CURRENT CLINICAL NEUROLOGY - PART 3 ppt

60 Merino and Hachinski Table 1 (continued) Diagnostic Criteria for Vascular Dementia Criteria SCADDTC (11) a NINDS-AIREN (12) a ICD-10 (Research) (10) DSM-IV (144) Imaging Required: evidence of at least Required: large-vessel infarcts Not required (VERIFY!) Not required one infarct outside the cere- or a single strategically placed bellum by CT or MRI infarct, as well as multiple gan- glia and white matter basal lacunes, or extensive periventri- cular white matter lesions, or combinations thereof Etiologic Temporal relationship A relationship is inferred by Not specified clearly, a rela- relationship required if only a single onset of dementia within 3 mo tionship must be “reasonably between CVD stroke is documented of stroke, abrupt deterioration judged” to exist and dementia or fluctuating, stepwise progression Subtypes Yes: cortical, subcortical, Do not specify but recommend Allows subtypes—6 with only None Binswanger’s disease, and description of stroke features superficial clinical description: thalamic dementia for research purposes acute onset, MID, subcortical, mixed cortical and subcortical, other, and unspecified Levels of Yes. also has mixed Yes, probable, possible, certainty dementia category definite WML WML do not qualify as imag- ing evidence of CVD for pro- bable diagnosis but may sup- port possible IVD Mixed Mixed dementia to be diag- AD with CVD—patients who dementia? nosed in the presence of one fulfill criteria for possible AD or more systemic or brain and who also present clinical or disorders that are believed imaging evidence of relevant to be causally related to the vascular brain lesions. Include dementia dementias resulting from hypo- perfusion from cardiac dysrhyth- mias and pump failure a Probable vascular dementia Abbr: AD, Alzheimer’s disease; CVD, cerebrovascular disease; CT, computed tomography; MID, multiinfarct dementia; MRI, magnetic reso nance imaging; WML, white matter lesion. Vascular Dementia: Conceptual Challenges 61 Data regarding the severity, nature, and course of cognitive impairment in patients with CVD must be collected, preferably through the prospective study of population cohorts (27). Issues to consider when drafting these criteria are the threshold of cognitive impairment that will identify cases at a point when therapeutic and preventive strategies are possible, the cognitive domains that must be affected to qualify as a case, and the course of cognitive impairment in patients with VaD. 3.1. Severity of Cognitive Impairment After Stroke Current criteria focus on patients with significant functional impairment and, therefore, identify patients with end-stage VaD (28). This is a tragic shortcoming because in many patients, CVD is preventable (29). Research and clinical efforts must identify patients who are at risk of developing dementia—those with vascular risk factors or CVD (1). Focusing on the broad concept of vascular cognitive impairment instead of VaD can help us identify subjects who are at risk of dementia in whom vascular risk factors have an etiopathogenetic role (30,31). The criteria should be set at a sensitive rather than specific level (32). 3.2. Cognitive Deficits in Patients With Vascular Disease In patients with CVD, other cognitive functions are affected as least as often as memory (33–43). Pohjasvaara and coworkers found that, 3 mo after a stroke, 62, 35, and 27% of patients had cogni- tive decline in 1, 2, and 3 or more domains, respectively, (44). In a separate series, Desmond et al. (43) found that patients with stroke and memory impairment at 3 mo always have deficits in one or more additional cognitive domains and that most patients have deficits in two or more. The domains Table 2 Agreement in Patient Classification Resulting From Various Criteria Chui et al., Pohjasvaara et al., Amar et al., Amar et al., Wetterling et al., Verhey et al., 2000 (5) 2000 (6) 1996 (20) a 1996 (20) b 1996 (21) 1996 (145) Criteria n = 25 n =107 n = 20 n = 20 n = 167 n = 124 DSM-IV 25.7% 91.6% 27% SCADDTC 10.3% 86.9% 40% 20% 13% 12% probable SCADDTC 14.3% 55% 35% possible SCADDTC 20.6% 95% 55% probable and possible NINDS-AIREN 5.1% 32.7% 40% 5% 7% 6% probable NINDS-AIREN 6.3% 40% 20% possible NINDS-AIREN 6.3% 80% 25% probable and possible DSM-III 36.4% ICD-10 36.4% 13% a Hachinski Ischemic score > = 7. b Hachinski Ischemic score = 4–6. Abbr: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.; SCADDTC, State of California Alzheimer Disease Diagnostic and Treatment Centers; NINDS-AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences. 62 Merino and Hachinski 62 Table 3 Sensitivity and Specificity of Diagnostic Criteria Gold et al., 2002 (7) Knopman et al., 2003 (24) n = 89 n = 89 Vascular dementia Pure vascular dementia Broad vascular dementia Sensitivity, % Specificity, % Sensitivity, % Specificity, % Sensitivity, % Specificity, % NINDS-AIREN probable, excluding WMLs 20 93 17 97 13 98 NINDS-AIREN possible, excluding WMLs 25 96 22 98 NINDS-AIREN possible 55 88 DSM-IV, excluding WMLs 50 84 67 69 70 76 DSM-IV, including MLs 75 64 74 70 ICD-10 20 94 75 74 70 80 SCADDTC possible 70 78 SCADDTC probable 25 94 67 79 57 83 Mayo criteria, excluding WMLs 75 81 65 86 Mayo criteria, including WMLs 75 73 70 79 Abbr: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.; ICD-10, International Classification of Diseases, 10th Ed.; NINDS-AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neuro sciences; SCADDTC, State of Cali- fornia Alzheimer Disease Diagnostic and Treatment Centers; WMLs, white matter lesions. Vascular Dementia: Conceptual Challenges 63 that were affected most often in these cohorts were construction and visuospatial skills, memory, executive function, orientation, and attention (41,44). Patients with vascular risk factors in midlife have cognitive impairment, particularly of executive function, later in life (45). If the diagnostic criteria for VaD require memory impairment for diagnosis, then they will prove in a circular argu- ment that memory is the major impairment (17). It also means that a large number of patients who have primary decline in other cognitive domains are not diagnosed with VaD (17,46,47). The do- mains that are affected in an individual patient depend on the nature, severity, and location of the vascular insults and on the coexistence of other pathologies. The relationship between neuropsycho- logical deficits and specific vascular pathologies must be researched further so that meaningful subgroups can be identified clinically for routine care and research purposes. 3.3. The Prognosis of Cognitive Impairment AD is an unrelenting progressive illness, but patients with VaD have a more variable course. Among 53 patients with minor stroke or TIA and cognitive impairment recruited from a stroke clinic, Bowler and colleagues found that only 24 had abrupt onset, and symptoms improved over time in all (48). Gradual evolution of cognitive decline is also found in some patients with stroke-related dementia (42,49,50), and it is clear that individuals can have a slowly progressive dementing illness caused by CVD (51,52). Some patients with cognitive impairment after a stroke can get better (34,53). Desmond and colleagues found that almost 15% of 151 patients who had cognitive impairment 3 mo after a stroke had improvement by the time of the 1-yr examination (54), and when only those who met prespecified criteria for cognitive impairment were considered, 36% had improvement. The course of the deficits in the various subgroups needs further clarification. 4. VASCULAR DISEASE LEADING TO DEMENTIA VaD is a syndrome that is as heterogeneous as CVD itself. However, traditional criteria treat it as a homogenous condition associated with a specific etiopathogenetic mechanism (55). Unless the heterogeneity is incorporated into the concept of VaD, the construct will be too narrow. In addition, lack of recognition of the heterogeneity means that it will not be addressed in clinical trials and prospective studies, potentially leading to the rejection of therapeutic interventions that may be use- ful for a subgroup of patients with CVD and cognitive decline. 4.1. Heterogeneity of Lesions Cognitive decline in patients with CVD results from the stroke itself, when a large volume of brain is affected by ischemia or hemorrhage (44,45) or when the lesion, because of its strategic location (46), interrupts brain circuits that are critical for cognition (47). Diseases of the large arteries and the heart can lead to cerebral hypoperfusion (56,57), and a variety of conditions that predispose to cere- bral hypoxia have been associated with the development of dementia after stroke (58,59). The NINDS-AIREN criteria specify the vascular lesions that support the diagnosis of vascular dementia but do not describe specific subgroups (12). These lesions include multiple large-vessel and single strategically placed infarcts, multiple basal ganglia and white matter lacunes, and extensive periventricular white matter lesions, or combinations thereof. 4.2. Volume and Location of Lesions The radiological and pathological features of the lesions that cause cognitive impairment are not well understood. Tomlinson et al. postulated that there is “an upper limit or threshold of cerebral degeneration beyond which some degree of intellectual deterioration usually occurs,” and concluded that in the case of “cerebral softening this is apparently around 100 mL” (60). More recent studies suggest that smaller volumes can lead to dementia, but a threshold has not been identified (26,61– 63). Furthermore, there are data to suggest that the level of functional tissue loss resulting from 64 Merino and Hachinski cortical deafferentation, rather than the total volume, is critical for the development of dementia (64,65). Location is at least as important as size. Strategically placed lesions lead to intellectual decline when specific cortical or subcortical areas that are important for cognition are damaged and when critical frontal-subcortical pathways are interrupted (37,66–68). However, the association between strategic lesions and cognitive deficits is based on case reports that relied on computed tomography (CT) scanning and had short follow-up (66,67,69–81). As a result, the contribution of cortical lesions and concurrent Alzheimer-type pathology cannot be excluded (82). Further research on the location of lesions that lead to dementia, using modern neuroimaging techniques and prolonged follow-up, is warranted. Lacunar strokes are independent predictors of dementia (83), and microvascular damage, but not macroscopic infarcts, may distinguish cases of VaD from cases of stroke without dementia (84). There is controversy about the role of small strokes when white matter lesion changes and atrophy are considered (51). Small-vessel disease leads to lacunar infarctions and subcortical ischemic white matter changes (85) and, when widespread, produces a distinct syndrome characterized by cognitive impairment, personality changes, gait disturbance, motor deficits, and urinary incontinence (85–87). This may constitute a clinically meaningful subgroup that may be the target of specific interventions (87). 4.3. Silent Infarcts Silent cerebral infarcts are common, 15–25% of individuals aged 65 or older have them (88–94). Patients with clinically apparent strokes generally have larger, cortically based infarcts (88–90,94) or multiple infarcts (92), and patients with subcortical disease often lack such a history (52). The burden of recurrent silent strokes can lead to an insidious dementia (24,93,95,96). Patients with silent infarcts may have symptoms of pure AD (Medical Research Council [MRC], NUN, Consortium to Establish a Registry for Alzheimer’s Disease [CERAD], etc.). Silent hypoperfusion can produce hippocampal neuronal loss (51) or severe white matter changes (97), and concurrent AD is likely important to the genesis of dementia in many individuals with asymptomatic CVD and dementia. In the Cardiovascu- lar Health Study, there was a significant increase in the number of individuals with a history of memory loss among those with silent cerebral infarction (98) and a significant association between silent cerebral infarcts and decreased performance on the Mini-Mental State Examination (MMSE) and the Digit-Symbol Substitution Test (93). If silent strokes and white matter changes are important, then the requirement that clinical stroke be present is inappropriate. In a neuropathological series, the need for a temporal requirement was the main limiting factor that lead to the low sensitivity and the high rate of false negatives associated with the SCADDTC and NINDS-AIREN criteria for probable VaD (7). In a separate series, the temporal relationship between stroke and dementia was the best clinical predictor of pure vascular neuropathology, but this feature had poor sensitivity because one-third of patients with pure VaD lacked a temporal relationship between a clinical stroke event and dementia (24). The relationship was missing in a higher proportion of patients with mixed dementia, and a few cases with pure vascu- lar pathology lacked a history of clinical stroke temporarily related to the onset of the dementia. Based on these findings, Knopman postulates that there are two types of VaD: one emerges from a clinical stroke event, the other more insidiously without clinically apparent stroke (24). This hypoth- esis merits further evaluation. 4.4. White Matter Lesions Changes in the white matter are related to cerebrovascular risk factors (99–101). They predict future stroke (102) and mortality (103). White matter pathology is not invariably linked with demen- tia, but even patients without dementia have selective cognitive deficits: attention, visuospatial memory, and frontal-executive skills are preferentially affected (99,104,105). Defects in sustained Vascular Dementia: Conceptual Challenges 65 mental concentration and attention, difficulty in organizing material to be learned, lack of consis- tency of recall, difficulties in spontaneous recalling, reduced speed of information procession (106), and slowness of thought (107) are most often found. In the Helsinki Aging Brain Study, for example, neurologically healthy individuals who had white matter changes performed worse on the Trailmaking test part A and in the Stroop test (108). The majority of studies using CT imaging in patients with dementia found an association of white matter changes with poorer cognitive performance, especially of those mediated by the frontal lobes. MRI studies have not consistently found this association (109). The association between white matter changes and cognitive impairment must be clarified. The NINDS-AIREN criteria accept changes involving more than 25% of the white matter as supportive radiological evidence for VaD, but it is not clear how that threshold was selected. The issue of white matter changes is further confounded because they are common in the brains of patients with AD. The precise relationship between white matter lesions (volume and location) and the clinical features of cognitive impairment has received little attention, but this is an important issue if sub- groups, including possibly mixed AD plus CVD, are to be made based on radiological features. There is insufficient data to propose a firm cutoff for the extent of white matter abnormalities or for the extent of infarction that is required (110). Future studies should be prospective, use standardized methods for structural brain imaging, and administer comprehensive neuropsychological assessments to investigate more rigorously the relationship between evolving white matter lesions and declining cognitive functions (111). 4.5. Vascular Dementia Without Stroke There is growing awareness that underlying vascular factors other than cerebral infarction can cause dementia (noninfarct vascular dementia) (55,112–114). The brains of individuals without dementia and hypertension have more senile plaques and neurofibrillary tangles, lower weight (115,116), and more radiographic white matter changes (117) than those of people with normal blood pressure. It is unknown if risk factors act directly by leading to stroke or whether they have a direct effect on the brain (118), but there is compelling evidence to suggest the latter possibility (96). 5. MIXED STATES AD and VaD are considered diagnoses of exclusion, but recent evidence suggests that this dicho- tomy is artificial (47). Data from population (119,120) and cohort studies (121) show that the brains of the elderly often have mixed Alzheimer-type and vascular pathology (122). Among 80 subjects from the Camberwell Dementia Case Register, 33.8% had mixed pathology (119), and in a large multicenter, community-based study vascular and Alzheimer-type pathology were seen in a majority of patients, and most patients had features of both (120). The effect of these processes in cognition are additive (97,121,123,124) or even multiplicative (32). Concurrent CVD may be seen in patients with a slowly progressing illness most consistent with AD (125), and a large proportion of patients with dementia after a stroke may have had cognitive impairment before the stroke. In the Framingham Study, half the people who developed cognitive impairment after stroke had preexisting difficulties (126). In stroke cohorts evaluated with a stan- dardized questionnaire that assesses cognitive function in the preceding 10 yr, cognitive decline preceded the stroke in up to 20% of patients (127,128), and two-thirds of patients had a course suggestive of AD (127). In a stroke cohort from New York, functional and cognitive deficits pre- ceded the index stroke in 40% of patients who had dementia after stroke (129,130). After excluding patients with prestroke dementia, 30% of patients with poststroke dementia meet criteria for AD (58), and in population series, the incidence of AD among patients with stroke is 50% higher than expected (131). VaD and AD have common risk factors (132–134) and may share etiologic pathways (132). AD is characterized by a slowly progressive capillary dysfunction in the absence of widespread focal 66 Merino and Hachinski infarction (135). Vascular factors may participate in the development of cytoskeletal alterations and amyloid deposits. Large population-based epidemiological studies that began in the 1980s and early 1990s have shown that vascular risk factors contribute to the clinical and pathological presentation of AD, and experimental and pathological studies support this view (133,136). Medial temporal lobe atrophy is strongly associated with AD (137) and is more common in stroke patients with prestroke dementia than those without (138). It is a predictor of dementia after stroke (61), and hippocampal and cerebral atrophy may be critical factors in determining dementia after stroke (51). Patients with subcortical ischemic vascular dementia have smaller volumes of the entorhinal cortex and hippocampus than normal controls, but for similar degrees of dementia, the volumes are smaller in patients with AD than VaD (139). A fundamental issue in each patient is whether the vascular changes seen in a particular patient are solely responsible for the dementia, contribute to it, or are coincidental. In addition, it is possible that the vascular and neurodegenerative changes have a com- mon etiology or precipitating mechanism. The border between AD and VaD has become blurred as shared pathophysiological processes have been identified (96,134,140). Recognizing this fact, Kalaria and Ballard propose a continuum of dementia with pure AD at one extreme, pure VaD at the other, and a wide intermediate area (141); most cases of dementia may actually have mixed origin (96). The burden of vascular risk factors and CVD goes beyond the traditional boundaries of the concept of VaD. Because these can be prevented, the concept of mixed etiology must be incorpo- rated, perhaps as a specific subgroup, into the construct of VaD. 6. FUTURE PERSPECTIVES The major obstacle to the diagnosis of VaD is that this complex nosological concept encompasses many clinical syndromes that result from a variety of pathogenic mechanisms that lead to different cognitive syndromes with varying evolution and progression (142). This fact must be incorporated into the theoretical construct. Emery has suggested that one way to recognize this heterogeneity is to place the nosologic concept of VaD at a superordinate level with a number of subtypes comprising the lower categories of this hierarchical level (55). These subtypes must be clinically meaningful and fulfill the criteria for a disease: the presence of a distinct pattern of clinical features that matches a distinct pathological picture (143). The classification may be based on: (1) primary vascular etiology, (2) primary type of ischemic brain lesions, (3) primary location of the brain lesions, and (4) primary clinical syndrome (87). Subcortical ischemic VaD is an example of such a subgroup (85). Other subgroups include poststroke dementia and mixed AD plus CVD. Only after data on the cognitive, radiological, and clinical features of patients with CVD and vascular risk factors are collected can criteria be established based on knowledge—building on the experience of large population-based epidemiological studies—and not supposition (17). All inves- tigators should use the same minimal set of standardized, validated measures and record key demo- graphic characteristics, so that patients can be reclassified and the findings reinterpreted in light of the emerging knowledge (1). Data collection must be done without the use of criteria originally to avoid proving them in a circular argument (30). The focus should be the spectrum of cognitive impairment caused by vascular disease (cerebral and cardiac) and by vascular risk factors, even in the absence of frank strokes. The label “dementia” should even be abandoned. The criteria could group individuals according to a large number of shared characteristics but not require a single feature as essential to group membership (thus avoiding, for example, sine qua non requirement of impairment in a specific cognitive domain. This nonexclusionary approach helps classify borderline cases and addresses the heterogeneity of VaD. The source of the patients will be important. The development and validation of diagnostic criteria for VaD cannot be done in the setting of a memory clinic, because patients with CVD may not be referred to it (17). Patients may come from vascular clinics or, ideally, the study should be population based (24). Vascular Dementia: Conceptual Challenges 67 REFERENCES 1. Hachinski V. Preventable senility: a call for action against the vascular dementias. Lancet 1992;340:645–648. 2. A Dictionary of Epidemiology. 3rd Ed. New York, NY: Oxford University Press,1995. 3. Poland J, von Eckardt B, Spaulding W. 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[...]... mice for Notch1 and Notch2 are embryonically lethal (34 ,35 ) However, the general scheme described previously seems to hold with RBP-Jk, as the mammalian CSL protein, and the HES genes Initial studies done in vitro (36 ,37 ) revealed that Notch3 IC binds to RBP-Jk but is a poor activator of the HES-1 and HES-5 promoters, contrary to the Notch-1 IC/RBP-Jk complex, which is a strong activator These studies... same paper, Wang et al also showed that Notch -3 , HRT1 and HRT-2 are all downregulated in response to arterial injury and that the time course for this decrease and recovery follows identical patterns for all three proteins They showed that Notch -3 signaling can occur without RBP-Jk in VSMC In this part of the pathway, Notch -3 upregulates c-FLIP via an ERK/MAPK-dependent pathway and prevents apoptosis... epithelial COS-7 cells However, more recent studies conducted by Wang et al in VSMCs and rat carotid artery proposed a different picture for the Notch3 signaling transduction pathway (38 ,39 ) In one of the papers, the group showed that Notch3 IC binds RBP-Jk and that the complex then activates the HRT-1 and -2 (Hairy-related transcription factor) genes, which are related to the HES genes39 The HRT family... 1998;29: 131 1– 131 4 36 Ito H, Kanno I, Ibaraki M, Hatazawa J Effect of aging on cerebral vascular response to PaCo2 changes in humans as measured by positron emission tomography J Cereb Blood Flow Metab 2002;22:997–10 03 37 Lartaud I, Bray-des-Boscs L, Chillon JM, Atkinson J, Capdeville-Atkinson C In vivo cerebrovascular reactivity in Wistar and Fischer 34 4 rat strains during aging Amer J Physiol 19 93; 264:H851–H858... recruiting caspase-8 c-FLIP inhibits the binding of caspase-8 to Fas, thus preventing apoptosis When there is arterial injury both Notch -3 and c-FLIP are downregulated for approx 1 wk A third study by the same group (40) showed that angiotensin II (Ang II) and platelet-derived growth factor (PDGF) down regulated the expression of Notch3 and of the ligand Jagged-1 and prevented glycosylation of Jagged-1 Ang II... mutations have been reported The gene contains 33 exons and encodes a transmembrane protein of 232 1 amino acids The Notch -3 protein is a receptor comprising several functional domains (see Fig 2) On its extracellular portion, it contains 34 epidermal growth factor-like (EGF) repeats followed by three notch/lin-12 repeats The intracellular domain contains six cdc-10/ankyrin repeats Interestingly, all the... dementia: clinical features and risk factors Stroke 2000 ;31 :1494–1501 129 Tatemichi TK, Desmond DW, Mayeux R, et al Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized cohort Neurology 1992;42:1185–11 93 130 Desmond DW, Moroney JT, Paik MC, Sano M, Mohr JP, Aboumatar S et al Frequency and clinical determinants of dementia after ischemic stroke Neurology 2000;54:1124–1 131 ... Challenges 71 131 Kokmen E, Whisnant JP, O’Fallon WM, Chu CP, Beard CM Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (196 0-1 984) Neurology 1996;46:154–159 132 Skoog I Status of risk factors for vascular dementia Neuroepidemiology 1998;17:2–9 133 Breteler MM Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective Neurobiol Aging 2000;21: 1 53 160 134 De La... OR, et al Development and progression of leukoaraiosis in patients with brain ischemia and carotid artery disease Stroke 20 03; 34:19 13 1916 104 Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A A population-based study of dementia in 85-year-olds N Engl J Med 19 93; 328:1 53 158 105 de Groot JC, de Leeuw FE, Oudkerk M, et al Cerebral white matter lesions and cognitive function: the Rotterdam Scan... identified the Notch -3 gene at locus 19p 13. 1-1 3. 2 6 In a subsequent article (7), the group published a list of the specific mutations found in these families Ultrastructural and immunohistochemical analysis of skin biopsies (8,9) have also been employed to develop a more extensive profile of the disease From: Current Clinical Neurology Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management . 6% probable NINDS-AIREN 6 .3% 40% 20% possible NINDS-AIREN 6 .3% 80% 25% probable and possible DSM-III 36 .4% ICD-10 36 .4% 13% a Hachinski Ischemic score > = 7. b Hachinski Ischemic score = 4–6. Abbr: DSM-IV, Diagnostic. disease. Stroke 20 03; 34:19 13 1916. 104. Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A population-based study of dementia in 85-year-olds. N Engl J Med 19 93; 328:1 53 158. 105. de Groot. 124 DSM-IV 25.7% 91.6% 27% SCADDTC 10 .3% 86.9% 40% 20% 13% 12% probable SCADDTC 14 .3% 55% 35 % possible SCADDTC 20.6% 95% 55% probable and possible NINDS-AIREN 5.1% 32 .7% 40% 5% 7% 6% probable NINDS-AIREN