Suitability of neuropsychological tests in patients with vascular dementia (VaD)

pa inn en edo ess f e d D. W ies tly, thi to a whole spectrum of vascular causes of co roduce flects t isease nitive i to VaD r assoc impairment involving at least one cognitive domain [3]. Evidence of of VaD are the NINDS-AIREN (National Institute of Neurological Disor- Within the large spectrum of dementias, it may be possible to dis- Journal of the Neurological Sciences 322 (2012) 41–45 Contents lists available at SciVerse ScienceDirect Journal of the Neur . e complex interactions between vascular causes, brain changes, host factors and cognition led to formulate the new concept of VCI. In cur- rent classifications, the main subtypes and causes of VCI are as fol- lows: post-stroke dementia, vascular dementia (multi-infarct dementia or cortical vascular dementia, subcortical ischaemic vascular dementia, strategic-infarct dementia, hypoperfusion dementia, hemorrhagic de- mentia, dementia caused by specific arteriopathies), mixed AD and VaD, and vascular mild cognitive impairment [1]. tinguish earlier among different forms on the basis of different cogni- tive and behavioral patterns with which they occur at onset. This reflects the involvement, by the disease, of specific brain structures. For example, the early involvement of the entorhinal cortex and hip- pocampus in AD often produces, as the first symptom, impairment in episodic memory [7]. Semantic dementia, with atrophy of the left an- terior temporal region, is characterized by a reduction in expressive vocabulary [8], word-finding difficulties and reduced comprehension The introduction of VCI is important beca to the concept of VaD we underestimate th ment of patients with vascular lesions. Dia ⁎ Corresponding author at: Department of Neurolog University of Florence, Largo Brambilla, 3, 50134 Fl 4271379; fax: +39 055 4271380. E-mail address: sorbi@unifi.it (S. Sorbi). 0022-510X/$ – see front matter © 2012 Elsevier B.V. Al doi:10.1016/j.jns.2012.05.045 iated with vascular fac- as a syndrome with clin- al lesions and cognitive 2. The role of neuropsychological tests in the early diagnosis of dementia tors [2]. More recently, VCI has been defined ical evidence of stroke or vascular subcritic origin, from the early and mild stages any cognitive impairment caused by o dementia and a new term has been int pairment (VCI) [1]. This expression re portance of the effects of vascular d decline and it includes all levels of cog s concept was extended gnitive impairment and d, vascular cognitive im- he awareness of the im- or lesions on cognitive mpairment of a vascular . The term “VCI” means l'Enseignement en Neurosciences) criteria [4]. The diagnosis of VaD may be “possible”, “probable” or “defined”, according to the level of diagnostic certainty. In a neuropathological series, sensitivity and specificity of the criteria for probable and possible VaD were respec- tively 58% and 80% [5]. Research criteria for subcortical vascular de- mentia have been proposed by Erkinjuntti and colleagues [6]. the concept of vascular dementia (V by small or large brain infarcts. Recen s of a dementia caused ders and Stroke and Association Internationale pour la Recherché et with risk factors for cerebrovascular disease (CVD). Until the 1990s, aD) wa Suitability of neuropsychological tests in Silvia Bagnoli, Ylenia Failli, Irene Piaceri, Valentina R Benedetta Nacmias, Sandro Sorbi ⁎ Department of Neurological and Psychiatric Sciences, University of Florence, Italy a b s t r a c ta r t i c l e i n f o Available online 12 June 2012 Keywords: Vascular dementia Neuropsychological tests Alzheimer's disease The concept of vascular dem (VCI). VaD patients show pr while memory deficits are l ical tests are available for th veloped specifically for Va evidence from different stud dementia. 1. Introduction In recent years, there has been an important evolution in the no- menclature used to characterize the cognitive impairment associated j ourna l homepage: www use if we limit ourselves e real cognitive impair- gnostic criteria for VaD ical and Psychiatric Sciences, orence, Italy. Tel.: +39 055 l rights reserved. tients with vascular dementia (VaD) oci, Valentina Bessi, Andrea Tedde, tia (VaD) has evolved with the introduction of vascular cognitive impairment minantly frontal cognitive deficits. The executive area is particularly affected, requent in patients with VaD than patients with AD. Several neuropsycholog- iagnosis and differentiation of dementias, but there are currently no tests de- e proposed to evaluate various neuropsychological tests, on the basis of , in order to clarify the utility of the neuropsychological assessment in vascular © 2012 Elsevier B.V. All rights reserved. require the demonstration of a cognitive disorder (by neuropsycho- logical assessment), a history of clinical stroke or presence of CVD (by neuroimaging) and the presence of a close relationship between them [3]. The most commonly used clinical criteria for the diagnosis ological Sciences l sev ie r .com/ locate / jns [9]. The first stages of “behavioral variant frontotemporal dementia” (bvFTD), with predominant atrophy in the antero-mesial and orbito-frontal cortices, are characterized by specific symptoms con- sisting of disinhibition, apathy and emotional disorders [10]. Similar- ly, the disruption of subcortical-frontal loops that usually occurs in subcortical dementia (such as, VaD with multiple subcortical infarcts, normal pressure hydrocephalus (NPH) and Parkinson's disease with dementia (PDD), is characterized by psychomotor slowing and 42 S. Bagnoli et al. / Journal of the Neurological Sciences 322 (2012) 41–45 executive dysfunctions. From this emerges the enormous importance of the neuropsychological tests, particularly in the assessment of early stage dementia. Ramos-Estèbanez and colleagues, in a study per- formed on 314 patients with pVaD (prodromal stages of ischemic vas- cular dementia) or clinical diagnosis of VaD (lacunar infarctions, Binswanger's Disease, cortical VaD, corticosubcortical and strategic infarctions), showed a typical pattern of onset consisting of early ex- ecutive dysfunction, initial gait disturbances, personality changes and early urinary incontinence. In most patients, prodromal symptoms and signs had begun several months before the study. In addition, it was found that an onset with cognitive impairment no dementia (CIND), being under anti-coagulant and anti-platelet therapy at the moment of the VaD diagnosis and an age b85 years does not improve the recognition of pVaD. The authors therefore suggest that neuro- psychological assessment and informant interviews should be com- monly performed in clinical practice for all elderly patients with cardiovascular risk factors [11]. Desmond also showed that there are several reasons why it is better to study patients with VCI who are not demented: firstly, a diagnosis of VCI does not require memory im- pairment, eliminating a source of recognition bias; secondly, less se- vere patients are more likely to show subtle cognitive deficit specific to the frontal lobes; thirdly, they will be more testable than patients with full dementia on complex and challenging frontal tests, allowing the evaluation and recognition of their deficits. Lastly, it is likely that they would be the most appropriate candidates for clinical trials [12]. 3. Neuropsychological assessment of VaD: overview There are currently no neuropsychological tests specifically devel- oped for vascular dementia. The assessment starts from the need to make a diagnosis of dementia and this requires an extensive battery of neuropsychological tests. The introduction of the concept of VCI makes the process more complex because it is necessary to identify mild cognitive deficits. In clinical practice it's very useful to differentiate the MCI due to neurodegenerative diseases, such as AD, from that due to vascular causes. In this regard it was recommended that patients with vascu- lar MCI should show deficits in executive functions, whereas memo- ry may be normal. However, the differentiation of the two pathologies only on the basis of the involvement of memory in AD, and executive functions in vascular disease, is not strictly correct. Several studies have shown that both diseases have an impairment involving multiple cognitive domains. Consequently, patients with vascular disease may have a broader cognitive impairment including memory deficits [3]. Considering the mainly compromised domains in the pathology, we decided to make an overview of the currently available tests in order to screen the cognitive impairment and dementia of vascular origin. Each test is characterized by specific values of sensitivity and specificity and is designed to explore specific cognitive domains. In clinical practice, the most commonly used screening test for the eval- uation of cognitive impairment is the Mini Mental State Examination (MMSE) [13]. The MMSE investigates orientation in space and time, recording capacity, attention and calculation, recall, language and constructive praxis and has acceptable levels of accuracy. Sensitivity ranges between 71% and 92%, specificity is 56–96%, the positive pre- dictive value is 15–72% and the negative predictive value is 95–99% [14]. Nevertheless, the MMSE has several limitations. Its accuracy var- ies according to age, educational level and ethnicity [15,16] and it is unable to investigate frontal lobe dysfunction. In addition to the MMSE, other screening tests with good accuracy are available for gen- eral diagnosis of dementia. These tests may also be useful in the dif- ferential diagnosis between different types of dementia and consequently in distinguishing VaD from other neurodegenerative disorders such as AD. The Addenbrooke's Cognitive Examination Revised (ACE-R), a modi- fied version of the original “ACE” [17], is a brief screening tool that is both reliable and useful in the early stages of cognitive dysfunction. The test, which requires about 16 min for administration, investigates five cognitive domains: attention/orientation, memory, fluency, lan- guage and visual-spatial. Test sensitivity and specificity for detecting dementia are respectively 94% and 89% [18]. Kwak and colleagues showed that the Korean version of the ACE-R (K-ACER) may be useful to differentiate AD from subcortical ischemic vascular dementia [19]. The Mattis Dementia Rating Scale (MDRS) is a widely used stan- dardized and reliable measure of global cognitive function, consisting of 144 points which investigate five cognitive domains: attention, ini- tiation/perseveration, construction, conceptualization and memory. The Clock Drawing Test (CDT) is a common and quick cognitive screening instrument for the diagnosis of dementia, able to investi- gate specific domains such as construction, conceptualization, visuo- spatial function and executive functions [20]. The CDT consists in ask- ing patients to draw a clock face with the hands set for ten after elev- en. Shulman and colleagues have shown that the CDT has good sensitivity (85%) and specificity (85%) values in cognitive screening with high inter-rater and test–retest reliability and positive predic- tive value [21]. According to other authors, however, the CDT is not sensitive in diagnosing the milder stages of dementia [22–24]. Several studies have shown a correlation of CDT with the MMSE [25,26]. The Philadelphia Brief Assessment of Cognition (PBAC) is a short screening instrument that investigates five cognitive domains: working memo- ry/executive control; language; visuo spatial/visuo constructional operations; verbal/visual episodic memory; and behavior/social comportment [27]. The Frontal Assessment Battery (FAB) is a quick and easy battery consisting of six subtests exploring conceptualiza- tion and abstract reasoning, mental flexibility, motor programming and executive control of action, resistance to interference, inhibitory control and environmental autonomy. The CAMCOG, which forms part of the Cambridge Examination for Mental Disorders of the Elder- ly (CAMDEX) [28], is a standardized instrument investigating cogni- tive domains required for the diagnosis of dementia: orientation, language (comprehension and expression), visuospatial praxis, mem- ory, attention, calculation, abstract thinking and perception [29]. Because of the specific patterns of cognitive dysfunction in the early stages, it is very important to evaluate the specific cognitive domains with tests administered ad-hoc. Different types of memory need to be investigated to differentiate VaD from other dementia forms. Impairment of episodic memory can be investigated through the Free and Cued Selective Reminding Test (FCSRT) [30] and the California Verbal Learning Test (CVLT) [31], while semantic memory can be assessed by categorical fluency and Boston naming test [32]. The visuo-spatial memory can be evaluated through the Rey–Osterrieth Figure Recall [33]. Using the FCSRT, Grober evaluated the sensitivity and specificity of free recall and total recall in patients with AD or VaD. It was found that 83% of AD patients and 79% of VaD patients showed impaired free recall. It was also found that 71% of AD patients showed impaired total recall, compared with only 21% of VaD patients. Specificity of free recall and total recall was respectively 76% and 94%. These data indicate that impairment in free recall was common in both AD and VaD patients, while an im- pairment of total recall was present only in AD patients, emphasizing the role of memory deficits in AD. In fact, 79% of VaD patients had an intact total recall, emphasizing a probable prominent role of frontal and attention circuits in VaD. The FCSRT is therefore a useful instru- ment in the differential diagnosis between AD and other forms of non-AD dementia because supply of a cue considerably improves the memory scores of patients with lesions involving the frontal and subcortical structures [30]. Alexander and colleagues [34] compared performances on the CVLT of subjects with focal frontal lesions with those with non-frontal lesions. The results of this study showed that patients with frontal lesions may have difficulties with any aspect of an unstructured list-learning task but a single frontal lobe syndrome of memory impairment does not exist. In addition, within the group of patients with frontal lesions, there were differences according to the specific site of injury. Patients with posterior left dorsolateral frontal lesions (and, to a lesser extent, patients with posterior medial frontal and posterior right dorsolateral frontal lesions) showed great- er impairment on immediate free recall. Patients with posterior left dorsolateral frontal lesions and patients with posterior medial frontal lesions also showed impairment on delayed recall. Therefore, damage in these specific areas could affect the recall. Impairment in recogni- tion memory is only present in the group with posterior left dorsolat- eral frontal lesions. As a result, the location of the lesion in these specific areas could affect the patterns of memory impairment. Bal- lard and colleagues [35] evaluated performances on the CAMCOG of a sample of patients with DLB, AD or VaD and showed that the DLB group exhibited significantly better performance on recent memory but worse performance on visuo-spatial praxis compared to VaD and AD patients. The authors calculated and analyzed the memory: model [38]. However, it should be noted that recently Reed and col- leagues [40] analyzed the neuropsychological profile in autopsy- defined AD and CVD and raised questions about the usefulness of ex- ecutive function impairment as a diagnostic marker of VaD or VCI. In fact, the results of the study showed that a predominant memory im- pairment was present in 71% of the analyzed cases with AD, while a predominant impairment of executive functions was present in only 45% of CVD cases, showing that if memory loss exceeded executive dysfunction in AD patients, executive dysfunction did not exceed memory loss in CVD patients. Therefore, the pattern of neuropsycho- logical impairment (and in particular a predominant memory loss as a marker of AD) may be useful in distinguishing patients with pure VaD from those with co-morbid AD in MCI/dementia. In contrast, the extent of ischemic disease does not appear to well correlate with the severity and profile of the neuropsychological deficits. Visual-spatial functions can be correctly assessed through some tests, such as the Judgment of Line Orientation [41] and the CDT [20]. Lee and colleagues studied and determined the early and characteris- T,FA ,CV opT y,To cop 43S. Bagnoli et al. / Journal of the Neurological Sciences 322 (2012) 41–45 praxis ratio (recent memory subscale score/praxis subscale score) for each patient, and concluded that, using an optimal cut-off, it could be useful to distinguish DLB from AD and VaD. Executive dysfunction has long been considered by many authors to be a characteristic manifestation of VaD and consequently evalua- tion should include neuropsychological tests exploring this domain. Patients with VaD show a significant impairment in planning and se- quencing, speed of mental processing, performance on unstructured tasks and attention. They may also present an impairment in lan- guage production, decreased verbal fluency and more perseverations than patients with AD [12]. For the evaluation of the possible pres- ence of subcortical or frontal lesions, the verbal fluency test [36], the Wisconsin Card Sorting Test (WCST) [37], the Trail Making Test [11], the initiation–perseveration subtest of the MDRS and the Stroop Test [38] can be used. Language functions could also be investigated through the Token Test [39] and the naming tasks from Aachener Aphasie test. Kramer and colleagues evaluated and compared execu- tive functions of two groups: one group consisted of 27 control sub- jects and the other of 12 non-demented subjects presenting one or more subcortical lacunes. The study showed that the subcortical is- chemic vascular disease (SIVD) group performed below the level of the control group on recall of the Biber stimuli on trial 5 and again after a delay of 30 min, demonstrating a deficit in visual memory. Pa- tients with lacunes also showed worse performances on the interfer- ence condition of the Stroop Test, on the California Card Sort Test and on the initiation–perseveration subtest of the MDRS. These results in- dicate that, even in non-demented patients, SIVD is associated with subtle declines in visual memory and executive functioning. The pat- tern of cognitive impairment is consistent with a subcortical-frontal Predominant episodic memory imparment Episodic memory deficit due to impaired consolidation of mnesic traces • global cognitive function measures (MMSE,CD • verbal and visuo-spatial memory tasks (FCSRT • attention and executive tasks (WCST,TMT,Stro • language tests (phonemic and semantic fluenc • constructional praxis test (Rey Osterrieth figure Impared free and cued recall AD Fig. 1. Flowchart of tests that could be used to differentiate between VCI and degenerat tic patterns of errors on the CDT by dementia type. The analyzed sam- ple consisted of 143 patients with a diagnosis of dementia: 71 with AD, 39 with subcortical VaD and 33 with PDD. The study showed that patients with AD made many more conceptual deficit errors (loss or deficit in accessing knowledge of the attributes, features and meaning of a clock) than did patients with VaD or PDD, suggesting a loss of semantic memory. AD patients also showed more stimulus-bound response (SBR) (tendency of the drawing to be dominated or guided by a single stimulus) of type B (time written be- sides the “11” or between “10 and 11” or absent hands), and this is in- dicative of an impairment of semantic knowledge. In contrast, patients with VaD and PDD made more type A-SBR errors (hands set for 10:11 instead of 11:10) and this might be interpreted with regard to frontal dysfunction. Moreover, these patients made more spatial and/or planning deficits (SPD) (deficit in the layout of numbers on the clock, in most cases deficit in planning) and perseveration errors (continuation or recurrence of activity without an appropriate stimulus, in all cases perseveration of numbers) than did the AD patients. As a result, a dysfunction in the fronto- subcortical circuit may result in making planning and perseverative errors [20]. Several studies have shown the presence of behavioral and psy- chological symptoms in patients with dementia [42–46]. The coexis- tence of neuropsychiatric disorders seems to be very important from both a diagnostic and a prognostic point of view. In fact, the presence of these symptoms may be useful in differentiating demen- tias, such as VaD, AD, FTLD, DLB or PDD [47,48,10] and it seems to re- duce quality of life, increase the risk of institutionalization [49] and have a greater impact on the level of care required. Consequently, Impaired free recall improving with cues or recognition tasks Predominant executive and attention deficit Episodic memory deficit due to disturbance in the strategic aspects of episodic memory recall and retrieval B) LT,ReyOsterriethFigureRecall) est) kenTest, naming tasks from Aachner Aphasie test) y) VCI ive cognitive decline.AD: Alzheimer's disease; VCI: vascular cognitive impairment. 44 S. Bagnoli et al. / Journal of the Neurological Sciences 322 (2012) 41–45 their identification is extremely important for correct patient man- agement. Staekenborg and colleagues [50] showed that neuropsycho- logical symptoms were common in patients with VaD, with a different profile, depending on whether the patients had small- vessel or large-vessel disease. To emphasize the importance of the neuropsychiatric symptoms–dementia association, the term “BPSD” (Behavioral and Psychological Symptoms of Dementia) has been in- troduced, which includes a large and heterogeneous spectrum of non-cognitive symptoms that can occur in a patient with dementia [51]. Recognition of BPSD is facilitated by the use of standardized scale, such as the Neuropsychiatric Inventory (NPI) [52]. However, in most cases, these scales have been developed for AD and consequent- ly are not very sensitive for VaD. The Middelheim Frontality Score (MFS) is a clinical and behavioral validated assessment scale that measures frontal features and that reliably discriminates FTD from AD and has a sensitivity of 88.7% and a specificity of 89% (with a total MFS score of 5 as the cut-off) [53]. The Frontotemporal Behavioral Scale assesses frontal lobe dysfunction and is useful for early diagno- sis of FTD and for differential diagnosis for AD and VaD. Using a cut- off of 3 points, the specificity of the scale is 95% and the sensitivity is 91% [54]. In addition, there are also available scales for the focused assessment of specific symptoms that can greatly affect quality of life. Some examples are the 15 item‐Geriatric Depression Scale (GDS) [55] and the Cornell Scale for Depression in Dementia [56] for the assess- ment of depressive symptoms. Impulsive–compulsive disorders and REM sleep behavior disorder can be investigated through the Ques- tionnaire for Impulsive–Compulsive Disorders in Parkinson's disease (QUIP) [57] and the REM sleep behavior disorder screening question- naire [58] respectively. 4. Conclusions There are currently no neuropsychological tests developed specif- ically for VaD. In this manuscript we make an overview of the avail- able and widely used neuropsychological tests in the diagnosis of dementia. The early impairment of particular brain areas allows to identify VaD specific cognitive deficits. In fact VaD patients show an impairment of mainly frontal functions. Executive functions are par- ticularly affected, while memory deficits are less frequent in patients with VaD than patients with AD. In order to clarify the neuropsychological management of VaD pa- tients we suggest a flowchart of test that could be used to make a dif- ferential diagnosis between VCI and degenerative cognitive disorders like AD (Fig. 1). The assessment starts from the need to make a diag- nosis of dementia and this requires an extensive neuropsychological battery. We propose to use tests exploring global cognitive function, verbal and visuo-spatial memory, attention and executive function, language and constructional praxis. On the basis of the predominance of the cognitive deficits highlighted by the neuropsychological assess- ment it is possible to better differentiate VCI from AD. 5. 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Profiles of Suitability of neuropsychological tests in patients with vascular dementia (VaD) 1. Introduction 2. The role of neuropsychological tests in the early diagnosis of dementia 3. Neuropsychological assessment of VaD: overview 4. Conclusions 5. Methods section Disclosure statement References