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Journal of Alzheimer’s Disease 43 (2015) 849–855 DOI 10.3233/JAD-141257 IOS Press
Closing-in is related to Apathy in Alzheimer’s Disease Patients Dario Grossia , Natascia de Luciaa and Luigi Trojanoa,b,∗ a Neuropsychology b Salvatore
Laboratory, Department of Psychology, Second University of Naples, Italy Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy
Handling Associate Editor: Montse Alegret
Accepted 2 July 2014
Abstract. Background: Apathy and depression are behavioral manifestations that may occur often in Alzheimer’s disease (AD) patients. AD patients may also show Closing-in (CI) phenomenon, in graphic copying tasks. Recent evidence would suggest that apathetic symptoms are related to frontal dysfunctions in AD patients, whereas the cognitive bases of depressive symptoms in AD are still unclear. Recent studies demonstrated that frontal dysfunctions are also involved in the genesis of CI in AD patients. Objective: Since frontal dysfunctions are thought to be more strongly related to apathetic than depressive symptoms, here we tested the hypothesis that CI is significantly associated with apathy in AD patients. Methods: Forty-four AD patients were enrolled for this study. All patients completed a neuropsychological evaluation of visuospatial, frontal/executive, visuo-constructional, and memory skills. Moreover, graphic copying tasks were employed to detect CI, and behavioral scales to assess apathetic and depressive symptoms. Results: CI and apathetic and depressed symptoms occurred in more than half of the present AD sample, but regression models revealed that the number of CI was significantly related to apathy only. The number of CI was also significantly correlated with severity of apathetic but not of depressive symptoms. Conclusion: The present study demonstrated that CI and apathy are correlated with each other in mild to moderate AD, likely because they share common pathogenic mechanisms related to frontal/executive dysfunctions. Keywords: Alzheimer’s disease, apathy, closing-in, depression, frontal defect
INTRODUCTION Frontal executive dysfunctions very often occur in Alzheimer’s disease (AD), resulting in cognitive and behavioral abnormalities [1] since early stages of the illness [2]. Among dysexecutive behavioral disorders, AD patients very often show loss of motivation, diminished social and cognitive initiative, lack of interest, and reduced emotional responses, that are encompassed within the term Apathy [3, 4]. Converging evidence from neuroimaging and neuropsychological studies ∗ Correspondence to: Luigi Trojano, Neuropsychology Lab, Department of Psychology, Second University of Naples, Viale Ellittico 31, 81100 Caserta, Italy. Tel.: +39 0823274784; Fax: +39 0823274774; E-mail: [email protected].
would demonstrate a close relationship between apathy and frontal dysfunction in AD patients [5, 6]. For instance, it has been reported that apathetic AD patients achieve significantly lower scores than non-apathetic AD patients on frontal executive tests [7], and that apathetic AD patients show diffuse white matter hyperintensities in prefrontal regions [8]. AD patients may also show depressed mood, with possibly specific clinical features including hopelessness, sadness, irritability, and social withdrawal [9]; depressed mood is often associated with or overlaps apathy [8]. Cognitive and neural bases of depressive symptoms in AD are still a matter of debate. Some authors claimed that dysfunction of prefrontal regions may contribute to the genesis of the depressive symptoms in AD patients [10], as confirmed by
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recent neuroimaging studies [11], but other researchers reported contrasting findings, and suggested that frontal dysfunction is more strongly related to apathetic symptomatology than to depressed mood in AD patients [7, 8]. Recently, it has been proposed that frontal executive disorders are involved in the genesis of a peculiar neuropsychological sign, the so-called Closing-in (CI) phenomenon, characterized by the tendency to draw near to or superimposed on the model in copying tasks [12]. CI has been rarely described after focal brain lesions [13], whereas it appears to be quite frequent in progressive mental deterioration, particularly in AD [14, 15]. Early studies ascribed CI to an attempt to compensate for visuo-spatial defects, such as an inability in mentally representing the model to be copied, or, alternatively, as an impairment in the temporary storage of the model during the copying performance [16, 17]. However, available empirical data did not support unequivocally this visuo-spatial ‘compensation’ hypothesis, so that a competing account has been proposed, according to which CI is mainly related to attentional/executive defects [18, 19]. In recent years, several single case studies [20, 21] and prospective studies on patients with degenerative diseases [14, 15] supported the idea that defective cognitive monitoring of motor acts and attention, related to frontal executive dysfunction, can induce patients to deviate toward a salient model, thus contributing to the genesis of CI [14, 15, 18]. On the basis of the findings briefly outlined above, it is possible to hypothesize that CI is more strongly associated with apathetic than with depressive symptoms, since frontal dysfunctions are thought to be more strongly associated with the former behavioral disorders than with the latter. In the present study, we aimed to test this hypothesis by exploring whether any association exists between CI and apathy or depression in AD patients. To demonstrate specific links between cognitive and behavioral manifestations would contribute to clinical characterization of AD patients, and provide novel insights on the relationships among different facets of frontal/executive control. MATERIALS AND METHODS Patients Among a continuous series of outpatients referred for progressive memory disorders or diffuse cognitive impairment lasting for at least six months, we selected those who matched the following inclusion criteria:
i) clinical diagnosis of ‘probable’ AD according to the NINCDS-ADRDA criteria [22]; ii) mild to moderate level of AD severity, as assessed by a score ranging 0.5 to 2 points at the Clinical Dementia Rating scale (CDR) [23]; iii) formal education of at least two years. Exclusion criteria were: i) history of previous traumatic brain injury, stroke or psychiatric disorders; ii) concomitant severe organ insufficiency, or neoplastic diseases. The sample consisted of forty-four (23 females) AD patients, who had mean age of 72.9 ± 7.2 years, mean education of 8.2 ± 4.4 years, and mean CDR score of 1.2 ± 0.49. All patients received pharmacological treatment with acetylcholinesterase inhibitors. All patients (or their caregivers) gave their written informed consent to participate to the study. The study was approved by local Ethics’ Committees, and performed in accordance with the Ethical standards of Helsinki Declaration. Neuropsychological assessment All patients were assessed on neuropsychological tests tapping different cognitive abilities. All tests were given in their standardized Italian version. The Mini Mental State Examination (MMSE) [24], was used to assess general cognitive functioning; the Frontal Assessment Battery (FAB) [25], the phonological verbal fluency task [26], and the Stroop color-word test [27] were used to assess frontal high-level cognitive control abilities; the Corsi span forward [28], to evaluate working memory for visuo-spatial material; the Copying of drawings [28] and the immediate reproduction of Rey’s Complex Figure [29] were administered to assess visuo-constructional skills; the Clock drawing test [30] to evaluate semantic and planning abilities in the visuo-spatial domain; the immediate and delayed recall of 15-Word learning test [31] were used to evaluate anterograde long-term memory. CI was searched for in responses at the three above mentioned graphic tasks: the pentagon copying of the MMSE [24], the 7-figure copying task [28], and the immediate reproduction of the Rey’s Complex Figure [29]. The pentagon copying of the MMSE [24] and the 7-figure copying task [28] included black-andwhite geometrical figures, each centrally printed in the higher half of a vertically arranged A4 sheet of paper. Each stimulus was presented one at a time, centrally aligned with respect to the patients’ body midline, and the instruction was to reproduce the original figure in the lower space of the same sheet. In the traditional version of the 7-figure copying task [28], a horizontal line is printed in the center of the sheet in order to
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separate the model space from the copying space; in the present study, we deleted that line to avoid any visual cue that could interfere with the patients’ reproduction [14, 15]. The Rey’s Complex Figure [29] is a drawing including different geometrical elements, printed in the middle of an A4 horizontally arranged paper; the patient was required to reproduce the model on a blank sheet, placed 10 mm from the bottom edge of the model’s sheet, in landscape orientation [14, 15]. CI was classified as: adherent-CI when at least one element of the copy overlapped to at least one element of the model, and near-CI when any point of the copy was within 10 mm from the lower side of the model [14, 15]; for the Rey’s Complex Figure, the near-CI was identified when the copy was produced within the model’s sheet, and when the figure was copied within 10 mm from the upper edge of the response sheet [14, 15]. To identify the cognitive, emotional, and behavioral symptoms of apathy, we used the Italian Informant version of the Apathy Evaluation Scale (AES) [32, 33]. This scale consisted of a 18-item questionnaire, compiled by the patients’ caregivers, in which higher scores reflected greater apathy. To assess the presence and severity of depression symptoms, we used the Italian version of the Hamilton Depression Rating Scale (HDRS) [34, 35]. This scale consisted of a 17item scale, rated by the examiner during an interview with the patient. The presence of clinically relevant apathetic or depressive symptoms was identified by referring to Italian cut-off scores (AES: cut-off 44/72; HDRS: cut-off >7), but it is important to underline that such cut-off scores are not intended to provide definite diagnostic definitions, that would require a wide-range clinical assessment. For instance, it has been claimed that depressive features occurring within the course of AD can differ from those characterizing Major Depression in several respects, such as severity or persistence of symptoms or suicidal ideation, and that such differences may require specific diagnostic criteria [9]. Statistical analyses Two separate multivariate analyses of variance (MANOVAs) were performed to assess whether the demographic data (age, education) and the neuropsychological scores differed as a function of presence of clinically relevant apathy or depression (identified with reference to available cut-off scores for AES and HDRS, respectively). Then, we adopted conservative statistical procedures to identify variables strongly associated with the
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two behavioral disorders of interest. As a preliminary analysis, we run two logistic regression models in order to ascertain if age, education, general cognitive impairment (MMSE) and level of dementia severity (CDR) were independently related to apathy or depression. To specifically explore if CI was related to apathy or depression in our sample, we run two hierarchical logistic regression models, computing composite indices as average Z-scores for each neuropsychological domain. Thus, the Corsi span forward and the Clock drawing task were included in the visuo-spatial score; the Rey’s Complex Figure and Copying of drawings tests were included in the visuo-constructional score; the FAB, phonological verbal fluency score, and Stroop color-word test (time and errors) were included in the frontal executive score; the immediate and delayed recall of 15-Word learning test were included in the memory score. In the first regression model, we entered the presence of apathy as dependent measure (presence of apathy coded as 1, and lack of apathy coded as 0), whereas the total number of CI, and the composite Z-scores for frontal executive, visuo-spatial, visuoconstructional, and memory tests were sequentially entered as independent variables. In the second model, we entered the presence of depression as the dependent measure (presence of depression coded as 1, and lack of depression coded as 0), whereas the independent variables were the same as above. To test whether any possible association existed between CI, apathy and depression considered as quantitative and not qualitative variables, we computed the Pearson’s correlation coefficients among the number of CI, the raw total scores on the AES and the HDRS, and all neuropsychological scores.
RESULTS CI was detected in 26/44 AD patients (59%), who produced a mean of 5.15 CI errors (134 errors out of 396 copies). Among AD patients with CI, 5 (11.3% of the total sample) produced the near-CI only (16 errors), and 21 (47.7% of the total sample) exhibited adherentCI too (118 errors). All these patients produced CI on one or more items belonging to the 7-figure copying task, whereas 7/26 (26.9%) patients exhibited the phenomenon in pentagon copying (MMSE) and 5/26 (19.2%) in copying the Rey’s Complex Figure. In 17/44 AD patients apathy was found to be associated with depression, whereas 10 patients showed apathy in isolation (mean total AES score = 51, standard deviation = 6.05; mean HDRS score = 4.90,
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Table 1 Means and SDs on demographic data and neuropsychological scores in AD patients with or without apathy, and in AD patients with or without depression Apathy (n = 27) Age Education Mini Mental State Examination Clinical Dementia Rating Scale Total number of Closing-in phenomena Visuo-spatial skills Corsi span forward Clock drawing task Visuo-constructional skills Rey’s Complex Figure – immediate copying Copying drawings test Anterograde memory skills 15-Word learning test – immediate recall 15-Word learning test – delayed recall Frontal executive skills Frontal Assessment Battery Phonological verbal fluency Stroop color-word test – Time Stroop color-word test – Error Apathy Evaluation Scale score Hamilton Depression Rating Scale score ∗ Significantly
No-apathy (n = 17)
Depression (n = 24)
No-depression (n = 20)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
74.26 7.84 18.63 1.18 4.42*
7.92 4.77 2.89 0.44 2.83
72.00 8.52 19.00 1.38 2.00
6.72 4.29 2.91 0.52 2.08
72.64 8.14 18.81 1.15 3.42
7.17 4.94 2.94 0.43 3.17
73.56 8.38 18.86 1.37 2.31
7.63 3.63 2.88 0.52 2.08
2.92 4.07
0.86 2.31
2.95 4.62
0.97 1.70
2.86 3.87
0.89 1.74
3.06 4.67
0.92 2.08
7.78 5.05
9.58 4.00
9.84 6.84
9.92 4.30
8.00 6.04
7.55 4.69
9.50 6.13
10.86 3.40
15.32 0.74
7.18 1.48
15.32 1.20
6.80 2.04
15.04 0.86
6.52 1.62
15.81 1.25
7.67 2.14
5.79* 7.89 27.42 19.81* 52.05* 10.73*
3.37 5.80 18.30 4.53 5.99 7.76
8.68 9.88 35.68 12.26 37.24 3.80
3.84 5.88 51.81 9.21 3.86 4.05
6.61 8.94 36.96 16.16 45.85 9.17
3.50 6.28 51.72 8.39 8.89 7.39
8.88 9.07 29.33 14.40 39.75 2.62
4.22 5.72 33.60 8.52 7.55 2.39
different from No-apathy at p < 0.05; no significant differences were found in AD patients with or without depression.
standard deviation = 5.17), and 7 patients had clinically relevant depressive symptomatology only (mean total AES score = 41.8, standard deviation = 7.10; mean HDRS score = 11, standard deviation = 4.50). Among patients showing apathy alone or apathy associated with depression (n = 27), 17 showed CI (3 patients exhibited near-CI only, and 14 adherent-CI too), whereas 18 out of the 24 patients with depressive symptoms alone or associated with apathy showed CI (4 patients exhibited near-CI only, and 14 adherent-CI too). Detailed neuropsychological results as a function of presence of apathy or depression are reported in Table 1. The MANOVA run to compare neuropsychological and behavioral scores in AD patients with or without apathy revealed a main effect of the presence of apathy (Wilks’λ = 0.47; p = 0.04; η2p =0.52). AD patients with apathy achieved significantly lower scores than AD patients without apathy on the frontal executive skills (Frontal Assessment Battery, p = 0.01; Stroop color-word test – error, p < 0.005), but the two groups did not differ on demographic data (age: p = 0.031; education: p = 0.62), MMSE (p = 0.67), or CDR (p = 0.20), phonological verbal fluency (p = 0.27), Stroop color-word test – time (p = 0.51), visuo-spatial skills (Corsi span forward, p = 0.92; Clock drawing task, p = 0.37), or
visuo-constructional skills (immediate copying of the Rey’s Complex Figure, p = 0.49; Copying of drawings test, p = 0.16). Interestingly, AD patients with apathy produced a significantly higher number of CI phenomena than AD patients without apathy (p < 0.05). The MANOVA run to compare AD patients with or without depression showed no significant differences between the two groups (Wilks’λ = 0.63; p = 0.42; η2p =0.36). In particular, patients with or without depression did not differ for the demographic data and neuropsychological scores (all p > 0.05), and produced a similar number of CI phenomena (p = 0.23). On the basis of the above results, we also run one additional MANOVA to verify if patients with cooccurrent apathy and depression (APDE group; n = 17) achieved worse scores with respect to patients showing apathy only (AP-O group; n = 10), or depression only (DE-O group; n = 7). Results showed that the general model was not significant (Wilks’λ = 0.17; p = 0.17), but the analysis of the single effects revealed significant differences on the FAB (p = 0.03), and number of CI (p = 0.01) among the three groups. Bonferroni corrected post-hoc comparisons revealed that APDE group scored significantly lower on the FAB than the DE-O group (p = 0.04), whereas no significant differences were found between APDE and AP-O groups (p = 0.30). Moreover, the APDE group produced a
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Table 2 Pearson’s correlation coefficients between number of closing-in (CI), raw scores on the Apathy Evaluation Scale (AES), raw scores on the Hamilton Depression Rating Scale (HDRS), and neuropsychological tests in AD patients Number of CI AES score HDRS score Mini Mental State Examination Clinical Dementia Rating Scale Corsi span forward Clock drawing task Rey’s Complex Figure – immediate copying Copying drawings test 15-Word learning test – immediate recall 15-Word learning test – delayed recall Frontal Assessment Battery Phonological verbal fluency Stroop color-word test – time Stroop color-word test – error ∗ Correlation
0.427** 0.274 −0.104 −0.222 −0.302* −0.329* −0.482** −0.749** −0.133 −0.167 −0.375* −0.474** 0.427** 0.320*
AES score – 0.440** 0.009 −0.141 −0.032 0.084 −0.155 −0.273 −0.003 −0.020 −0.328* −0.184 −0.124 0.278
HDRS score – −0.112 0.102 −0.192 0.041 −0.091 −0.096 −0.140 −0.155 −0.362* −0.175 −0.047 0.211
significant at p < 0.05; ** correlation significant at p < 0.01.
number of CI significantly higher than the DE-O group (p = 0.01), but not than the AP-O group (p = 0.26). Results from the preliminary logistic regression analysis showed that the demographic data, MMSE and CDR were not related to presence of apathy (χ2 [4] = 2.71, p = 0.60; Cox & Snell R2 = 0.06) or depression (χ2 [4] = 2.80, p = 0.59; Cox & Snell R2 = 0.06). The first hierarchic logistic regression model was statistically significant (χ2 [5] = 11.14, p = 0.04; Cox & Snell R2 = 0.22). Apathy was significantly related to the total number of CI (odds ratio = 1.612; 95% confidence interval = 1.133–2.294; p = 0.008); the model did not change by entering the frontal executive composite Z-score (odds ratio = 0.932; 95% confidence interval = 0.859–1.010; p = 0.08), the visuo-spatial composite Z-score (odds ratio = 0.865; 95% confidence interval = 0.367–2.042; p = 0.74), the visuo-constructional composite Z-score (odds ratio = 1.068; 95% confidence interval = 0.902–1.266; p = 0.44), or the memory composite Z-score (odds ratio = 1.026; 95% confidence interval = 0.845–1.246; p = 0.79). The second hierarchic logistic regression model was not significant (χ2 [5] = 6.20, p = 0.28; Cox & Snell R2 = 0.13). Last, the Pearson’s coefficients computed to test the possible correlations between CI, apathy, depression, and the neuropsychological scores considered as quantitative variables are reported in Table 2. The total number of CI phenomena was significantly correlated with the raw total score on the AES (p < 0.005), but not with the raw total score on the HDRS (p = 0.07). Moreover, the total number of CI correlated with visuo-spatial skills (Corsi span forward, p = 0.04; Clock drawing task, p = 0.02), visuo-
constructional skills (immediate copying of the Rey’s Complex Figure, p < 0.005; Copying of drawings test, p < 0.001), and frontal executive skills (FAB, p = 0.01; phonological verbal fluency, p < 0.005; Stroop colorword test – time, p < 0.005; Stroop color-word test – error, p = 0.03). No significant correlations were found between the number of CI and MMSE (p = 0.50), CDR (p = 0.14) or memory skills (15-Word learning test: immediate recall p = 0.39; delayed recall p = 0.28). The raw total score on the AES was also significantly correlated to the raw total score on the HDRS (p = 0.003), and frontal executive skills (FAB, p = 0.03), but not with MMSE, CDR, visuo-spatial skills (Corsi span forward, and Clock drawing task), visuo-constructional skills (immediate copying of the Rey’s Complex Figure, and Copying of drawings test), memory skills (immediate and delayed recall of the 15-Word learning test), phonological verbal fluency test, or Stroop colorword test (all p > 0.05). Last, the raw total score on the HDRS correlated with the frontal executive skills (FAB, p = 0.01), but not with the other neuropsychological scores (MMSE, CDR, Corsi span forward, Clock drawing, copying of the Rey’s Complex Figure, copying of drawings, phonological verbal fluency, Stroop color-word test, immediate and delayed recall of the 15-Word learning test, all p > 0.05).
DISCUSSION The association between apathy and depression in AD has often been reported, and may be explained by the partial overlap of their neural bases, but also by the partial overlap of their symptomatology [8]. Instead, the association of apathy or depression with CI has
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not been explored as yet. The overall pattern of the present results would demonstrate that CI phenomenon is strongly associated to apathy in AD patients, whereas association of CI with depressive symptoms is weak. In the present study, apathy, depression, and CI occurred quite frequently and were detected in more than half of the sample, in agreement with previous findings [8, 14]. In particular, our data showed that CI can be frequently found in patients affected by apathy (17/27, 62.3%) or by depressive symptoms (18/24, 75%). However, the results from the first hierarchic logistic regression model demonstrated that the total number of CI phenomena produced across the three graphic tasks was significantly related to the presence of apathy. Conversely, the second hierarchic logistic regression model did not reveal significant associations between the total number of CI and the occurrence of depressive symptoms in our AD patients. These results would suggest that CI phenomena often appear in AD patients with both apathy and depression, but severity of CI (as expressed by higher number of CI errors) would have closer and stronger relationships with apathy than with depressive symptoms. This observation received support from the finding that the number of CI was significantly correlated to AES score but not to HDRS score in our sample, although raw AES and HDRS scores were correlated between each other. Stated in other terms, AD patients producing higher number of CI phenomena would seem more prone to show apathy than depressive symptoms. It has been observed that CI is associated to frontal executive defects both in AD and in other dementing conditions [14, 15]. Here we provided evidence that number of CI, i.e., CI severity, is related to the presence of behavioral disorders arising from a prevalent involvement of the frontal executive functions, that is apathy and not depression. These results would be consistent with recent neuroimaging findings on the brain structural correlates of apathy and depressive symptoms in AD patients. Indeed, significantly larger volume of frontal white matter hyperintensities has been found in AD patients with apathy, with respect to AD patients with depressive symptoms [8]. However, some limitations of the present study should be taken into account. First, since we enrolled a relatively small sample of AD patients, further studies are needed to confirm and extend the present findings, and verifying whether the relationship between CI and apathy also holds true in other kinds of degenerative diseases (e.g., frontotemporal dementia). Second, since we did not explore the relationship between different types of CI (near-CI versus adherent-CI),
apathetic and depressive symptoms, additional studies could consider to ascertain whether the qualitative evaluation of CI phenomena (near versus adherent CI) might provide further insight on the relationships between cognitive and behavioral frontal dysexecutive disorders. Third, since the depressive symptoms occurring within the course of AD can differ from those characterizing Major Depression in several respects, further studies could consider to adopt specific diagnostic criteria for diagnosis of depression in AD [9]. Notwithstanding these limitations, we believe that the present findings can contribute to clinical characterization of AD patients, and provide novel insights onto the relationships between cognitive and behavioral manifestations. Further studies might also test whether CI can be helpful to delineate progression of clinical, cognitive and behavioral disorders in AD. ACKNOWLEDGMENTS We are grateful to all the patients (and their legal guardians) for their consent to participate in the present study. This study has not received any external financial or material support. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2427). REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
Godefroy O, Azouvi P, Robert P, Roussel M, LeGall D, Meulemans T, Groupe de R´eflexion sur l’Evaluation des Fonctions Ex´ecutives Study, Group (2010) Dysexecutive syndrome: Diagnostic criteria and validation study. Ann Neurol 68, 855-864. Baudic S, Barba GD, Thibaudet MC, Smagghe A, Remy P, Traykov L (2006) Executive function deficits in early Alzheimer’s disease and their relations with episodic memory. Arch Clin Neuropsychol 21, 15-21. Vilalta-Franch J, Calv´o-Perxas L, Garre-Olmo J, Turr´oGarriga O, L´opez-Pousa S (2013) Apathy syndrome in Alzheimer’s disease epidemiology: Prevalence, incidence, persistence, and risk and mortality factors. J Alzheimers Dis 33, 535-543. Grossi D, Santangelo G, Barbarulo AM, Vitale C, Castaldo G, Proto MG, Siano P, Barone P, Trojano L (2013) Apathy and related executive syndromes in dementia associated with Parkinson’s disease and in Alzheimer’s disease. Behav Neurol 27, 515-522. Landes AM, Sperry SD, Strauss ME, Geldmacher DS (2001) Apathy in Alzheimer’s disease. J Am Geriatr Soc 49, 17001707. Craig AH, Cummings JL, Fairbanks L, Itti L, Miller BL, Li J, Mena I (1996) Cerebral blood flow correlates of apathy in Alzheimer’s disease. Arch Neurol 53, 1116-1120. Kuzis G, Sabe L, Tiberti C, Dorrego F, Starkstein SE (1999) Neuropsychological correlates of apathy and depression in patients with dementia. Neurology 52, 1403-1407.
D. Grossi et al. / Apathy and Closing-in in AD [8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
[16]
[17]
[18] [19]
[20]
[21]
Starkstein SE, Mizrahi R, Capizzano AA, Acion L, Brockman S, Power BD (2009) Neuroimaging correlates of apathy and depression in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 21, 259-265. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF 3rd, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD (2002) Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 10, 125-128. Terada S, Oshima E, Sato S, Ikeda C, Nagao S, Hayashi S, Hayashibara C, Yokota O, Uchitomi Y (2014) Depressive symptoms and regional cerebral blood flow in Alzheimer’s disease. Psychiatry Res 221, 86-91. Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, Hashimoto M, Yamashita H, Sasaki M (1998) Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 50, 380-383. Mayer Gross W (1935) Some observations on apraxia. Proc R S Med 28, 63-72. Trojano L, Conson M (2008) Visuospatial and visuoconstructive deficits. In Handbook of Clinical Neurology, Goldenberg G, Miller BL, eds. Elsevier, Amsterdam, pp. 373-392. De Lucia N, Grossi D, Trojano L (2014) The genesis of closing-in in Alzheimer disease and vascular dementia: A comparative clinical and experimental study. Neuropsychology 28, 312-318. De Lucia N, Grossi D, Fasanaro AM, Carpi S, Trojano L (2013) Frontal defects contribute to the genesis of closing-in in Alzheimer’s disease patients. J Int Neuropsychol Soc 19, 802-808. Lee BH, Chin J, Kang SJ, Kim EJ, Park KC, Na DL (2004) Mechanisms of the closing-in phenomenon in a figure copying task in Alzheimer’s disease patients. Neurocase 10, 393-397. Serra L, Fadda L, Perri R, Caltagirone C, Carlesimo GA (2010) The closing-in phenomenon in the drawing performance of Alzheimer’s disease patients: A compensation account. Cortex 46, 1031-1036. Kwak YT (2004) Closing-in phenomenon in Alzheimer’s disease and subcortical vascular dementia. BMC Neurol 4, 3-7. Ambron E, McIntosh RD, Allaria F, Della Sala S (2009) A large-scale retrospective study of closing-in behaviour in Alzheimer’s disease. J Int Neuropsychol Soc 15, 787-792. McIntosh RD, Ambron E, Della Sala S (2008) Evidence for an attraction account of Closing-in Behaviour. Cogn Neuropsychol 25, 376-394. Conson M, Salzano S, Manzo V, Grossi D, Trojano L (2009) Closing-in without severe drawing disorders: The fatal consequences of pathological attraction. Cortex 45, 285-292.
[22]
[23]
[24]
[25]
[26]
[27]
[28] [29]
[30] [31]
[32] [33]
[34] [35]
855
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34, 939-944. Hughes CP, Berg L, Danziger WL, Coben LA, Marin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140, 566-572. Measso G, Cavarzeran F, Zappala G, Lebowitz BD, Crook TH, Pirozzolo FJ, Amaducci LA, Massari D, Grigoletto F (1993) The Mini-Mental State Examination: Normative study of an Italian random sample. Dev Neuropsychol 9, 77-85. Appollonio I, Leone M, Isella V, Piamarta F, Consoli T, Villa ML, Forapani E, Russo A, Nichelli P (2005) The Frontal Assessment Battery (FAB): Normative values in an Italian population sample. Neurol Sci 26, 108-116. Carlesino GA, Caltagirone C, Gainotti G (1996) The mental deterioration battery: Normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 36, 378-384. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) Una versione abbreviata del test di Stroop. Dati normativi nella popolazione italiana. Nuova Riv Neurol 12, 111-115. Spinnler H, Tognoni G (1987) Standardizzazione e taratura italiana di tests neuropsicologici. Ital J Neurol Sci 6, 8-96. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) Rey-Osterrieth complex figure: Normative values in an Italian population sample. Neurol Sci 22, 443-447. Mondini S, Mapelli D, Vestri A, Bisiacchi PS (2003) Esame neuropsicologico breve, Cortina Editore, Milano. Caltagirone C, Gainotti G, Carlesimo GA, Parnetti L (1995) Batteria per la valutazione del deterioramento mentale (parte I): Descrizione di uno strumento per la diagnosi neuropsicologica. Arch Psicol Neurol Psichiatr 55, 461-470. Marin RS (1991) Apathy: A neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3, 243-254. Isella V, Appolonio I, Meregalli L, Melzi P, Iurlaro S, Frattola L (1998) Normative data for the Italian version of the apathy and anhedonia scale. Arch Psicol Neurol Psichiatr 59, 356375. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23, 56-62. Fava GA, Kellner R, Munari F, Pavan L (1982) The Hamilton Depression Rating Scale in normals and depressives. Acta Psychiatr Scand 66, 26-32.
Journal of Alzheimer’s Disease 43 (2015) 849–855 DOI 10.3233/JAD-141257 IOS Press
Closing-in is related to Apathy in Alzheimer’s Disease Patients Dario Grossia , Natascia de Luciaa and Luigi Trojanoa,b,∗ a Neuropsychology b Salvatore
Laboratory, Department of Psychology, Second University of Naples, Italy Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy
Handling Associate Editor: Montse Alegret
Accepted 2 July 2014
Abstract. Background: Apathy and depression are behavioral manifestations that may occur often in Alzheimer’s disease (AD) patients. AD patients may also show Closing-in (CI) phenomenon, in graphic copying tasks. Recent evidence would suggest that apathetic symptoms are related to frontal dysfunctions in AD patients, whereas the cognitive bases of depressive symptoms in AD are still unclear. Recent studies demonstrated that frontal dysfunctions are also involved in the genesis of CI in AD patients. Objective: Since frontal dysfunctions are thought to be more strongly related to apathetic than depressive symptoms, here we tested the hypothesis that CI is significantly associated with apathy in AD patients. Methods: Forty-four AD patients were enrolled for this study. All patients completed a neuropsychological evaluation of visuospatial, frontal/executive, visuo-constructional, and memory skills. Moreover, graphic copying tasks were employed to detect CI, and behavioral scales to assess apathetic and depressive symptoms. Results: CI and apathetic and depressed symptoms occurred in more than half of the present AD sample, but regression models revealed that the number of CI was significantly related to apathy only. The number of CI was also significantly correlated with severity of apathetic but not of depressive symptoms. Conclusion: The present study demonstrated that CI and apathy are correlated with each other in mild to moderate AD, likely because they share common pathogenic mechanisms related to frontal/executive dysfunctions. Keywords: Alzheimer’s disease, apathy, closing-in, depression, frontal defect
INTRODUCTION Frontal executive dysfunctions very often occur in Alzheimer’s disease (AD), resulting in cognitive and behavioral abnormalities [1] since early stages of the illness [2]. Among dysexecutive behavioral disorders, AD patients very often show loss of motivation, diminished social and cognitive initiative, lack of interest, and reduced emotional responses, that are encompassed within the term Apathy [3, 4]. Converging evidence from neuroimaging and neuropsychological studies ∗ Correspondence to: Luigi Trojano, Neuropsychology Lab, Department of Psychology, Second University of Naples, Viale Ellittico 31, 81100 Caserta, Italy. Tel.: +39 0823274784; Fax: +39 0823274774; E-mail: [email protected].
would demonstrate a close relationship between apathy and frontal dysfunction in AD patients [5, 6]. For instance, it has been reported that apathetic AD patients achieve significantly lower scores than non-apathetic AD patients on frontal executive tests [7], and that apathetic AD patients show diffuse white matter hyperintensities in prefrontal regions [8]. AD patients may also show depressed mood, with possibly specific clinical features including hopelessness, sadness, irritability, and social withdrawal [9]; depressed mood is often associated with or overlaps apathy [8]. Cognitive and neural bases of depressive symptoms in AD are still a matter of debate. Some authors claimed that dysfunction of prefrontal regions may contribute to the genesis of the depressive symptoms in AD patients [10], as confirmed by
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recent neuroimaging studies [11], but other researchers reported contrasting findings, and suggested that frontal dysfunction is more strongly related to apathetic symptomatology than to depressed mood in AD patients [7, 8]. Recently, it has been proposed that frontal executive disorders are involved in the genesis of a peculiar neuropsychological sign, the so-called Closing-in (CI) phenomenon, characterized by the tendency to draw near to or superimposed on the model in copying tasks [12]. CI has been rarely described after focal brain lesions [13], whereas it appears to be quite frequent in progressive mental deterioration, particularly in AD [14, 15]. Early studies ascribed CI to an attempt to compensate for visuo-spatial defects, such as an inability in mentally representing the model to be copied, or, alternatively, as an impairment in the temporary storage of the model during the copying performance [16, 17]. However, available empirical data did not support unequivocally this visuo-spatial ‘compensation’ hypothesis, so that a competing account has been proposed, according to which CI is mainly related to attentional/executive defects [18, 19]. In recent years, several single case studies [20, 21] and prospective studies on patients with degenerative diseases [14, 15] supported the idea that defective cognitive monitoring of motor acts and attention, related to frontal executive dysfunction, can induce patients to deviate toward a salient model, thus contributing to the genesis of CI [14, 15, 18]. On the basis of the findings briefly outlined above, it is possible to hypothesize that CI is more strongly associated with apathetic than with depressive symptoms, since frontal dysfunctions are thought to be more strongly associated with the former behavioral disorders than with the latter. In the present study, we aimed to test this hypothesis by exploring whether any association exists between CI and apathy or depression in AD patients. To demonstrate specific links between cognitive and behavioral manifestations would contribute to clinical characterization of AD patients, and provide novel insights on the relationships among different facets of frontal/executive control. MATERIALS AND METHODS Patients Among a continuous series of outpatients referred for progressive memory disorders or diffuse cognitive impairment lasting for at least six months, we selected those who matched the following inclusion criteria:
i) clinical diagnosis of ‘probable’ AD according to the NINCDS-ADRDA criteria [22]; ii) mild to moderate level of AD severity, as assessed by a score ranging 0.5 to 2 points at the Clinical Dementia Rating scale (CDR) [23]; iii) formal education of at least two years. Exclusion criteria were: i) history of previous traumatic brain injury, stroke or psychiatric disorders; ii) concomitant severe organ insufficiency, or neoplastic diseases. The sample consisted of forty-four (23 females) AD patients, who had mean age of 72.9 ± 7.2 years, mean education of 8.2 ± 4.4 years, and mean CDR score of 1.2 ± 0.49. All patients received pharmacological treatment with acetylcholinesterase inhibitors. All patients (or their caregivers) gave their written informed consent to participate to the study. The study was approved by local Ethics’ Committees, and performed in accordance with the Ethical standards of Helsinki Declaration. Neuropsychological assessment All patients were assessed on neuropsychological tests tapping different cognitive abilities. All tests were given in their standardized Italian version. The Mini Mental State Examination (MMSE) [24], was used to assess general cognitive functioning; the Frontal Assessment Battery (FAB) [25], the phonological verbal fluency task [26], and the Stroop color-word test [27] were used to assess frontal high-level cognitive control abilities; the Corsi span forward [28], to evaluate working memory for visuo-spatial material; the Copying of drawings [28] and the immediate reproduction of Rey’s Complex Figure [29] were administered to assess visuo-constructional skills; the Clock drawing test [30] to evaluate semantic and planning abilities in the visuo-spatial domain; the immediate and delayed recall of 15-Word learning test [31] were used to evaluate anterograde long-term memory. CI was searched for in responses at the three above mentioned graphic tasks: the pentagon copying of the MMSE [24], the 7-figure copying task [28], and the immediate reproduction of the Rey’s Complex Figure [29]. The pentagon copying of the MMSE [24] and the 7-figure copying task [28] included black-andwhite geometrical figures, each centrally printed in the higher half of a vertically arranged A4 sheet of paper. Each stimulus was presented one at a time, centrally aligned with respect to the patients’ body midline, and the instruction was to reproduce the original figure in the lower space of the same sheet. In the traditional version of the 7-figure copying task [28], a horizontal line is printed in the center of the sheet in order to
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separate the model space from the copying space; in the present study, we deleted that line to avoid any visual cue that could interfere with the patients’ reproduction [14, 15]. The Rey’s Complex Figure [29] is a drawing including different geometrical elements, printed in the middle of an A4 horizontally arranged paper; the patient was required to reproduce the model on a blank sheet, placed 10 mm from the bottom edge of the model’s sheet, in landscape orientation [14, 15]. CI was classified as: adherent-CI when at least one element of the copy overlapped to at least one element of the model, and near-CI when any point of the copy was within 10 mm from the lower side of the model [14, 15]; for the Rey’s Complex Figure, the near-CI was identified when the copy was produced within the model’s sheet, and when the figure was copied within 10 mm from the upper edge of the response sheet [14, 15]. To identify the cognitive, emotional, and behavioral symptoms of apathy, we used the Italian Informant version of the Apathy Evaluation Scale (AES) [32, 33]. This scale consisted of a 18-item questionnaire, compiled by the patients’ caregivers, in which higher scores reflected greater apathy. To assess the presence and severity of depression symptoms, we used the Italian version of the Hamilton Depression Rating Scale (HDRS) [34, 35]. This scale consisted of a 17item scale, rated by the examiner during an interview with the patient. The presence of clinically relevant apathetic or depressive symptoms was identified by referring to Italian cut-off scores (AES: cut-off 44/72; HDRS: cut-off >7), but it is important to underline that such cut-off scores are not intended to provide definite diagnostic definitions, that would require a wide-range clinical assessment. For instance, it has been claimed that depressive features occurring within the course of AD can differ from those characterizing Major Depression in several respects, such as severity or persistence of symptoms or suicidal ideation, and that such differences may require specific diagnostic criteria [9]. Statistical analyses Two separate multivariate analyses of variance (MANOVAs) were performed to assess whether the demographic data (age, education) and the neuropsychological scores differed as a function of presence of clinically relevant apathy or depression (identified with reference to available cut-off scores for AES and HDRS, respectively). Then, we adopted conservative statistical procedures to identify variables strongly associated with the
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two behavioral disorders of interest. As a preliminary analysis, we run two logistic regression models in order to ascertain if age, education, general cognitive impairment (MMSE) and level of dementia severity (CDR) were independently related to apathy or depression. To specifically explore if CI was related to apathy or depression in our sample, we run two hierarchical logistic regression models, computing composite indices as average Z-scores for each neuropsychological domain. Thus, the Corsi span forward and the Clock drawing task were included in the visuo-spatial score; the Rey’s Complex Figure and Copying of drawings tests were included in the visuo-constructional score; the FAB, phonological verbal fluency score, and Stroop color-word test (time and errors) were included in the frontal executive score; the immediate and delayed recall of 15-Word learning test were included in the memory score. In the first regression model, we entered the presence of apathy as dependent measure (presence of apathy coded as 1, and lack of apathy coded as 0), whereas the total number of CI, and the composite Z-scores for frontal executive, visuo-spatial, visuoconstructional, and memory tests were sequentially entered as independent variables. In the second model, we entered the presence of depression as the dependent measure (presence of depression coded as 1, and lack of depression coded as 0), whereas the independent variables were the same as above. To test whether any possible association existed between CI, apathy and depression considered as quantitative and not qualitative variables, we computed the Pearson’s correlation coefficients among the number of CI, the raw total scores on the AES and the HDRS, and all neuropsychological scores.
RESULTS CI was detected in 26/44 AD patients (59%), who produced a mean of 5.15 CI errors (134 errors out of 396 copies). Among AD patients with CI, 5 (11.3% of the total sample) produced the near-CI only (16 errors), and 21 (47.7% of the total sample) exhibited adherentCI too (118 errors). All these patients produced CI on one or more items belonging to the 7-figure copying task, whereas 7/26 (26.9%) patients exhibited the phenomenon in pentagon copying (MMSE) and 5/26 (19.2%) in copying the Rey’s Complex Figure. In 17/44 AD patients apathy was found to be associated with depression, whereas 10 patients showed apathy in isolation (mean total AES score = 51, standard deviation = 6.05; mean HDRS score = 4.90,
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Table 1 Means and SDs on demographic data and neuropsychological scores in AD patients with or without apathy, and in AD patients with or without depression Apathy (n = 27) Age Education Mini Mental State Examination Clinical Dementia Rating Scale Total number of Closing-in phenomena Visuo-spatial skills Corsi span forward Clock drawing task Visuo-constructional skills Rey’s Complex Figure – immediate copying Copying drawings test Anterograde memory skills 15-Word learning test – immediate recall 15-Word learning test – delayed recall Frontal executive skills Frontal Assessment Battery Phonological verbal fluency Stroop color-word test – Time Stroop color-word test – Error Apathy Evaluation Scale score Hamilton Depression Rating Scale score ∗ Significantly
No-apathy (n = 17)
Depression (n = 24)
No-depression (n = 20)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
74.26 7.84 18.63 1.18 4.42*
7.92 4.77 2.89 0.44 2.83
72.00 8.52 19.00 1.38 2.00
6.72 4.29 2.91 0.52 2.08
72.64 8.14 18.81 1.15 3.42
7.17 4.94 2.94 0.43 3.17
73.56 8.38 18.86 1.37 2.31
7.63 3.63 2.88 0.52 2.08
2.92 4.07
0.86 2.31
2.95 4.62
0.97 1.70
2.86 3.87
0.89 1.74
3.06 4.67
0.92 2.08
7.78 5.05
9.58 4.00
9.84 6.84
9.92 4.30
8.00 6.04
7.55 4.69
9.50 6.13
10.86 3.40
15.32 0.74
7.18 1.48
15.32 1.20
6.80 2.04
15.04 0.86
6.52 1.62
15.81 1.25
7.67 2.14
5.79* 7.89 27.42 19.81* 52.05* 10.73*
3.37 5.80 18.30 4.53 5.99 7.76
8.68 9.88 35.68 12.26 37.24 3.80
3.84 5.88 51.81 9.21 3.86 4.05
6.61 8.94 36.96 16.16 45.85 9.17
3.50 6.28 51.72 8.39 8.89 7.39
8.88 9.07 29.33 14.40 39.75 2.62
4.22 5.72 33.60 8.52 7.55 2.39
different from No-apathy at p < 0.05; no significant differences were found in AD patients with or without depression.
standard deviation = 5.17), and 7 patients had clinically relevant depressive symptomatology only (mean total AES score = 41.8, standard deviation = 7.10; mean HDRS score = 11, standard deviation = 4.50). Among patients showing apathy alone or apathy associated with depression (n = 27), 17 showed CI (3 patients exhibited near-CI only, and 14 adherent-CI too), whereas 18 out of the 24 patients with depressive symptoms alone or associated with apathy showed CI (4 patients exhibited near-CI only, and 14 adherent-CI too). Detailed neuropsychological results as a function of presence of apathy or depression are reported in Table 1. The MANOVA run to compare neuropsychological and behavioral scores in AD patients with or without apathy revealed a main effect of the presence of apathy (Wilks’λ = 0.47; p = 0.04; η2p =0.52). AD patients with apathy achieved significantly lower scores than AD patients without apathy on the frontal executive skills (Frontal Assessment Battery, p = 0.01; Stroop color-word test – error, p < 0.005), but the two groups did not differ on demographic data (age: p = 0.031; education: p = 0.62), MMSE (p = 0.67), or CDR (p = 0.20), phonological verbal fluency (p = 0.27), Stroop color-word test – time (p = 0.51), visuo-spatial skills (Corsi span forward, p = 0.92; Clock drawing task, p = 0.37), or
visuo-constructional skills (immediate copying of the Rey’s Complex Figure, p = 0.49; Copying of drawings test, p = 0.16). Interestingly, AD patients with apathy produced a significantly higher number of CI phenomena than AD patients without apathy (p < 0.05). The MANOVA run to compare AD patients with or without depression showed no significant differences between the two groups (Wilks’λ = 0.63; p = 0.42; η2p =0.36). In particular, patients with or without depression did not differ for the demographic data and neuropsychological scores (all p > 0.05), and produced a similar number of CI phenomena (p = 0.23). On the basis of the above results, we also run one additional MANOVA to verify if patients with cooccurrent apathy and depression (APDE group; n = 17) achieved worse scores with respect to patients showing apathy only (AP-O group; n = 10), or depression only (DE-O group; n = 7). Results showed that the general model was not significant (Wilks’λ = 0.17; p = 0.17), but the analysis of the single effects revealed significant differences on the FAB (p = 0.03), and number of CI (p = 0.01) among the three groups. Bonferroni corrected post-hoc comparisons revealed that APDE group scored significantly lower on the FAB than the DE-O group (p = 0.04), whereas no significant differences were found between APDE and AP-O groups (p = 0.30). Moreover, the APDE group produced a
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Table 2 Pearson’s correlation coefficients between number of closing-in (CI), raw scores on the Apathy Evaluation Scale (AES), raw scores on the Hamilton Depression Rating Scale (HDRS), and neuropsychological tests in AD patients Number of CI AES score HDRS score Mini Mental State Examination Clinical Dementia Rating Scale Corsi span forward Clock drawing task Rey’s Complex Figure – immediate copying Copying drawings test 15-Word learning test – immediate recall 15-Word learning test – delayed recall Frontal Assessment Battery Phonological verbal fluency Stroop color-word test – time Stroop color-word test – error ∗ Correlation
0.427** 0.274 −0.104 −0.222 −0.302* −0.329* −0.482** −0.749** −0.133 −0.167 −0.375* −0.474** 0.427** 0.320*
AES score – 0.440** 0.009 −0.141 −0.032 0.084 −0.155 −0.273 −0.003 −0.020 −0.328* −0.184 −0.124 0.278
HDRS score – −0.112 0.102 −0.192 0.041 −0.091 −0.096 −0.140 −0.155 −0.362* −0.175 −0.047 0.211
significant at p < 0.05; ** correlation significant at p < 0.01.
number of CI significantly higher than the DE-O group (p = 0.01), but not than the AP-O group (p = 0.26). Results from the preliminary logistic regression analysis showed that the demographic data, MMSE and CDR were not related to presence of apathy (χ2 [4] = 2.71, p = 0.60; Cox & Snell R2 = 0.06) or depression (χ2 [4] = 2.80, p = 0.59; Cox & Snell R2 = 0.06). The first hierarchic logistic regression model was statistically significant (χ2 [5] = 11.14, p = 0.04; Cox & Snell R2 = 0.22). Apathy was significantly related to the total number of CI (odds ratio = 1.612; 95% confidence interval = 1.133–2.294; p = 0.008); the model did not change by entering the frontal executive composite Z-score (odds ratio = 0.932; 95% confidence interval = 0.859–1.010; p = 0.08), the visuo-spatial composite Z-score (odds ratio = 0.865; 95% confidence interval = 0.367–2.042; p = 0.74), the visuo-constructional composite Z-score (odds ratio = 1.068; 95% confidence interval = 0.902–1.266; p = 0.44), or the memory composite Z-score (odds ratio = 1.026; 95% confidence interval = 0.845–1.246; p = 0.79). The second hierarchic logistic regression model was not significant (χ2 [5] = 6.20, p = 0.28; Cox & Snell R2 = 0.13). Last, the Pearson’s coefficients computed to test the possible correlations between CI, apathy, depression, and the neuropsychological scores considered as quantitative variables are reported in Table 2. The total number of CI phenomena was significantly correlated with the raw total score on the AES (p < 0.005), but not with the raw total score on the HDRS (p = 0.07). Moreover, the total number of CI correlated with visuo-spatial skills (Corsi span forward, p = 0.04; Clock drawing task, p = 0.02), visuo-
constructional skills (immediate copying of the Rey’s Complex Figure, p < 0.005; Copying of drawings test, p < 0.001), and frontal executive skills (FAB, p = 0.01; phonological verbal fluency, p < 0.005; Stroop colorword test – time, p < 0.005; Stroop color-word test – error, p = 0.03). No significant correlations were found between the number of CI and MMSE (p = 0.50), CDR (p = 0.14) or memory skills (15-Word learning test: immediate recall p = 0.39; delayed recall p = 0.28). The raw total score on the AES was also significantly correlated to the raw total score on the HDRS (p = 0.003), and frontal executive skills (FAB, p = 0.03), but not with MMSE, CDR, visuo-spatial skills (Corsi span forward, and Clock drawing task), visuo-constructional skills (immediate copying of the Rey’s Complex Figure, and Copying of drawings test), memory skills (immediate and delayed recall of the 15-Word learning test), phonological verbal fluency test, or Stroop colorword test (all p > 0.05). Last, the raw total score on the HDRS correlated with the frontal executive skills (FAB, p = 0.01), but not with the other neuropsychological scores (MMSE, CDR, Corsi span forward, Clock drawing, copying of the Rey’s Complex Figure, copying of drawings, phonological verbal fluency, Stroop color-word test, immediate and delayed recall of the 15-Word learning test, all p > 0.05).
DISCUSSION The association between apathy and depression in AD has often been reported, and may be explained by the partial overlap of their neural bases, but also by the partial overlap of their symptomatology [8]. Instead, the association of apathy or depression with CI has
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not been explored as yet. The overall pattern of the present results would demonstrate that CI phenomenon is strongly associated to apathy in AD patients, whereas association of CI with depressive symptoms is weak. In the present study, apathy, depression, and CI occurred quite frequently and were detected in more than half of the sample, in agreement with previous findings [8, 14]. In particular, our data showed that CI can be frequently found in patients affected by apathy (17/27, 62.3%) or by depressive symptoms (18/24, 75%). However, the results from the first hierarchic logistic regression model demonstrated that the total number of CI phenomena produced across the three graphic tasks was significantly related to the presence of apathy. Conversely, the second hierarchic logistic regression model did not reveal significant associations between the total number of CI and the occurrence of depressive symptoms in our AD patients. These results would suggest that CI phenomena often appear in AD patients with both apathy and depression, but severity of CI (as expressed by higher number of CI errors) would have closer and stronger relationships with apathy than with depressive symptoms. This observation received support from the finding that the number of CI was significantly correlated to AES score but not to HDRS score in our sample, although raw AES and HDRS scores were correlated between each other. Stated in other terms, AD patients producing higher number of CI phenomena would seem more prone to show apathy than depressive symptoms. It has been observed that CI is associated to frontal executive defects both in AD and in other dementing conditions [14, 15]. Here we provided evidence that number of CI, i.e., CI severity, is related to the presence of behavioral disorders arising from a prevalent involvement of the frontal executive functions, that is apathy and not depression. These results would be consistent with recent neuroimaging findings on the brain structural correlates of apathy and depressive symptoms in AD patients. Indeed, significantly larger volume of frontal white matter hyperintensities has been found in AD patients with apathy, with respect to AD patients with depressive symptoms [8]. However, some limitations of the present study should be taken into account. First, since we enrolled a relatively small sample of AD patients, further studies are needed to confirm and extend the present findings, and verifying whether the relationship between CI and apathy also holds true in other kinds of degenerative diseases (e.g., frontotemporal dementia). Second, since we did not explore the relationship between different types of CI (near-CI versus adherent-CI),
apathetic and depressive symptoms, additional studies could consider to ascertain whether the qualitative evaluation of CI phenomena (near versus adherent CI) might provide further insight on the relationships between cognitive and behavioral frontal dysexecutive disorders. Third, since the depressive symptoms occurring within the course of AD can differ from those characterizing Major Depression in several respects, further studies could consider to adopt specific diagnostic criteria for diagnosis of depression in AD [9]. Notwithstanding these limitations, we believe that the present findings can contribute to clinical characterization of AD patients, and provide novel insights onto the relationships between cognitive and behavioral manifestations. Further studies might also test whether CI can be helpful to delineate progression of clinical, cognitive and behavioral disorders in AD. ACKNOWLEDGMENTS We are grateful to all the patients (and their legal guardians) for their consent to participate in the present study. This study has not received any external financial or material support. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2427). REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
Godefroy O, Azouvi P, Robert P, Roussel M, LeGall D, Meulemans T, Groupe de R´eflexion sur l’Evaluation des Fonctions Ex´ecutives Study, Group (2010) Dysexecutive syndrome: Diagnostic criteria and validation study. Ann Neurol 68, 855-864. Baudic S, Barba GD, Thibaudet MC, Smagghe A, Remy P, Traykov L (2006) Executive function deficits in early Alzheimer’s disease and their relations with episodic memory. Arch Clin Neuropsychol 21, 15-21. Vilalta-Franch J, Calv´o-Perxas L, Garre-Olmo J, Turr´oGarriga O, L´opez-Pousa S (2013) Apathy syndrome in Alzheimer’s disease epidemiology: Prevalence, incidence, persistence, and risk and mortality factors. J Alzheimers Dis 33, 535-543. Grossi D, Santangelo G, Barbarulo AM, Vitale C, Castaldo G, Proto MG, Siano P, Barone P, Trojano L (2013) Apathy and related executive syndromes in dementia associated with Parkinson’s disease and in Alzheimer’s disease. Behav Neurol 27, 515-522. Landes AM, Sperry SD, Strauss ME, Geldmacher DS (2001) Apathy in Alzheimer’s disease. J Am Geriatr Soc 49, 17001707. Craig AH, Cummings JL, Fairbanks L, Itti L, Miller BL, Li J, Mena I (1996) Cerebral blood flow correlates of apathy in Alzheimer’s disease. Arch Neurol 53, 1116-1120. Kuzis G, Sabe L, Tiberti C, Dorrego F, Starkstein SE (1999) Neuropsychological correlates of apathy and depression in patients with dementia. Neurology 52, 1403-1407.
D. Grossi et al. / Apathy and Closing-in in AD [8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
[16]
[17]
[18] [19]
[20]
[21]
Starkstein SE, Mizrahi R, Capizzano AA, Acion L, Brockman S, Power BD (2009) Neuroimaging correlates of apathy and depression in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 21, 259-265. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF 3rd, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD (2002) Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 10, 125-128. Terada S, Oshima E, Sato S, Ikeda C, Nagao S, Hayashi S, Hayashibara C, Yokota O, Uchitomi Y (2014) Depressive symptoms and regional cerebral blood flow in Alzheimer’s disease. Psychiatry Res 221, 86-91. Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, Hashimoto M, Yamashita H, Sasaki M (1998) Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 50, 380-383. Mayer Gross W (1935) Some observations on apraxia. Proc R S Med 28, 63-72. Trojano L, Conson M (2008) Visuospatial and visuoconstructive deficits. In Handbook of Clinical Neurology, Goldenberg G, Miller BL, eds. Elsevier, Amsterdam, pp. 373-392. De Lucia N, Grossi D, Trojano L (2014) The genesis of closing-in in Alzheimer disease and vascular dementia: A comparative clinical and experimental study. Neuropsychology 28, 312-318. De Lucia N, Grossi D, Fasanaro AM, Carpi S, Trojano L (2013) Frontal defects contribute to the genesis of closing-in in Alzheimer’s disease patients. J Int Neuropsychol Soc 19, 802-808. Lee BH, Chin J, Kang SJ, Kim EJ, Park KC, Na DL (2004) Mechanisms of the closing-in phenomenon in a figure copying task in Alzheimer’s disease patients. Neurocase 10, 393-397. Serra L, Fadda L, Perri R, Caltagirone C, Carlesimo GA (2010) The closing-in phenomenon in the drawing performance of Alzheimer’s disease patients: A compensation account. Cortex 46, 1031-1036. Kwak YT (2004) Closing-in phenomenon in Alzheimer’s disease and subcortical vascular dementia. BMC Neurol 4, 3-7. Ambron E, McIntosh RD, Allaria F, Della Sala S (2009) A large-scale retrospective study of closing-in behaviour in Alzheimer’s disease. J Int Neuropsychol Soc 15, 787-792. McIntosh RD, Ambron E, Della Sala S (2008) Evidence for an attraction account of Closing-in Behaviour. Cogn Neuropsychol 25, 376-394. Conson M, Salzano S, Manzo V, Grossi D, Trojano L (2009) Closing-in without severe drawing disorders: The fatal consequences of pathological attraction. Cortex 45, 285-292.
[22]
[23]
[24]
[25]
[26]
[27]
[28] [29]
[30] [31]
[32] [33]
[34] [35]
855
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34, 939-944. Hughes CP, Berg L, Danziger WL, Coben LA, Marin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140, 566-572. Measso G, Cavarzeran F, Zappala G, Lebowitz BD, Crook TH, Pirozzolo FJ, Amaducci LA, Massari D, Grigoletto F (1993) The Mini-Mental State Examination: Normative study of an Italian random sample. Dev Neuropsychol 9, 77-85. Appollonio I, Leone M, Isella V, Piamarta F, Consoli T, Villa ML, Forapani E, Russo A, Nichelli P (2005) The Frontal Assessment Battery (FAB): Normative values in an Italian population sample. Neurol Sci 26, 108-116. Carlesino GA, Caltagirone C, Gainotti G (1996) The mental deterioration battery: Normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 36, 378-384. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) Una versione abbreviata del test di Stroop. Dati normativi nella popolazione italiana. Nuova Riv Neurol 12, 111-115. Spinnler H, Tognoni G (1987) Standardizzazione e taratura italiana di tests neuropsicologici. Ital J Neurol Sci 6, 8-96. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) Rey-Osterrieth complex figure: Normative values in an Italian population sample. Neurol Sci 22, 443-447. Mondini S, Mapelli D, Vestri A, Bisiacchi PS (2003) Esame neuropsicologico breve, Cortina Editore, Milano. Caltagirone C, Gainotti G, Carlesimo GA, Parnetti L (1995) Batteria per la valutazione del deterioramento mentale (parte I): Descrizione di uno strumento per la diagnosi neuropsicologica. Arch Psicol Neurol Psichiatr 55, 461-470. Marin RS (1991) Apathy: A neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3, 243-254. Isella V, Appolonio I, Meregalli L, Melzi P, Iurlaro S, Frattola L (1998) Normative data for the Italian version of the apathy and anhedonia scale. Arch Psicol Neurol Psichiatr 59, 356375. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23, 56-62. Fava GA, Kellner R, Munari F, Pavan L (1982) The Hamilton Depression Rating Scale in normals and depressives. Acta Psychiatr Scand 66, 26-32.
