Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. dn1
[DOI: 10.1126/sageke.2006.10.dn1]

NEURODEGENERATIVE DISEASE CASE STUDIES

Dementia with Cerebrovascular Disease

Clinton B. Wright, Jean Paul G. Vonsattel, Karen Bell, and Lawrence S. Honig

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

http://sageke.sciencemag.org/cgi/content/full/2006/10/dn1

Key Words: Alzheimer's disease • cerebrovascular disease • stroke • dementia • subcortical arteriosclerotic encephalopathy

Abstract: In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.

Introduction Back to Top

Mrs. R. was a 72-year-old right-handed woman who presented for neurological evaluation because of progressive decline in memory. For approximately the last 5 years, she had spent increasing time looking for misplaced items about the home. She started to find it necessary to write notes to herself to remember short shopping lists or appointments. She would fail to remember things she wished to tell her daughter when they spoke on the phone. She became frustrated by these problems. Her sister reported that Mrs. R had gotten lost twice on her way to visit her at her home. Her sister also related some personality change in Mrs. R. She had become more withdrawn and participated less in social situations. She was also more restless and did not like to stay in one place for very long periods of time. She more easily became emotionally upset, although she denied feeling depressed. She had not lost any weight. However, her sleep was poor, and she frequently awoke in the middle of the night and was unable to go back to sleep. Many of these problems became more noticeable after the death of her husband earlier in the year. He had taken care of their household affairs. After his death, she lived alone, but a housekeeper was hired to take care of most household chores.

Medical History Back to Top

Mrs. R. had a long-standing history of high blood pressure, high blood cholesterol, low thyroid hormone status, and adult-onset (type 2) diabetes mellitus. She had a myocardial infarction 5 years before presentation, treated with coronary artery bypass grafting. More recently, her coronary artery disease required percutaneous coronary angioplasty (during which blood vessels are unblocked with instruments inserted through the arterial system). Her medications at the time of evaluation included glyburide for her diabetes, amlodipine and atenolol for high blood pressure, pravastatin to decrease cholesterol, aspirin as cardiovascular prophylactic therapy, and levothyroxine as thyroid replacement therapy.

Family History Back to Top

Her mother had problems with memory beginning around age 80 and died at 83. Her father died of suicide at age 58 but did not have cognitive problems. A maternal uncle and aunt had been diagnosed with Alzheimer's Disease (AD) late in life.

Social history Back to Top

Mrs. R. had 18 years of education, including a Masters degree. She had been a schoolteacher until her retirement 10 years prior to presentation.

Neurological Examination Back to Top

On initial examination, Mrs. R. was noted to have some cognitive deficits. Her concentration and attention were normal. She was able to successfully repeat strings of digits forward and backward, and spell a word backward. She spoke rather normally but had mild problems with some aspects of language. She was able to understand written or oral commands adequately and was able to repeat a phrase normally. However, she displayed anomia, correctly naming only seven of ten pictured common objects. When she was asked to write a complete sentence of her choice, she did not do so but instead was "concrete" in that she simply wrote, "Write a sentence." She was fully oriented to place, but not to time: She was able to correctly state the day of the month, year, and day of the week, but not the correct date or the season of the year. Memory was clearly impaired. On a short-term memory task, she was able to register and immediately repeat three words but was unable to recall any of them after 5 minutes delay, even when subsequently given cues. Long-term memory was also impaired, with ability to recall the names of only the two most recent U.S. presidents. Her drawing ability was affected, and she was unable to successfully copy a drawing of a cube. Overall, her score on a global cognitive screening measure, the Columbia modified Mini-mental status examination (C-mMMS) was 42 out of 57 total possible points. (She would have been expected, given her age and education, to score about 57.)

The remainder of her neurological examination revealed normal cranial nerve and motor function, including gait and reflexes. Sensory examination did show a greater loss of vibration and temperature sensation in distal versus proximal regions (known as a "glove-and-stocking" distribution because hands and feet are more affected). This finding is typical of diabetic nerve disease (diabetic neuropathy; see Fink Perspective), for which she was at risk. The general examination was unremarkable except for the signs of her cardiac surgery.

Laboratory Testing Back to Top

Blood tests were performed to exclude thyroid or vitamin deficiency, or other factors that might affect cognition. Tests for thyroid hormone, vitamin B12, and serologic tests for evidence of infection with syphilis were all negative (normal). Brain magnetic resonance imaging (MRI; see Gazzaley Perspective) was performed to look for evidence of occult structural lesions. These images did show evidence of multiple small strokes involving the deeper brain structures. Specifically, lacunar infarcts were noted in the basal ganglia on both sides of the brain and in the left thalamus (Fig. 1). There was also evidence of MRI signal change suggesting ischemic damage in white matter located both periventricularly (Fig. 2) and in the pons. Dilated perivascular spaces were also evident (Fig. 3).


Figure 1
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Fig. 1 Lacunar infarct evident on MRI tomographic section. This axial section of the brain at the level of the thalamus, acquired using a T1-weighted sequence, shows a small hypointense area (white arrowhead). This area most likely represents a lacunar infarct and usually results from a past history of blockage in a small penetrating arterial blood vessel.

 

Figure 2
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Fig. 2 White matter signal change in MRI brain sections. Axial sections of the brain acquired with a proton-weighted sequence show areas of abnormally increased signal (black arrowheads) in the centrum semiovale (the mass of white matter inside the cerebral hemisphere) next to the lateral ventricles. Such areas are usually regions of injury from ischemia caused by cerebrovascular disease.

 

Figure 3
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Fig. 3. Enlarged perivascular spaces in an MRI image. Axial section of the brain acquired with a T1-weighted sequence that shows signal hypointensities (white arrowheads) characteristic of enlarged perivascular spaces. These findings are common in persons with long-standing high blood pressure, although the mechanism is unknown. It is possible that the penetrating vessels have minuscule movement that is more than usual, causing expansion of the space around the arteries and damage to the surrounding tissue (see Figs. 5 and 6).

 
Neuropsychological testing was performed to more precisely ascertain the nature and importance of the observed cognitive changes. The most substantial abnormalities were in tests of memory. Short-term memory was impaired for verbal material when required after a delay to freely recall the substance of two paragraphs or when required to recall a list of words. It was also impaired for visual material when she was asked to recall which of several simple drawn figures had been previously displayed. Long-term memory, examined using tests involving recall of items of common knowledge, was also impaired. In addition, Mrs. R.'s ability to copy several drawings was poor. "Executive function," a frontal lobe function assessed by tests of abstract reasoning and mental flexibility, was also impaired. On tests of abstract reasoning, she was concrete in that she showed decreased judgment and decreased complexity of content in her responses. On tests of mental flexibility, she was unable to inhibit inappropriate responses or shift from one "rule" to another. Language performance was relatively preserved, although she had some difficulty with naming and had some paraphasias. Attention, orientation, and drawing abilities were deemed within normal limits. Thus, the findings were mostly of memory and executive function difficulties and were deemed consistent with AD.

Clinical Diagnosis Back to Top

Mrs. R. was given a diagnosis of mild dementia likely caused by AD but with possible contribution of cerebrovascular disease visualized on the MRI. Her symptoms of memory loss and spatial disorientation and the pronounced memory change noted on neurological exam and formal neuropsychological testing seemed more suggestive of AD, and she had never had a clinical stroke. However, her neuroimaging studies, which included several brain MRI scans, did show cerebral infarcts in both left and right basal ganglia and in the left thalamus. MRI also showed that she had white matter T2-signal hyperintensities (areas of abnormality of proton spin-lattice relaxation time consistent with increased brain water content), likely ischemic in nature, in the periventricular white matter and pons, as well as enlarged perivascular spaces. These lesions were consistent with her known risk factors for cerebrovascular disease, including a lengthy history of cardiac disease, diabetes mellitus, and hypertension. The clinical contribution of these lesions to her cognitive state was unclear, however, in part because of their locations and extent and in part because of the lack of a history of temporally discrete changes. Her cognitive decline had been gradual, and the overall findings and course were deemed more consistent with AD than any other dementia.

Mrs. R. was prescribed the centrally acting acetylcholinesterase inhibitor tacrine hydrochloride (Cognex) in gradually increasing doses over the ensuing months. (Drugs that inhibit acetylcholinesterase are used in AD to increase synaptic levels of the neurotransmitter acetylcholine, which is ordinarily reduced in AD.) She was also deemed mildly depressed and was prescribed the selective serotonin reuptake inhibitor paroxetine hydrochloride (Paxil). She continued to show a gradual decline in cognitive abilities. She moved into an assisted living facility 1 year after presentation. Initially, she participated in activities at the facility. Over the next 2 years, she had more trouble carrying out basic chores, balancing her checkbook, and remembering recent events and appointments. Four years after presentation, she was rated as only 60% independent in her activities of daily living, a decline from 90% at the initial evaluation. Her eating was described as "messy," and she made mistakes in dressing herself. Her score on the C-mMMS declined from 42 to 30 out of 57 possible points. Repeat measures on formal neuropsychological testing continued to show declines in memory and language despite relatively normal attention and concentration. For example, her age-adjusted verbal fluency performance on a word-generation task declined from the 9th to the 2nd percentile. (She would have been expected to perform at least at the 50th percentile.) On neurological examination she was found to have parkinsonism with bradykinesia (slowness of movement) and a shuffling gait but no tremor or postural instability. These findings were attributed either to progression of AD, as is often seen as the disease progresses, or to progression of cerebrovascular damage, as is often seen with subcortical white matter disease. Parkinson's disease itself was considered unlikely given the symmetry of the findings and the development of these symptoms late during the course of dementia. She died of unknown causes 4 years later.

Neuropathologic Examination Back to Top

Gross examination of the brain at autopsy did not reveal externally evident structural abnormalities of the gyri of the cerebral cortex, but mild changes of atherosclerosis were evident in the large arteries at the base of the brain, with yellow plaques visualized in these arteries. The brain weight was 1100 grams, slightly below what is considered normal for women (1200 grams) and consistent with mild loss of brain tissue (atrophy). Both AD and vascular disease cause tissue loss leading to lower brain weight. The brain was sectioned in the coronal plane in 1-cm-thick slabs. The ventricles appeared of normal size (Fig. 4). A section of the temporal lobe at the level of the caudate nucleus showed a chronic infarct involving both the caudate and the internal capsule. Extensive dilatation of the spaces surrounding the cerebral arteries, or etat crible, was seen throughout the brain parenchyma (functional elements) (Fig. 5). The brainstem was sectioned. In the midbrain, the substantia nigra, the dopaminergic nucleus that projects to the basal ganglia, was normally pigmented, suggesting that the slowed movements and gait disorder that developed in this patient were not a result of Parkinson's disease (see Constantino Case Study). In the pons, the locus ceruleus showed only mild loss of pigment, unlike the more severe pallor typically seen in cases of AD, caused by losses of pigmented neurons.


Figure 4
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Fig. 4. Gross autopsy section of the brain. Photograph from gross examination of the formalin-fixed right half of the brain shows a 1-cm coronal slice including the hippocampus. There is evidence of mild atrophy (loss of brain substance) because of the somewhat dilated temporal horn of the lateral ventricle (asterisk), but overall atrophy is not prominent in the brain gyri and sulci (arrowheads).

 

Figure 5
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Fig. 5. Gross autopsy section of the right temporal lobe. There are small dark flecks in the white matter of this coronal slice of the temporal lobe pole. They represent abnormal dilatation of the perivascular spaces. Such changes were also seen in other brain regions, including the basal ganglia and cortex.

 
Microscopic examination was performed upon selected brain regions, using 10-µm sections of paraffin-embedded tissue generated by microtome. There were widespread changes of cerebrovascular injury in the brain parenchyma, as well as the cerebrovascular arterial disease noted in the vessels. Small lacunar infarctions were noted in the deep white matter of the frontal lobe (Fig. 6). Some regions of white matter showed demarcated areas of demyelination (Fig. 7). The presence in these areas of macrophages containing myelin debris is consistent with these areas being infarcts (Fig. 8). Enlarged perivascular spaces were microscopically confirmed in the sectioned white matter, basal ganglia, and thalamus (Fig. 9). In these areas, the neuropil (the network of cell processes surrounding the neurons in brain gray matter) was depleted of cells, and the perivascular spaces were filled with fibrous material (Fig. 10). Some perivascular areas showed macrophages containing iron, suggesting that the vessels were damaged to the point that red blood cells had leaked into the surrounding tissue (Fig. 11). There was extensive arteriosclerosis. Small arteries in the brain parenchyma, as well as in the leptomeninges showed thickened, sclerotic walls; smooth muscle cells had been replaced by protein (Fig. 10) (Fig. 11). There were also some findings of mild pathological changes seen with AD (see Honig Case Study ), but these were limited in extent and distribution. Neurofibrillary tangles were frequent in regions of the limbic system, including the entorhinal cortex, transentorhinal cortex, amygdala, and CA1 subfield of the hippocampus, which is not uncommon at this age. These were only moderate in number in the basal forebrain and temporal neocortex and only scattered and infrequent elsewhere in the neocortex. Neuritic senile plaques were present in neocortical sections, but only sparsely. Diffuse plaques, which consist primarily of beta-amyloid protein and are a form of amyloid plaque, were present in the temporal and frontal neocortex and amygdala. Diffuse plaques are commonly seen in aging brain and are not diagnostic for a specific disease. Overall, the plaques and tangles were not sufficient for a pathological diagnosis of probable or "high likelihood" AD.


Figure 6
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Fig. 6. White matter infarction. Microscopic image at medium-high magnification (20x objective) of a brain section stained with hematoxylin and eosin and counterstained with Luxol fast blue, which stains myelin. Infarcted tissue (arrow) begins to be invaded by macrophages within the first week after the event, and they digest the damaged tissue, which leaves a cavitation when this process is over.

 

Figure 7
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Fig. 7. White matter infarction and thickened arterioles. Photomicrograph of a section of the brain frontal lobe white matter was taken at medium magnification (20x objective). The section was stained with hematoxylin and eosin and counterstained with Luxol fast blue. The black bar separates an area of normal myelin (above bar) from an area in which the white matter tracts appear rarefied because of myelin loss (below bar). Two arterioles with markedly thickened walls may also be seen.

 

Figure 8
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Fig. 8. Photomicrograph of infarct at high magnification. This is a high-magnification (64x objective) view of the white matter rarefaction seen in Fig. 7. Macrophages containing myelin debris are seen (arrows).

 

Figure 9
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Fig. 9. Photomicrograph of perivascular spaces. This image shows a section of the dorsomedial nucleus of the thalamus, at low magnification, stained with hematoxylin and eosin. Several arterioles, seen in cross section, show prominent perivascular spaces (arrowheads).

 

Figure 10
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Fig. 10. Perivascular spaces and arterial changes. This image shows a medium magnification (20x objective) view of a brain section stained with hematoxylin and eosin. An enlarged perivascular space (black bar) extends from the surrounding brain tissue (A) to the arterial wall (B). The arterial wall is thickened, including an eosinophilic ring (B) and space filled with fibrous tissue (bar).

 

Figure 11
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Fig. 11. Extravascular blood products. This image shows a high magnification (40x objective) view of a brain slice stained with hematoxylin and eosin. Visible are macrophages (arrowheads), which are stained orange because of the presence of ferric oxide from phagocytosed red blood cells that leaked from the vessel into the surrounding tissue.

 

Discussion Back to Top

This woman presented at age 72 with changes in cognition, including memory and navigational ability. There was no history of clinical strokes, although she was at risk because of high blood pressure, diabetes, and a history of heart disease and showed neuroimaging findings of cerebrovascular injuries. The history and examination during life were thought to be possibly consistent with AD. After death, pathological examination revealed some changes characteristic of early AD, but cerebrovascular pathology was widespread and deemed important. It is likely that both types of pathology contributed to her cognitive dysfunction, neurological decline, and associated ultimate demise.

Vascular cognitive impairment is usually one of three major types: (i) multi-infarct dementia, in which a stepwise deterioration in cognitive abilities occurs because of multiple, temporally discrete, cerebral infarcts, typically involving the neocortex through medium or large artery occlusions. This condition is usually evident as motor deficits, absent in this patient; (ii) subcortical arteriosclerotic encephalopathy or dementia, also sometimes termed Binswanger disease, in which there is a gradual, progressive cognitive decline marked by increasing injury to subcortical white matter and basal ganglia from small vessel occlusive disease. This condition results in small lacunar infarctions and white matter ischemic damage. Typically, the only motor signs are those of "vascular parkinsonism," including gait dysfunction, with reduced stride and shuffling, urinary frequency and incontinence, and sometimes pathological laughing or crying (pseudobulbar palsy). This patient did indeed have some of these features; and (iii) strategic infarct dementia, in which a single large infarct in a strategic location, such as the thalami or bilateral frontal lobes, may cause marked cognitive decline, usually in a cataclysmic fashion. Of these three recognized syndromes, the case described here has many of the features of subcortical arteriosclerotic encephalopathy.

This case presents a common clinical scenario in that a dementia syndrome consistent with AD was present, but imaging findings suggested subclinical vascular damage, in this case lacunar infarcts and white matter hyperintensities. In this situation, the diagnosis may be termed "mixed dementia." In most such cases, the neuropathological findings are more strikingly those of AD than of cerebrovascular disease. In this case, the reverse is true, with the cerebrovascular changes rather extensive but the AD-like changes only mild. The degree to which these two different pathologies, when coexistent, contribute to the signs and symptoms of dementia is not fully understood. Studies have shown that patients with both vascular disease and AD-related changes are more likely to have dementia and have greater severity of clinical symptoms than those with AD alone. There are two broad hypotheses for the interaction of vascular disease and AD pathology. First, there may be a superposition of both pathologies, resulting in greater clinical dysfunction. Second, vascular disease might contribute to the formation or acceleration of the pathological changes of AD.

The high prevalence of vascular disease in older populations means that clinical stroke, as well as subclinical cerebrovascular damage and associated cognitive changes as seen in mixed dementia, are quite common. Pure vascular dementia, caused solely by infarcts, ischemic damage, or hemorrhages, is quite uncommon in the United States. Pathological series show, however, that one-third of patients who die of clinical and pathological AD have evidence of cerebrovascular infarctions. Cerebrovascular disease involvement in dementia has treatment implications. In the appropriate setting, prophylactic therapies with drugs that reduce the risk of thrombotic events, such as antiplatelet agents (aspirin, dipyridamole, and clopidogrel) and oral anticoagulants (warfarin), as well as those that prevent further damage from high cholesterol [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or "statins"] and hypertension [diuretics and angiotensin converting enzyme (ACE) inhibitors] may decrease the likelihood of further cerebral infarctions and white matter damage.


June 28, 2006

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. • 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. The amygdala is also referred to as the amygdaloid body. • Amyloid plaque. An abnormal neuropathological feature consisting predominantly of beta-amyloid protein but also containing other proteins, and often aberrant neuronal cell processes (neurites), as well as reactive astrocytes and microglial cells. Amyloid plaques can be found throughout the brain in AD but are often particularly concentrated in the temporal lobes. Plaques are extracellular structures (found outside of neurons); together with neurofibrillary tangles, which are intracellular (found inside neurons), they are defining neuropathologic features of AD. • Anomia. Difficulty in finding words or naming things. • Atrophy. Shrinkage. In AD, brain atrophy is evident in enlarged ventricles (normal fluid-filled cavities of the brain) and enlarged brain sulci (crevices), which are wider and deeper than in healthy brains. Atrophy associated with AD is often particularly prominent in the temporal lobes.beta-amyloid. beta-amyloid is a short protein, also called Abeta, that clumps into plaques in AD. This protein consists of a particular 39- to 43-amino acid-long sequence derived from a normal transmembrane cellular protein, called beta-amyloid precursor protein. The two most common forms are the 40-amino acid peptide Abeta40, which is less associated with AD, and the 42-amino acid peptide Abeta42, whose deposition appears to be more associated with the symptoms of AD. • Basal ganglia. The basal ganglia are a set of deeply located brain nuclei (groups of neurons), including the caudate, putamen, and globus pallidus. These nuclei are involved in the programming, timing, maintenance, and execution of body posture and movements. • 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, including the cerebral cortex, pass through this region. • Caudate nucleus. A nucleus (group of neurons) that is part of the basal ganglia in each cerebral hemisphere. • Cerebral cortex. Thin mantle of gray matter covering the cerebral hemispheres, folded into ridges and furrows (gyri and 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 affected. • Dementia. The loss of cognitive and intellectual capacities characterized by deficits in memory, attention, orientation, language, judgment, and motor and spatial skills, and altered emotional behavior and personality. Dementia is most commonly caused by conditions that injure the brain at tissue or cellular levels. In elderly individuals, AD is the most common dementia. • Diffuse plaques. Early-stage amyloid plaques that appear less dense than neuritic plaques and do not have associated neurites (nerve cell fibers). Diffuse plaques consist primarily of amyloid protein and have little associated detritus from nearby dead or dying neurons. • Entorhinal cortex. Anterior portion of the parahippocampal gyrus, located on the medial surface of the temporal lobe and involved in odor processing and memory. This area serves as a relay station between the association cortex and the hippocampus. It often shows some AD pathology even in normal elderly but is frequently the first region of the brain to exhibit pathology in AD. • Forebrain. The forward-most 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. The anterior region of each cerebral hemisphere, where motor cortex, expressive speech regions, 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 composed of nerve cell bodies, dendrites, unmyelinated portions of axons, and glial cells, and it forms the cortex of the cerebrum and the cerebellum. • Gyri. A gyrus is 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 each medial temporal lobe. The hippocampus is important in memory formation. • Infarcts. An infarct is a localized area of tissue death usually caused by ischemia from cerebrovascular disease. Typically, the cause is occlusion of a local arterial vessel. Occlusion may occur locally due to arteriosclerosis or atherosclerosis, with cholesterol-laden plaque, proteinaceous connective tissue, or a blood clot (thrombus) occluding the vessel lumen locally, or it may occur from an embolus (either a thrombus or other substance travelling to the affected artery from some upstream part of the arterial system or from the heart). • Internal capsule. A tract of white matter that lies within the basal ganglia. It consists largely of fibers running between the brainstem and the cerebral cortex. • Ischemic damage. Destructive change in brain tissue due to ischemia (local changes in blood flow). In general, ischemic damage causes infarcts, whether microscopic or grossly visible, but in some cases there is no frank death of neurons but simply, for example, loss of nerve cell fibers in white matter. • Lacunar infarcts. These are small infarcts, typically less than 1 cm in diameter, that are usually situated in deep brain regions such as the basal ganglia, thalamus, brainstem, or hemispheric white matter. These are usually caused by local occlusion of deep penetrating arterial branches. This occlusion is typically due to arteriosclerosis or atherosclerosis or, less commonly, an embolus (for example, from a small thrombus emanating from the heart). Lacunar infarcts are common in the presence of diabetes or hypertension. • Limbic system. A group of interconnected brain structures including the hippocampus, cingulate gyrus, hypothalamus, and amygdala. This system is thought to play a crucial role in processing emotions. • Locus ceruleus. A brainstem nucleus (group of neurons) located on both sides of the dorsal pons, which has pigmented neurons that produce the neurotransmitter norepinephrine (noradrenaline). It may play a role in arousal, control of anxiety and blood pressure, and REM (rapid eye movement) sleep. This nucleus is typically affected in both AD and in Parkinson's disease. • Leptomeninges. The delicate "lighter" membranes of connective tissue that cover the brain and spinal cord, consisting of pia and arachnoid. • Magnetic resonance imaging. Magnetic resonance imaging (MRI) is a diagnostic technique based on the physical principle of nuclear magnetic resonance. The portion of the body to be imaged is inserted into a magnetic field, causing a slightly increased alignment of the magnetic spin of hydrogen nuclei. Radio signals are used to transiently perturb this alignment. As the nuclei snap back to alignment, weak electromagnetic signals are produced. Multiple signals are integrated by computer to construct an image of the tissue. MRI provides excellent sensitivity and resolution for detecting and localizing brain pathologies. • Midbrain. Also known as the mesencephalon, it is the most rostral portion of the brainstem. Among the functions localizing in this region are control of certain eye movements. • Mini-mental status examination. One of several standardized, commonly used, quick "screening" assessment measures of a person's thinking and memory function. These tests include asking the individual for today's month, day, and year; to spell a word backward; and to remember some words and recall them some minutes later. • Neocortex. Six-layered portion of the cerebral cortex that has arisen most recently during evolution. Frontal, temporal, and parietal lobes all have neocortex tissue, but some brain cortex tissue, such as in the olfactory, hippocampal, and piriform regions, is more primitive and is not "neocortex." The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and integrative association functions. • Neuritic senile 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 pieces 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 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 neuritic senile plaques, are major pathologic hallmarks of AD. There is some correlation of the number of these tangles seen postmortem with the degree of dementia during life. • Neuropsychological testing. Standardized measures of memory, attention, visuospatial abilities, problem solving, and other mental performance. Tests can include paper-and-pencil tasks, answering questions aloud, drawing a figure seen previously, or building patterns with blocks. These tests allow comparison of the performance of a subject with individuals of similar age and education. The patterns of performance assist in the diagnosis of various neurological and psychiatric disorders. • Paraphasias. Speech defects. A paraphasia occurs when an unintended word, related to the intended word, is produced while speaking. • Parkinsonism. Symptoms of the type seen in Parkinson's disease, such as rigidity, loss of balance, certain tremors, or bent posture. • Parkinson's disease. A degenerative disorder of the central nervous system distinguished by symptoms that may include slowness of movement, rigidity, postural instability, and resting tremor. Other symptoms may include specific changes in speech and gait, stooped posture, and "masklike" facial expression. This disease is caused by a progressive loss of brainstem neurons in the substantia nigra and the resultant depletion of the neurotransmitter dopamine in the brain. • Perivascular spaces. These spaces consist of subarachnoid fluid-containing spaces surrounding vessel walls within brain tissue. They frequently occur in basal ganglia or white matter. There may or may not be some change in the bordering brain tissue. There is some association of these spaces with hypertension. • Pons. The middle portion of the brainstem, lying between midbrain and 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 some aspects of eye movements. • Short-term memory. Memory for events that took place in the preceding minutes or few hours. • Substantia nigra. A pigmented brainstem nucleus that has projecting neurons that synthesize the neurotransmitter dopamine. This region is important to movement control. Cellular degeneration in the substantia nigra, as seen in Parkinson's disease, can result in symptoms of motor slowness, rigidity, and tremor. • Temporal lobe. The temporal lobes are the lower lateral portions of the cerebral hemispheres involved in auditory perception, visual recognition, emotion, and the processing and retrieval of memory. Temporal lobes contain amygdala and hippocampus. In most people, right temporal lobe damage may result in greater interference in nonverbal memory (e.g., pictures), whereas left temporal lobe injury may be more associated with difficulties with verbal memory (e.g., words and stories) and with understanding spoken or written language. • Thalamus. Ovoid mass of gray matter that forms part of the two lateral walls of the third ventricle, on each side. 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. • 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 pathologies. • 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

  • A. Constantino, L. S. Honig, Parkinson's disease. Sci. Aging Knowl. Environ. 2001(7), dn4 (2001). [Abstract] [Full Text]
  • H. Chui, I. Skoog, Advances in vascular cognitive impairment 2005. Stroke 37, 323-325 (2006). [Abstract]
  • L. Helmuth, Detangling Alzheimer's disease. Sci. Aging Knowl. Environ. 2003(43), oa2 (2003). [Abstract] [Full Text]
  • L. S. Honig, S. S. Chin, Alzheimer's disease. Sci. Aging Knowl. Environ. 2001(1), dn2 (2001). [Abstract] [Full Text]
  • L. S. Honig, W. Kukull, R. Mayeux, Atherosclerosis and AD: Analysis of data from the US National Alzheimer's Coordinating Center. Neurology 64, 494-500 (2005). [Abstract]
  • D. S. Knopman, Dementia and cerebrovascular disease. Mayo Clin. Proc. 81, 223-230 (2006). [Abstract]
  • D. Leys, H. Henon, M. A. Mackowiak-Cordoliani, F. Pasquier, Poststroke dementia. Lancet Neurol. 4, 752-759 (2005). [Abstract]
  • The Alzheimer Research Forum, an excellent source for debates, summaries of research issues, information on publications, and upcoming conferences.
Citation: C. B. Wright, J. P. G. Vonsattel, K. Bell, L. S. Honig, Dementia with Cerebrovascular Disease. Sci. Aging Knowl. Environ. 2006 (10), dn1 (2006).








Science of Aging Knowledge Environment. ISSN 1539-6150