Sci. Aging Knowl. Environ., 17 October 2001
Vol. 2001, Issue 3, p. dn3
[DOI: 10.1126/sageke.2001.3.dn3]

NEURODEGENERATIVE DISEASE CASE STUDIES

Dementia with Lewy Bodies

Holly Posner, Steven Chin, and Karen Marder

The authors are at the College of Physicians and Surgeons, Columbia University, in the Departments of Neurology and Pathology, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY 12345, USA.

http://sageke.sciencemag.org/cgi/content/full/sageke;2001/3/dn3

Abstract: In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with dementia with Lewy bodies. Dementia with Lewy bodies might be the second most common form of degenerative dementia in the elderly. Progressive cognitive decline, well-formed visual hallucinations, and parkinsonism are core features of this disease. This case was marked by preserved verbal expression despite impairment in memory, visuospatial skills, and attention span. Development of visual symptoms and parkinsonism occurred very early in the course of the disease.

Introduction Back to Top

When H.Z. finally walked into the neurologist's office for initial evaluation, he had been having progressive memory impairment for 2 to 3 years (video clip 1). Remembering the names of familiar people and objects had become harder, and in the months prior, he had been begun experiencing strange visual phenomena. He had (illusions), perceiving inanimate objects as familiar people. In H.Z.'s own words:

"I came home one day and found my daughter (who lives in California) asleep on the living room couch. I was startled to see her because we were not expecting a visit. As I approached the couch, my daughter turned into a small pile of coats and throw cushions. It was somewhat disconcerting, but like 'Harvey,' the six foot rabbit from the Broadway theater, I found the experience more funny than ominous. As time progressed, each of my children appeared singly, in pairs, or in groups of three. They were non-vocal, frequently appeared to be sleeping, and did not relate to me or to each other."

Note to his doctor.

Eight years before the initial visit to his neurologist, he took early retirement from his Board of Education job. His wife and friends were still employed, so he had taken up watercolor and collage to occupy his time. Two to three years before seeking help from a neurologist, he began noticing lapses in short-term memory. At first they were extremely mild: a name, a misplaced item. He thought nothing of it. But slowly it progressed. He taught himself to compensate by becoming more organized, always keeping his keys in the same place and writing down everything from what he needed to buy to appointments he needed to keep. He developed noticeable word-finding difficulty over the next several years. He would find himself stuck midsentence as he wracked his brain for names to attach to faces and things. Song lyrics and lines of poetry once came quickly during conversations; now, he was suddenly losing words and "screwing up" jokes. In the 11 months before his visit to the neurologist, simple, routine tasks required more active thought. Several times he was momentarily stuck, unable to conceive how to find the door handle inside his car. Similarly, he spent an hour of uncertainty trying to add simple numbers, comparing his account and his expenses, so he could pay bills. H.Z. had difficulty recalling words at the pace needed for normal conversation. His speech was punctuated with unnatural gaps and pauses. Six months before H.Z. presented to the doctor's office, the first visual illusion occurred.

"One afternoon I was taking a stroll when I suddenly caught a glimpse of a dim shadow over my left shoulder. I felt a strong presence, which seemed to be directly behind me and dogging my footsteps. I remember thinking at the time that some friend or acquaintance was playing a childish prank. Finally, I turned my head to the left and in the words of Edgar Allen Poe's, 'The Raven': 'Darkness there, and nothing more...' I had this experience numerous times since and would describe it as more annoying than frightening."

Note to his doctor.

Later he realized he was always by himself when the manifestations occurred. Sometimes, for the first few moments after first seeing them, it would feel like the images were really there. He was never able to control when they would appear, but soon he learned how to make them vanish by reaching out to touch them, looking away for a second then turning back, or just blinking his eyes. When the false image faded, an inanimate, everyday object was always there in its stead. The images never spoke to him. They could not be attributed to poor lighting. He had cataracts, but they were at an early stage and did not need removal. In the beginning, he recognized the fictitious nature of the visual illusions; he had insight that they were not real. As time passed, however, they left him with the feeling that the house occupied by he and his wife was overcrowded and that he was deprived of privacy. With time and the progression of disease, his ability to separate the illusions from reality began to wane; the illusions became as real to him as everything else he could see.

The disease brought other nonperceptual changes as well. His style of being and personality began shifting. He opted for less social interaction, not wanting to leave home very often. He found his new artistic hobbies unattractive and complained that a "block" stopped his painting or making collages. He became more anxious. When he did go out, he found his way easily. The perceptual changes did not interfere with his ability to navigate. And, as his memory worsened, he compensated by relying more and more upon self-made lists. Chores took twice as long, apparently because it took longer to think things through. He had never been treated for depression and did not have depressive symptoms on direct questioning. His only medications were for stomach irritation and to reduce his blood pressure to within the normal range. Neither caused cognitive problems.

Physical changes eventually became apparent as well. In the year before H.Z. went to the neurologist, his walking slowed. And, in the 2 months preceding his neurological exam, he noticed that if he lightly touched his left toe to the ground and added a bit of weight, it would start bouncing on its own. This was self-induced clonus, an occasional indicator of a progressive intracerebral process. Urinary and fecal continence remained normal, although some trouble with erections occurred. Incontinence and impotence both have autonomic nervous system components and can be disrupted by some of the diseases that cause dementia. A disease that prominently affects frontal systems, such as frontotemporal dementia, might show incontinence earlier in the course of disease than do other diseases that do not typically affect this area until later.

These visuoperceptual, motor, and personality changes all worsened over the year before the first neurological evaluation. The memory decline had started insidiously 2 years before and then chronically and progressively worsened over time. At the time of the initial evaluation, he was still able to give his own medical history and to speak eloquently about his abnormal visual perceptions. The memory impairment was moderate, but not yet severe.

Medical History and Examination Back to Top

His prior medical history, which included hypertension since age 55 and radiation treatment to the vocal cords for lymphoma 40 years ago, were both unrelated to his current symptoms. He had stopped smoking cigarettes in the 1970s and did not drink. His parents, siblings, and children had not suffered progressive memory loss, illusions, or involuntary movements.

The general physical examination showed that his treated blood pressure was normal when sitting (120/80) and did not change inappropriately when he stood up. This observation indicated that he had no orthostatic hypotension or dysautonomia and further indicated that the autonomic nervous system was intact. Had he experienced changes in blood pressure upon standing, he would have required intervention to reduce the risk of falls. Blood tests ruled out reversible causes of dementia such as syphilis, thyroid disease, or vitamin B12 deficiency.

Neurological Examination Back to Top

The general neurological examination most notably revealed slowness of movement, (bradykinesia), muscle rigidity, and tremor at rest--the three signs that make up the triad of parkinsonism. They were recognized through careful assessment of the fluidity, rhythm, accuracy, and voluntary control of movement. Specifically, the exam revealed normal speech rhythm, mildly reduced facial expression, and an occasional tremor of the legs at rest, but no tremor of the arms (video clip 2). There was no tonal rigidity of the neck or upper extremities when the examiner bent them. His neurologist found mild rigidity upon bending H.Z.'s legs symmetrically (video clip 3). Finger tapping (joining and parting the thumb and second digit) was mildly slow and inaccurate on both the left and right sides. He had no difficulty with other rapidly alternating movements. Findings of this sort reflect impairment in the integrity of the extrapyramidal system as opposed to the primary motor system. On a scale of 1+ to 5+ (where 2+ is normal), reflexes were 4+ throughout (hyperreflexia) with clonus (rapid, involuntary, persistent bouncing when the ankle is quickly and forcefully flexed) easily elicited.

Further examination indicated that pathways related to cranial nerves (CN) II to XII were functioning normally. H.Z.'s optic discs were appropriately flat, showing no abnormalities for the second cranial nerve (CN II). Pupils reacted appropriately to light and showed full extraocular movements. That is, he could move his eyes smoothly and fully in all directions so that the whites of his eyes were barely visible in the corners when he gazed to the extreme left, right, up, and down (CN III, IV, and VI). His eyes shut involuntarily when the corneas were lightly stroked with a cue tip (CN V and VII) . His face moved symmetrically (CN VII). Gag reflex was present (CN IX and X). He had slight difficulty protruding his tongue (CN XII). The skin over his body was symmetrically and equally sensitive to pin prick, light touch, and vibration. Both a glabellar reflex and bilateral palmomental reflexes were present. These "frontal release signs" indicate general cerebral malfunctioning of the pathways that descend from the frontal lobe. He could easily rise from a chair. His gait was significant for slightly stooped posture (although not unstable, as is often found in Parkinson's disease) and a lack of spontaneous movement (video clip 4).

Mental Status Testing Back to Top

Formal neuropsychological testing a month later revealed severely impaired acquisition and retrieval of novel verbal and nonverbal information, with deficient retention over time. He also performed poorly in attention-related tasks. Visuospatial construction, which links what is seen to movement of the body in space, was poor, reflecting a deficit in the visuospatial nerve network. Language functions were intact, as demonstrated by his ability to organize words both phonemically (by sound) and semantically (by meaning) and to complete a test of confrontational naming, in which the patient is asked to name an object that is in front of him. Other measured abilities were within normal limits, including general knowledge store, comprehension, and repetition. His particular pattern of deficits was consistent with dementia. Overall, this testing showed abnormalities in the domains of memory, visuospatial skills, and attention out of proportion to impairment in other areas such as language function. This confirmed the patient's complaints and served as a baseline for future comparison.

As the disease progressed over time, he gradually lost awareness of the fictitious nature of the illusions. He began to find them intrusive and bothersome. Eventually they provoked overt paranoia in him (video clip 5). Over the years, the neurologist prescribed various atypical neuroleptic medications and increased the dosage as needed for effectiveness. These included risperidone, olanzapine, and eventually clozapine. The last was the only effective medication for him. (Use of the typical neuroleptics, like haloperidol, can be associated with adverse outcomes, even death in people with Dementia with Lewy bodies). When one medication stopped working or had intolerable side effects, H.Z. tried another instead. This made the illusions more tolerable. H.Z. required a gradually increasing dose of the drugs to counter the "armies of people" around him who provoked paranoia and irritation. Even though bedside cognitive testing remained quite good, formal neuropsychologic testing deteriorated. In the beginning of 1999, he developed orthostatic blood pressure changes accompanied by dizziness. Tight elastic "Ted" stockings and salt pills were added to his regimen to minimize the risk of falling. His mood fell over the ensuing months and the antidepressant Zoloft was added, which succeeding in lifting his spirits. Several months later, he was hospitalized for severe problems swallowing. H.Z. passed away several days later from secondary complications of aspiration pneumonia.

Brain Autopsy Back to Top

An autopsy limited to the brain only was performed on this patient. The fresh brain weight was 1380 grams, which is normal (normal brain weight varies from 1300 to 1400 grams). Examination of the macroscopic features of the surface of the brain showed the cerebral hemispheres to be symmetrical. The frontal lobe, temporal lobe, parietal lobe, and occipital lobe each appeared normal. The brainstem and cerebellum were also externally unremarkable. There were no areas of discoloration, softening, or herniations. The leptomeningeal membrane covering the brain was normally thin and translucent. The blood vessels at the base of the brain showed a normal adult configuration of the circle of Willis and showed mild evidence of atherosclerosis.

The cerebral hemispheres were sequentially sectioned along a coronal plane. The lateral ventricles were unremarkable. The cortical gray mantle was of normal thickness and the underlying white matter was also grossly unremarkable. The basal ganglia and thalamus were grossly unremarkable.

Sequential sections of the midbrain, pons, and medulla at right angles to the neuraxis showed severe depigmentation of the substantia nigra, indicative of loss of the normally pigmented neurons in these region. The cerebellar hemispheres were sectioned along sagittal and parasagittal planes and did not reveal any detectable abnormalities.

The left half of the brain was frozen and placed in our brain tissue bank for special research studies, while the right half was fixed in formalin and subsequently sampled for histopathological examination. A standard set of neuroanatomic sites were sampled, and the resulting paraffin sections were examined with hematoxylin-eosin, thioflavine S, modified Bielschowsky silver, and Gallyas silver stains.

Sections of the midbrain confirmed the moderate to severe loss of pigmented neurons within the substantia nigra (Fig. 1). This was associated with a moderate amount of astrogliosis (Fig. 2). Within some of the remaining pigmented neurons of the substantia nigra were Lewy bodies and occasional pale bodies (Fig. 3, Fig. 4, and Fig. 5). The sections of the pons also showed mild loss of pigmented neurons and presence of Lewy bodies and pale bodies in the locus ceruleus. Lewy bodies scattered throughout the cortex were also identified with the routine hematoxylin-eosin stain (Fig. 6) and immunohistochemical stains utilizing antibodies directed against ubiquitin and alpha-synuclein proteins (Fig. 7). These cortical Lewy bodies were identified within neurons located in the lower cortical layers of the middle frontal gyrus, superior temporal gyrus, cingulate gyrus, insular cortex, transentorhinal cortex, and nucleus basalis. Semiquantitative assessment of the number of cortical Lewy bodies present satisfied current criteria for the clinicopathological diagnosis of dementia with Lewy bodies.



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Fig. 1. Substantia nigra of the midbrain visualized by light microscopy. This low magnification view of the midbrain shows the pigmented substantia nigra extending from the upper left corner to the lower left corner. The area of neuronal cell loss (arrow) stands out against the adjacent, less affected region (arrowheads). A 2X objective was used.

 


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Fig. 2. Astrogliosis surrounding the substrantia nigra shown using light microscopy. At the center of this high magnification micrograph are two relatively normal appearing, pigmented neurons of the substantia nigra. The surrounding brain tissue, however, is depopulated of neurons and is occupied by astrocytic glial cells (arrowheads). A 20X objective was used.

 


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Fig. 3. Visualization of Lewy bodies by light microsopy. In areas of the substantia nigra that appeared at lower magnification to be well populated with pigmented neurons, pathological changes such as intracytoplasmic Lewy bodies (arrows) and secondarily phagocytized neuromelanin (arrowheads) are evident. The clusters of phagocytized neuromelanin appear after pigmented nigral neurons die, disintegrate, and are scavenged by microglial cells. A 20X objective was used.

 


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Fig. 4. High magnification micrograph of Lewy body. The Lewy body is typically round and may show concentric layers of different staining intensities, as is seen in this hematoxylin-eosin-stained section. The normal intracytoplasmic, brown neuromelanin granules are pushed aside and a distinct pale zone is seen surrounding the Lewy body. A 60X objective was used.

 


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Fig. 5. Multiple intracytoplasmic Lewy bodies (arrowheads) may be seen in affected neurons. A 60X objective was used.

 


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Fig. 6. Lewy bodies in cortical neurons are not as morphologically dramatic as those found in the brainstem. Cortical Lewy bodies (arrow) do not show distinct concentric staining or a surrounding pale zone. A 60X objective was used.

 


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Fig. 7. Immunohistochemical staining with antibodies directed against alpha-synuclein protein dramatically highlights the cortical Lewy bodies (arrows). A 60X objective was used.

 
Sparse neuritic type senile plaques (Fig. 8), as well as moderate numbers of diffuse and amyloid core-type senile plaques were detected in the sections of the neocortex, hippocampus, amygdala, and basal forebrain. Neurofibrillary tangles were not, however, identified in these same regions, except for the focal presence of frequent neurofibrillary tangles within neurons of the entorhinal cortex (Fig. 9). The amount of senile plaque and neurofibrillary tangle pathology was not enough to qualify for a diagnosis of Alzheimer's disease and so the more descriptive diagnosis of "senile changes of the Alzheimers type" was rendered (see "Detangling Alzheimers Disease" and Honig). Moderate amounts of cerebral amyloid angiopathy, particularly within leptomeningeal blood vessels (Fig. 10), were also detected in some of the sample neocortical regions. Senile changes of the Alzheimers type and cerebral amyloid angiopathy are commonly seen in patients with dementia with Lewy bodies.



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Fig. 8. Special silver staining reveals the presence of neuritic type senile plaques (arrows) and neurofibrillary tangles (arrowheads) in the region of the entorhinal cortex. A 40X objective was used.

 


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Fig. 9. Neurofibrillary tangles are focally numerous in the entorhinal cortex. In this fluorescence micrograph, the neurofibrillary tangles (arrows) appear as bright yellow fibrillar material. The fainter orange, granular material is lipofuscin pigment, a normal component of neuronal cells. A 40X objective was used.

 


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Fig. 10. This collection of leptomeningeal blood vessels from the inferior parietal region shows bright yellow-staining amyloid within the vessel walls. A 20X objective was used.

 
The diagnoses based on the autopsy include

1. dementia with Lewy bodies (neocortical type)

2. senile changes of the Alzheimers type (mild, focal)

3. cerebral amyloid angiopathy (focally moderately severe); and

4. cerebral atherosclerosis (mild).

Discussion Back to Top

After completion of the initial history and physical, the diagnostic impression was of a 64-year-old gentleman with 1 to 2 years of progressive cognitive decline (mainly memory), a half-year of visual illusions, and more recent onset of tremor and slight rigidity. It was quite striking to hear him give such eloquent descriptions of his progressive memory loss and visual illusions given his degree of memory impairment. This is not typical of those with Alzheimer's disease. At the time, he experienced no syncope nor abnormalities of eye movement. There was no orthostatic hypotension, no fluctuating cognition beyond the ordinary (as would be seen in delirium), and no family history of a similar set of symptoms and signs. Reversible causes of dementia were excluded: Routine blood work was normal for syphilis, thyroid abnormalities, and vitamin B12 deficiency. Cognitive decline that interferes with normal function, well-formed, recurrent visual hallucination, and extrapyramidal features are core clinical features of dementia with Lewy bodies. This was considered the most likely diagnosis. The lack of orthostasis made diagnoses with prominent, early dysautonomia, like Shy-Drager Syndrome, much less likely. Full extraocular movements and relative equality of peripheral and axial body tone lowered the likelihood of Progressive Supranuclear Palsy. If this were Idiopathic Parkinson's disease with subsequent dementia, then usually the parkinsonism would have predated the cognitive symptoms by a longer period of time. According to the consensus criteria (see McKeith et al. in related reading) it is suggested that if dementia occurs within 12 months of onset of extrapyramidal motor symptoms, the patient should be assigned a primary diagnosis of possible dementia with Lewy bodies. If the clinical history of parkinsonism is longer than 12 months prior to the onset of cognitive impairment, Parkinson's disease with dementia will usually be a more appropriate diagnostic label. In advanced Alzheimer's disease and other dementia, parkinsonian signs may also be found in up to 30% of cases. These criteria are guidelines still under review. In the case of H.Z., parkinsonism, dementia, and psychiatric symptoms were prominent early in the course of the disease, though after slightly more than one year. For this reason dementia with Lewy bodies and not Alzheimer's disease or Idiopathic Parkinson's disease was the primary diagnosis entertained.

The diagnosis of dementia with Lewy bodies has several central core features. It requires progressive cognitive decline of a magnitude sufficient to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention, frontal-subcortical skills, and visuospatial ability may be especially prominent. The presence of two of the following three core features is also essential for a diagnosis of probable dementia with Lewy bodies (only one is essential for a diagnosis of possible dementia with Lewy bodies): fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are typically well formed and detailed, and spontaneous motor features of parkinsonism. Features that are supportive of the diagnosis are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and hallucinations in other modalities. It has been suggested that accuracy in the disctinction between dementia with Lewy bodies and Alzheimer's disease may be improved by emphasizing early hallucinations in the former.

October 17, 2001

Abbreviations: Amygdala. Almond-shaped mass of subcortical gray matter within the tip of the temporal lobe, with olfactory, limbic, thalamic, and hypothalamic connections. The amygdala receives highly preprocessed sensory impressions, is responsible for initiation and integration of somatic and autonomic responses, and is associated with affective behavior function. The amygdala also is referred to as the amydaloid body. • Basal ganglia. Several large clusters of neurons located within the cerebral hemisphere and upper brainstem, 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. • Bradykinesia. A slowness of voluntary motor activity and a reduction of autonomic movement. Bradykinesia can be a symptomatic of neurological disorders of the basal ganglia, such as Parkinson's disease, or can be a side effect of medication. • 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 many 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. • 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. • Cerebral amyloid angiopathy. A disorder that affects the small and medium arteries of the leptomeninges and cerebral cortex. It is characterized by amyloid deposits in the vessel walls, which can lead to hemorrhage or infarct. • Clonus. The term used to describe the most severe response to tapping of a muscle tendon (deep tendon reflex). It is characterized by rapid, repetitive alternating muscular contraction and relaxation. On rare occasions it occurs spontaneously. • Delusions. Irrational beliefs or incorrect inferences--regarding oneself, others, or external reality--maintained in spite of contrary evidence or the prevailing views of the culture. Besides being symptoms of various neurodegenerative disorders including Alzheimer's disease and dementia with Lewy bodies, they may also be symptoms of disorders like schizophrenia and manic-depressive psychosis. • Dysautonomia. This describes dysfunction of the autonomic nervous system, which includes the sympathetic and parasympathetic nervous systems. These systems are not under conscious control, but work in the background to regulate the cardiovascular, gastrointestinal, and urinary systems, and body temperature, metabolism, and the endocrine function. Commonly, blood pressure falls markedly upon standing (orthostatic hypotension). Dysautonomia can occur in association with neurodegenerative diseases such as Shy-Drager syndrome or in connection with other diseases such as alcoholism or diabetes mellitus. • Extrapyramidal. Refers to multisynaptic motor system that originates in cortical and subcortical centers and reaches the medulla and spinal cord by pathways outside the pyramidal (corticospinal) tracts. The extrapyramidal tracts synapse in the basal ganglia, other subcortical nuclei, and the brainstem. They are critical in modulation of movement and maintenance of muscle tone and posture. • Forebrain. The forwardmost part of the brain, composed of the telencephalon and diencephalon. The forebrain is divided into six anatomical areas: neocortex, basal ganglia, limbic system, thalamus, olfactory bulb and tract, and lateral ventricles. • 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. • Frontal release signs. Pathological reflexes originally described as associated with frontal lobe lesions but also common with diffuse cerebral impairments. Grasp, snout, rooting, palmomental, and glabellar reflexes are frontal release signs. • Glabellar reflex. Frontal release sign consisting of an inability to inhibit eye blinking when tapped above the bridge of the nose. In normal individuals, this response extinguishes after a few taps. The glabellar reflex is seen in Parkinson's disease, frontal lobe impairment, and diffuse cerebral disease. • Gyrus. A convolution or ridge on the surface of the cerebrum, separated from other gyri by grooves or furrows known as sulci. • Hallucinations. Sensations or perceptions experienced as real in the absence of any corresponding external stimuli. Occurring in any sensory modality, hallucinations may be provoked by drugs, epilepsy, psychiatric illness, neurodegenerative disease, or sensory deprivation. Degenerative brain changes may be marked by fragmentary visual hallucinations, while auditory hallucinations of voices are a primary symptom of schizophrenia. • 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). • Hyperreflexia. Abnormally exaggerated reflex strength associated with a lack of corticospinal inhibition, suggesting upper motor tract disease. • Illusions. False perceptions due to misinterpretation of real external stimuli. Illusions differ from hallucinations because they derive from an actual object or occurrence in external reality. Illusions may be secondary to neurologic or psychiatric diseases. • Insular cortex. A region of cortical gray matter located on the lateral aspects of the cerebral hemispheres that during normal development become covered over by growth of the frontal and temporal lobes. Part of the insular cortex is included in the limbic system. The region of the insular cortex appears to be very susceptible to various neurodegenerative pathologies. • Leptomeningeal membrane. The membranous covering of the brain and spinal cord, consisting of the arachnoid and the pia mater. The pia mater rests on the brain tissue and the arachnoid lies on the dura mater, the outermost membrane. Between the two layers of the leptomeningeal membrane is the subarachnoid space, which contains the cerebrospinal fluid. • 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. • Neocortex. Six-layered portion of the cerebral cortex that has arisen most recently during evolution. Frontal, temporal, and parietal lobes all have neocortex, but some certain brain cortex, such as in olfactory, hippocampal, and piriform regions, is more primitive and not "neocortex." The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and integrative association functions. • Neurofibrillary tangles. Abnormal structures located in various parts of the brain composed of dense arrays of paired helical filaments, now known to be composed of a hyperphosphorylated form of the microtubule-associated protein tau. Tangles, along with amyloid plaques, are major pathologic hallmarks of Alzheimer's disease. There appears to be some correlation of the number of these tangles seen postmortem with the degree of dementia during life. • Neuroleptic medications. Drugs that are used to treat psychotic symptoms (hallucinations and delusions) or aggression. Whereas early neuroleptics acted as dopamine antagonists, the newer antipsychotic agents target both serotonin and dopamine systems. • Nucleus basalis. A small region of the basal forebrain with wide projections to the neocortex and rich in acetylcholine and choline acetyltransferase. In Alzheimer's disease, there is marked cellular degeneration in the region with concommitant disorientation, motor unrest, and impairment of memory and speech. • 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. • Orthostatic hypotension. Sudden drop in blood pressure that occurs upon rising from sitting or reclining to standing position, causing symptoms of dizziness, blurred vision, and occasionally fainting. This condition is associated with Addison's Disease, diabetes, and some neurological disorders, such as Shy-Drager syndrome and other dysautonomias. • Pale bodies. A descriptive term that refers to abnormal accumulations of intracytoplasmic, pale staining material that is commonly encountered in neurons of the substantia nigra or locus ceruleus of patients with Lewy body pathology. The histological and immunohistochemical staining characteristics of pale bodies and Lewy bodies are very similar and it has been speculated that pale bodies may represent a "precondensed" form of Lewy bodies. • Parkinson's disease. A degenerative disorder of the central nervous system distinguished by bradykinesia, rigidity, postural instability, and resting tremor. Additional symptoms include changes in gait, stooped posture, "masklike" facial expression, and vocal weakness. A progressive loss of neurons in the substantia nigra and the resultant depletion of dopamine underlie this condition. • Palmomental reflexes. Frontal release sign exhibited as abnormal reflex contraction of the mental muscle of the chin when the palm of the ipsilateral hand is scraped with a sharp object (key). • 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 visual-spatial relationships, awareness of body position and orientation in space, mathematical function, languge recognition, and word memory. Aphasia, apraxia, difficulty calculating, astereognosis, right-left disorientation, and global confusion are identified with lesions in this region. • 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. • Senile changes of the Alzheimers type. A descriptive term used to indicate the presence of neurofibrillary tangle and/or senile plaque pathology but in quantities that are judged to be insufficient to make a diagnosis of Alzheimer's disease. • Senile plaques. Microscopic masses composed of fragmented axon terminals and dendrites surrounding an amyloid core. These plaques occur in small amounts in the cerebral cortex of normal elderly people and in much higher levels in those affected with Alzheimer's disease. • Shy Drager Syndrome. Progressive, degenerative disease of the central and autonomic nervous systems, with symptoms of orthostatic hypotension, impotence in men, lack of bowel and bladder control, loss of sweating, parkinsonian-like symptoms of muscle tremor and rigidity, slow movement, and other widespread neurologic deficits. Preganglionic sympathetic neurons in the lateral horn of the spinal cord are affected, and cell loss in the striatonigral and olivopontocerebellar regions is observed. • Substantia nigra. Deeply pigmented subcortical nucleus of the basal ganglia where cells synthesize the neurotransmitter dopamine. This region is critical to movement control, and cellular degeneration in the substantia nigra, as seen in Parkinson's disease, can result in symptoms of rigor, tremor, and akinesia. • Syncope. Similar to the lay term 'fainting', syncope often relates to a rapid fall in circulatory pressure (blood pressure, BP) on standing with resultant inadequate blood flow to the brain • Alpha-synuclein. A small protein originally found associated with synaptic vesicles. The function of this protein has yet to be defined. This protein appears to be a major component of the pathologic inclusions Lewy bodies, characteristic of Parkinson's disease and dementia with Lewy bodies, and glial cytoplasmic inclusions, characteristic of Multiple System Atrophy • 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., music), while severe interference with recognition, memory, and language formation can signal lesions in the left temporal lobe. • Thalamus. Ovoid mass of gray matter forming 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 sensitvity to sensory stimuli. • Transentorhinal cortex. A transition zone of cortical gray matter that bridges the more phylogenetically older three layered entorhinal cortex with the more recent six-layered neocortex. This region appears to be very susceptible to Alzheimer's type and Lewy body pathologies. • Tremor. A low-amplitude, high-frequency oscillation that most people show when they hold out their hands. Stress, fatigue, or certain drugs can exaggerate the tremor. • Ubiquitin. An ubiquitous small protein that is used for various cellular functions, including ATP-dependent protein degradation. Many of the abnormal cellular inclusions associated with various neurodegenerative diseases are tagged with ubiquitin protein.

Suggested ReadingBack to Top

  • I.G. McKeith, D. Galasko, K. Kosaka, E.K. Perry, D.W. Dickson, L.A. Hansen, D.P. Salmon, J. Lowe, S.S. Mirra, E.J. Byrne, G. Lennox,N.P. Quinn,J.A. Edwardson,P.G. Ince,C. Bergeron, A. Burns,B.L. Miller,S. Lovestone, D. Collerton, E.N. Jansen, C. Ballard, R.A. de Vos, G.K. Wilcock, K.A. Jellinger, R.H.Perry, Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47, 1113-1124.








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