides excellent sensitivity and resolution for detecting and localizing brain pathologies. • Mini-mental status examination. One of several standardized, commonly used, quick "screening" assessment measures of a person's thinking and memory function. The test includes measures of orientation (asking the patient for today's month, day, and year), concentration (ability to spell a word backward), language, drawing skills, and memory for words that individuals are asked to remember after a delay of some minutes. • Neuritic plaques. Pathologic protein clumps found outside of cells in the brains of people with AD. The clumps consist of {beta}-amyloid protein knit together with twisted, irregularly shaped axons and dendrites from neurons, as well as portions of other brain cells called glia. Neuritic plaques and diffuse plaques are two subsets of amyloid plaques. Neuritic plaques are more associated with symptoms of AD. • Neurofibrillary tangles. Abnormal structures located in neurons in various parts of the brain, composed of dense arrays of paired helical filaments. These filaments likely incorporate intermediate filaments, microtubule-associated proteins tau and MAP-2, actin, and ubiquitin. One of the hallmarks of AD, the number of these tangles as seen postmortem has some correlation with the degree of dementia during life. • Neuropsychological testing. Standardized measures of memory, language function, attention, visuospatial abilities, problem solving, and other mental performance, allowing quantitative estimates of a person's abilities in each of these spheres, relative to other persons of the same age. These tests include paper-and-pencil tasks, answering questions aloud, memory tests, tasks designed to assess analytic and organizational abilities, drawing a figure seen previously, or building patterns with blocks. Many of the tests have been used for decades, and a variety of neurological and psychiatric disorders have been correlated with characteristic patterns of scores. • Occipital lobe. Posterior region of the cerebral hemisphere where the primary visual cortex and other visual processing and association areas are located. Damage to the occipital lobe can result in loss of object vision and light perception, impaired visual memory and pattern recognition, spatial disorientation, and visual word blindness. • Parietal lobe. Upper central area of the cerebral hemisphere, containing the sensory cortex and some association areas. The parietal lobe is involved in integration of sensory stimuli, understanding of visuospatial relationships, awareness of body position and orientation in space, mathematical function, language recognition, and word memory. Apraxia, difficulty calculating, astereognosis, right-left disorientation, and global confusion can be identified with lesions in this region. • Perseveration. A tendency to repeat the same sentence, question, or idea inappropriately. Perseveration can be a symptom of damage to the frontal part of the brain, which is responsible for self-control and decision making, among other things. • Pons. Brainstem region lying superior to the medulla. The pons serves as a relay station between the cerebral hemispheres and the cerebellum and is involved in regulating blood pressure, respiration, facial sensation and movements, and aspects of eye movement. Alterations in eye movement are symptomatic of lesions in this region, usually due to stroke. • Precentral gyrus. The primary motor area of the cerebral cortex, lying between the precentral sulcus and the central sulcus. All voluntary movement is orchestrated by this area, and damage to this region alone results in paralysis on the opposite side. • Rigidity. Stiffness or inflexibility due to an increase in muscle tone at rest and characterized by increased resistance to passive movement of a limb. In Parkinson's disease, cell degeneration in the substantia nigra results in rigidity. • Single photon emission computed tomography. SPECT is a functional imaging method using injection of a drug labeled with a radioisotope, such as Tc-99m, into the body. Tc-99m emits a single gamma-ray photon that is detected externally. Use of appropriate radioisotope-labeled drug, with detections of the photons at different angles, allows construction of a map of blood flow through various brain regions. Although SPECT has lower resolution than PET (positron emission tomography), it is used as a more widely available and less expensive assessment of cerebral blood flow and brain function. • Substantia nigra. Deeply pigmented subcortical nucleus in the midbrain where cells synthesize the neurotransmitter dopamine. This region is critical to movement control; cellular degeneration in the substantia nigra, as seen in Parkinson's disease, can result in symptoms of rigidity, tremor, slowed movement (bradykinesia), and postural imbalance. • Temporal lobe. Lower lateral portion of the cerebral hemisphere involved in visual recognition, auditory perception, emotion, and the processing and retrieval of memory. Right temporal lobe damage may result in loss of acuity for nonverbal auditory stimuli (e.g., visual material), while severe interference with verbal memory, and language formation can signal lesions in the left temporal lobe. • Thalamus. Ovoid mass of gray matter that forms part of the lateral wall of the third ventricle. It is the principle relay site for sensory signals traveling to the cerebral cortex and is involved in emotional associations of sensations and in arousal and alerting mechanisms. Thalamic lesions can cause decreased or increased sensitivity to sensory stimuli. • Ventricles. Four fluid-filled cavities situated centrally in the brain, including the two lateral ventricles, the third ventricle, and the fourth ventricle. They contain cerebrospinal fluid. Ventricle size may be increased in various neurodegenerative disorders in which there is a loss of brain substance, offsetting this tissue loss in the context of the fixed size of the cranial vault. • White matter. The portion of the brain and spinal cord that appears white in unstained specimens and occurs in the more central (nonsurface) regions of the brain. It is composed of myelinated nerve fibers and myelin-producing oligodendrocytes.

Suggested ReadingBack to Top

  • M. Goedert, R. A. Crowther, M. G. Spillantini, Tau mutations cause frontotemporal dementias. Neuron 21, 955-958 (1998). [Abstract]
  • M. Goedert, B. Ghetti, M. G. Spillantini, Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Their relevance for understanding the neurodegenerative process. Ann. NY Acad. Sci. 920, 74-83 (2000). [Abstract]
  • J. R. Hodges, Frontotemporal dementia (Pick's disease): Clinical features and assessment. Neurology 56, S6-S10 (2001). [Abstract]
  • A. Kertesz, D. G. Munoz, Frontotemporal dementia. Med. Clin. N. Am. 86, 501-518 (2002). [Abstract]
  • G. M. McKhann, M. S. Albert, M. Grossman, B. Miller, D. Dickson, J. Q. Trojanowski, Clinical and pathological diagnosis of frontotemporal dementia: Report of the work group on frontotemporal dementia and Pick's disease. Arch. Neurol. 58, 1803-1809 (2001). [Abstract]
  • H. J. Rosen, J. Lengenfelder, B. Miller, Frontotemporal dementia. Neurol. Clin. 18, 979-992 (2000). [Abstract]
Citation: L. S. Honig, K. Bell, S. S. Chin, Frontotemporal Dementia. Sci. SAGE KE 2003, dn1 (2 April 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/13/dn1








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