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In the behavioral variant of frontotemporal dementia (bvFTD) memory deficits have been traditionally considered as due to difficulties in encoding/retrieval frontal strategies. However, the frontal origin of memory deficits in bvFTD has been questioned and hippocampal dysfunction has been also proposed. Here we analyzed bvFTD patients' proficiency in subjectively organizing memories without an external criterion. Twenty bvFTD patients and 20 healthy individuals were assessed with memory and executive tasks. The ability to subjectively organize memories in the immediate recall of a 15 unrelated word list was measured by calculating the index of subjective clustering (ISC) based on the constancies in response order across the five consecutive free recall trials. Results revealed reduced ISC in bvFTD patients with respect to normal controls. In the bvFTD group, the ISC score correlated with the Corsi span backward score and the number of categories achieved on the Modified Card Sorting Test. The bvFTD patients' reduced ISC and its correlation with executive performance suggest that executive deficits underlie their defective strategic organization of memories. However, as ISC did not predict memory accuracy in these patients, the memory deficit may not be the mere expression of their executive difficulties.

Background: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue., Methods: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms., Results: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward., Conclusions: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings., (© 2022. The Author(s).)

Objective: In a previous study (Zannino et al., 2012), it was demonstrated that individuals with amnestic mild cognitive impairment (MCI) were unimpaired on a new prototype learning task consisting of morphed faces (face prototype learning task [FPLT]). This paradigm was devised to improve on the classical dot pattern task by ruling out any reliance on residual episodic memory or working memory resources. In the present study, we aimed to demonstrate: first, that people with even more severe episodic memory impairment than MCI are unimpaired on a fully implicit prototype learning task and second, that the dot pattern task, at variance with the FPLT, requires a no negligible contribution from the episodic memory system., Method: Twenty-four persons with Alzheimer's disease (AD) and 48 healthy controls took part in this experiment. As in the original study, in addition to the FPLT, they were also administered the classical dot pattern task and an ordinary forced-choice face recognition task., Results: AD performed like normal controls in the FPLT but scored significantly worse on the dot pattern task and the face recognition task. Interestingly, although performance on the face recognition task did not correlate with that on the FPLT, a significant correlation was observed between the face recognition and the dot pattern task., Conclusions: Results support both of our claims: first, that also severe amnesic people can learn new visual prototypes with a fully implicit paradigm and, second, that the classical dot pattern task requires some degree of episodic resources. Further research is needed to rule out the role of working memory in solving the FPLT. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The aim of the current study was to test the accuracy of practice effects, that is, improvement in test performance due to repeated neuropsychological evaluations, in identifying patients with amnestic mild cognitive impairment (a-MCI) at greater risk of conversion to Alzheimer disease (AD). For this purpose, we conducted a longitudinal study of 54 patients diagnosed with a-MCI at the first assessment and followed-up for 4 years. During this time, 18 patients converted to AD. Baseline and 6- to 12-month follow-up performances on a large set of neuropsychological tests were analyzed to determine their diagnostic ability to predict later conversion to dementia. Results demonstrate that a lack of practice effects on episodic memory tests is an accurate prognostic indicator of late conversion to AD in a-MCI patients. In fact, even though the performance of both groups was substantially comparable at the baseline evaluation, stable a-MCI patients greatly improved their memory performance at retest after 6 to 12 months; instead, scores of converter a-MCI remained stable or decreased passing from baseline to follow-up. Standardized z-change scores on memory tasks, which were computed as a reliable measure of performance change, classified group membership with very good overall accuracy, which was higher than the classification of converter and stable a-MCIs provided by baseline or follow-up scores. We hypothesize that the lack of practice effects on memory tasks mirrors the early involvement of medial temporal lobe areas in converter a-MCI that are fundamental for the consolidation of new memory traces.

Backround and Objectives : It is widely agreed that patients suffering from Alzheimer's disease (AD) and patients suffering from semantic dementia (SD) might fail clinically administered semantic tasks due to a different combination of underlying cognitive deficits: namely, degraded semantic representations in SD and degraded representations plus executive control deficit in AD. However, no easy administrable test or test battery for differentiating the semantic impairment profile in these populations has been devised yet. Materials and Methods : In this study, we propose a new easy administrable task based on a free association procedure (F-Assoc) to be used in conjunction with category fluency (Cat-Fl) and letter fluency (Lett-Fl) for quantifying pure representational and pure control deficits, thus teasing apart the semantic profile of SD and AD patients. Results : In a sample of 10 AD and 10 SD subjects, matched for disease severity, we show that indices of asymmetric performance contrasting F-Assoc and each of the two verbal fluency tasks yield a clearly distinguishable discrepancy pattern across SD and AD. We also provide empirical support for the validity of an asymmetry measure contrasting F-Assoc and Cat-FL as an index of control impairment. Conclusions : The present study suggests that the free association procedure provides a pure measure of degradation of semantic representations avoiding the confound of possible concomitant executive deficits.

Objectives: Working memory (WM) for verbal and visual material may be affected early in individuals with mild cognitive impairment (MCI). Verbal and visuospatial span tasks, that is neuropsychological procedures commonly used for the clinical assessment of WM, have been scarcely investigated in these patients. Therefore, this study was aimed at evaluating whether performance on tests of verbal and visual-spatial span (which rely to different extents on distinct components of the WM system) is differently sensitive to the presence of MCI and, in particular, of a preclinical AD condition in patients with MCI., Materials & Methods: 99 patients with amnesic MCI were given the Digit Span Forward (DSF) and Digit Span Backward (DSB) tests and the Corsi span task (CS) at baseline and were followed up for two years. 32 MCI patients converted to Alzheimer's disease (MCIc), but 67 patients did not deteriorate to meet the criteria for AD (MCIs)., Results: Results showed that although performance on DSF did not differ between groups, performance on DSB and CS and ratio indexes indicative of a performance decline passing from DSF to DSB and from DSF to CS significantly discriminated between a group of matched healthy controls and the overall group of MCI patients. Moreover, the ratio indexes significantly discriminated between MCIc and MCIs individuals., Conclusions: These data are consistent with the hypothesis that individuals with MCI, particularly those destined to convert to AD, are affected by reduced central executive resources even though the phonological loop is still functioning normally., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The role of the hippocampus and neocortical areas in the retrieval of past memories in pre-dementia Alzheimer's disease (AD) patients was investigated. The aim was to assess whether the hippocampus has a temporary role in memory trace formation, according to the Cortical Reallocation Theory (CRT), or whether it continuously updates and enriches memories, according to the Multiple Trace Theory. According to the former theory, hippocampal damage should affect more recent memories, whereas the association cortex is expected to affect memories of the entire lifespan. In the second case, damage to either the hippocampus or the association cortices should affect memories of the entire lifespan. Seventeen patients with amnestic Mild Cognitive Impairment due to AD were submitted to autobiographical (i.e., episodic and semantic personal) memory assessment. Patients underwent MRI for the acquisition of T1-weighted brain volumes. Voxel-based morphometry was used to assess correlations between grey matter (GM) volumes and autobiographical memory. Correlation analyses revealed a strict association between GM volumes in the hippocampus and patients' ability to retrieve the most recent but not the oldest autobiographical memories in both aspects, episodic and semantic. Moreover, patients' GM volumes in the pre-frontal and temporal polar areas were associated with recollection of episodic and semantic events, respectively. Finally, GM volumes in the precuneus and occipital cortex were associated with retrieval of the most recent episodic events. These findings indicate that the hippocampus has a specific time-dependent role; thus, they support the CRT., (© 2018 The British Psychological Society.)

Retrograde amnesia has been largely documented in patients with amnestic mild cognitive impairment (a-MCI) and Alzheimer's disease (AD). However, it is still not clear whether ineffectiveness in recalling past acquired information reflects loss of individual memory traces or failure to access specific stored traces. We aimed to disentangle the differential contribution of storage and retrieval processes to the pattern of retrograde amnesia in these patients. This issue was investigated in 18 a-MCI and 19 AD patients who were compared to 20 healthy controls. A novel questionnaire about public events was used; it consisted of two procedures (i.e., a free recall test and a true/false recognition test). Crucial differences emerged in the way the two groups of patients performed the experimental tasks. In fact, although both a-MCI and AD patients showed a similar pattern of impairment on the free recall test, a-MCI patients were able to normalise their performance on the recognition test, thus overcoming their deficits at the time of recall. Conversely, AD patients showed both reduced free recall ability and diminished sensitivity to benefit from recognition in recalling public events. Our findings suggest that the memory processes underlying RA were different for a-MCI and AD. Deficits in remote memory are prevalently explained by impaired retrieval abilities in a-MCI and by impaired storage in AD. This distinction between retrograde amnesia due to defective trace utilisation in a-MCI and trace storage in AD is consistent with the temporal unfolding of declining anterograde memory over the course of disease progression to AD.

Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer's disease (AD). Consistent with AD patients' distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients' conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD.

Background: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall, performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance., Objective: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia., Methods: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer's disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs)., Results: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance., Conclusion: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks.

Background: Recently, a growing body of evidence has shown that, from the early stage of impairment, Alzheimer's patients (AD) present difficulties on a variety of tasks mostly relying on executive functions. These strongly impact their daily life activities causing a severe loss of independency and autonomy., Objective: To evaluate the efficacy of transpinal direct current stimulation (tsDCS) combined with cognitive trainings for improving attentional and executive function abilities in a group of AD patients., Methods: In a randomized-double blind design, sixteen AD patients underwent different cognitive trainings combined with tsDCS. During the treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: 1) anodal, and 2) sham while performing three computerized tasks: alertness, selective attention, and executive functions. Each experimental condition was run in ten consecutive daily sessions over two weeks., Results: After anodal tsDCS, a greater improvement in executive functions compared to sham condition was found. More importantly, the follow-up testing revealed that these effects lasted over 1 month after the intervention and generalized to the different neuropsychological tests administered before, after the treatment and at one month after the end of the intervention. This generalization was present also in the attentional domain., Conclusion: This evidence emphasizes, for the first time, that tsDCS combined with cognitive training results efficacious for AD patients. We hypothesize that enhancing activity into the spinal sensorimotor pathways through stimulation improved cognitive abilities which rely on premotor activity, such as attention and executive functions.

Patients with subcortical ischemic vascular dementia (SIVD) perform better than Alzheimer's disease patients (AD) on the Free and Cued Recall Selective Reminding test (FCSRT). In this test, SIVD are able to overcome their strategic retrieval deficit, whereas AD patients, whose memory impairment is due to a hippocampal storage deficit, are not. However, the FCSRT does not assess the advantage passing from free to assisted learning, which is expected to be different in frontal and hippocampal damage. We compared SIVD, AD and healthy subjects on the free recall of a 15-word list not assisted at encoding and on the free and cued recall of the FCRST. Indexes of Encoding, Cueing and Total (measuring the advantage passing from the 15-word list free recall to the free and cued recall of the FCRST) were computed. The two groups performed comparably poorly on the free recall of the 15-word list, but SIVD outperformed AD patients in the free and cued recall of the FCSRT and took greater advantage than AD patients on both learning and recall when passing from the unassisted to the assisted paradigms. All indexes significantly predicted diagnostic group membership, but the Total Index showed the larger classification accuracy with 80% of AD and 71% of SIVD correctly classified. These results confirm that the FCRST is able to differentiate AD and SIVD patients with a good level of accuracy. However, the evaluation of memory performance variation as a function of support to encoding provides additional data able to increase diagnostic reliability.

Experiments with semantic priming (SP) paradigms have documented early hypopriming in patients with AD when concepts are used as primes and attribute concept features as targets, suggesting that concept attributes are vulnerable to damage very early in the disease course. The aims of this study were to confirm early priming reduction in the attribute condition in patients with AD and to determine which of several semantic indexes (such as the level of distinctiveness, correlation or feature dominance of concept features) best predicts the priming effect size in AD. We administered an SP attribute condition paradigm to 20 mildly demented patients with AD and to 10 NCs. We used concept-attribute pairs for which normative data of semantic indexes relative to both concept primes (i.e., number, type, mean level of dominance, distinctiveness and correlation of features constituting the concepts) and target features (i.e., level of feature dominance, correlation and distinctiveness) were available. Results showed that compared to NCs, the AD group obtained very reduced priming facilitation. Furthermore, the item regression analyses showed that the priming decrement in the AD group was predicted by the feature dominance of the target in the related pairs; that is, the lower the target feature dominance, the lower the priming effect elicited. These results confirmed hypopriming in the attribute condition from the very early phase of AD and support the view that attributes which are more salient for the identification of a given concept are also those most resistant to semantic memory degradation in AD pathology., (© 2018 The British Psychological Society.)

The research of reliable procedures for predicting cognitive decline or stability in persons with amnestic mild cognitive impairment (a-MCI) is a major goal for the early identification of subjects in the prodromal stages of dementia. The aim of this study was to evaluate whether different memory performances on two procedures commonly used for the neuropsychological assessment of episodic memory (i.e., free recall and recognition) might be a key in predicting a-MCI patients' subsequent progression to Alzheimer's disease (AD). For this purpose, 80 patients diagnosed with a-MCI at the first assessment and followed-up for at least 3 years were included. During this time, 41 subjects remained in a stable condition of cognitive impairment or improved (stable-MCI) and 39 patients converted to AD dementia (converter-MCI). Sixty-two age- and education-matched healthy individuals were also recruited as healthy controls (HC). Baseline memory performance on the free recall (5th immediate and 15-min delayed) and yes/no recognition (the sensitivity measure d') of a 15-word list were analyzed. Results showed that stable-MCIs forgot significantly more information from immediate to delayed recall of the word list than HC, but exhibited a pronounced improvement of memory performance in the recognition test format. On the contrary, converter-MCIs showed diminished sensitivity in benefiting from cues for recognizing studied words. Word list recognition correctly classified group membership with good overall accuracy, which was higher compared to the classification of converter and stable a-MCIs provided by free recall; therefore, it could be a useful diagnostic tool for predicting progression to AD dementia from the prodromal stage.

Apathy symptoms include different dimensions: cognitive (C), emotional-affective (E-Aff) and auto-activation; they have been related to dysfunctions of the dorsolateral, orbito-basal prefrontal cortex and the subcortical frontal connections to the basal ganglia, respectively. In Alzheimer's disease (AD), an association has been found between apathy severity and both executive deficits and atrophy of the dorso-lateral prefrontal cortex; however, it is not clear whether these associations concern only the cognitive aspects of apathy. Furthermore, whether there is an association in AD between E-aff apathy and theory of mind (ToM),the cognitive functions subsumed by the orbito-basal prefrontal cortex, has not been investigated. Aim of the study was to investigate the relationship between C, E-Aff and auto-activation apathy and performance on tasks investigating executive and ToM cognitive functions in AD. For this purpose, 20 AD patients with apathy and 20 matched controls were submitted to an executive and ToM neuropsychological assessment. Apathy was assessed with a weekly diary (ApD) created specifically to assist caregivers in quantifying the C, E-Aff and auto-activation symptomatology of apathy. Correlational analyses showed that AD patients' scores on the Modified Card Sorting Test (MCST) and Emotion Attribution tasks were correlated with most ApD scores. However, regression analyses showed that C diary scores were predicted by MCST performance, E-Aff diary scores by performance on the E-Attribution task and ApD scores measuring auto-activation apathy were predicted by both the MCST and the Emotion Attribution scores. These results confirm the co-occurrence of apathy and executive-function deficits in AD and suggest a specific association between AD patients' executive deficits and the cognitive component of apathy. Furthermore, they document, for the first time, an association between poor performance on tests assessing ToM abilities and the emotional-affective component of apathy in AD patients. Finally, these results are in line with the view that auto-activation apathy reflects the sum of emotional and cognitive processing deficits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Episodic memory impairment is the most common and initial cognitive symptom of AD related to the early involvement of the medial temporal lobe (MTL). In this study, we compared performance on tasks routinely used in the neuropsychological assessment of episodic memory to evaluate which test is more sensitive in predicting subsequent progression to AD in patients with amnestic mild cognitive impairment (a-MCI). For this purpose, we conducted a longitudinal study in 61 patients diagnosed as a-MCI at baseline and followed for 3 years. Baseline memory performance on the word list and short story tests was analyzed to determine the diagnostic ability of the tests to predict subsequent conversion to AD. Results showed that stable a-MCI patients performed worse on word list than on story recall, whereas patients who later converted to AD tended to have similar poor memory performance on both tasks. Furthermore, a pronounced memory decay passing from immediate to delayed recall on the short story test was significantly associated with both higher risk and faster mean time of conversion to AD. We hypothesized that this pattern of results is a consequence of the early involvement in converter a-MCI of MTL areas which are fundamental in the consolidation of new memory traces.

Objective: The aim of this paper was to assess the efficacy of process-based cognitive training (pb-CT) combined with reminiscence therapy (RT) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and in healthy elderly (HE) subjects., Methods: This multicenter, randomized, controlled trial involved 348 participants with mAD, MCI, and HE from four European countries. Participants were randomly assigned to two arms of a crossover design: those in arm A underwent 3 months of computerized pb-CT for memory and executive functions combined with RT and 3 months of rest; those in arm B underwent the reverse. The primary outcome was the effect of the training on memory and executive functions performance. The secondary outcome was the effect of the training on functional abilities in mAD assessed with the instrumental activities of daily living., Results: We found a significant effect of the training for memory in all three groups on delayed recall of the Rey Auditory Verbal Learning Test and for executive functions in HE on the phonological fluency test. MCI and HE participants maintained these effects at follow-up. MCI and mAD participants also showed a significant effect of the training on the Mini-mental state examination scale. Participants with mAD showed more stable instrumental activities of daily living during the training versus the rest period., Conclusions: Our results corroborate the positive effect of pb-CT and its maintenance primarily on memory in HE and MCI participants that did not seem to be potentiated by RT. Moreover, our results are very promising for the mAD participants., (Copyright © 2015 John Wiley & Sons, Ltd.)

Episodic autobiographical memory (ABM) has been found to be impaired from the early stage of Alzheimer's disease (AD). Previous works have focused on how ABM decreases over the lifespan, but no study has deeply investigated whether the extent of episodic autobiographical amnesia is mediated by the retrieval frequency of the episodic trace itself. The aim of the present study was to determine whether the frequency of trace retrieval has an effect on the quality of autobiographical incidents recall and whether the extent of this contribution changes over time. For this purpose, the episodic component of ABM was assessed in patients in the early stage of AD through a questionnaire which allowed evaluating memory of past personal incidents as a function of both their age of acquisition and retrieval frequency. We found that both AD patients and healthy controls took advantage of greater retrieval frequency across all time segments, because of their better memory performance on frequently retrieved episodes than less frequently retrieved ones. Although in the AD group the retrieval frequency effect (i.e., higher scores on the episodes rated as more frequently retrieved) was found in all time segments, the extent of its beneficial effect on memory performance was temporally-graded and inversely related to the time course. Our findings provide new evidence that the combined action of both age of memory and retrieval frequency could provide a valuable framework for predicting patterns of ABM loss, at least in early AD patients. In line with the Multiple Trace Theory, we speculated that retrieval frequency protects episodic trace recall against hippocampal damage by reinforcing the neural representation of personal context-rich memories, which consequently are easier to access and recall. Furthermore, the age of memory should change the amplitude of this beneficial effect as a function of the remoteness of the trace., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.

The aim of this study was to investigate the neuropsychological correlates of behavioral and psychological symptoms (BPSD) in patients affected by various forms of dementia, namely Alzheimer's disease (AD), frontal-variant frontotemporal dementia (fvFTD), Lewy body dementia (LBD), and subcortical ischemic vascular dementia (SIVD). 21 fvFTD, 21 LBD, 22 AD, and 22 SIVD patients matched for dementia severity received a battery of neuropsychological tests and the Neuropsychiatry Inventory (NPI). The possible association between performance on neuropsychological tests and severity of BPSD was assessed by correlational analysis and multivariate regression. BPSD were present in 99% of patients. Most behavioral symptoms were not related to a particular dementia group or to a specific cognitive deficit. Euphoria and disinhibition were predicted by fvFTD diagnosis. Hallucinations correlated with the severity of visuospatial deficits in the whole sample of patients and were predicted by LBD diagnosis. Apathy, which was found in all dementia groups, correlated with executive functions and was predicted by both reduced set-shifting aptitude and fvFTD diagnosis. The results confirm the high prevalence of BPSD in the mild to moderate stages of dementia and show that most BPSD are equally distributed across dementia groups. Most of the cognitive and behavioral symptoms are independent dimensions of the dementia syndromes. Nevertheless, hallucinations in LBD and euphoria and disinhibition in fvFTD are related to the structural brain alterations that are responsible for cognitive decline in these dementia groups. Finally, apathy arises from damage in the frontal cortical areas that are also involved in executive functions.

Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.

According to the semantic hub hypothesis, a supramodal semantic hub is equally needed to deal with verbal and extraverbal "surface" representations. Damage to the supramodal hub is thought to underlie the crossmodal impairment observed in selective semantic deficits. In the present paper, we provide evidence supporting an alternative view: we hold that semantic impairment is not equal across domains but affects verbal behavior disproportionately. We investigated our hypothesis by manipulating the verbal load in an object decision task. Two pathological groups showing different levels of semantic impairment were enrolled together with their normal controls. The severe group included 10 subjects with semantic dementia and the mild group 10 subjects with Alzheimer's disease. In keeping with our hypothesis, when shifting from the low verbal load to the high verbal load condition, brain-damaged individuals, as compared to controls, showed a disproportionate impairment as a function of the severity of their semantic deficit., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system., Objective: The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks., Methods: 20 patients with Alzheimer's disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and 20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks., Results: All groups performed similarly on both the immediate and delayed recall of the word-list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups., Conclusion: The combined use of the prose and word-list tasks evidenced a "mesio-temporal" memory profile in AD patients as opposed to a "frontal" one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia.

Alzheimer's disease (AD) is characterized by altered functional cortico-cortical connectivity likely due to loss of afferent and efferent connections between different cortical areas. Here we explored parieto-frontal functional connectivity in 15 AD patients and 12 healthy control subjects by means of bifocal transcranial magnetic stimulation (TMS). Conditioning stimuli were applied over the right posterior parietal cortex (PPC) at different intensities (90% and 110% of resting motor threshold, RMT). Motor evoked potentials (MEPs) were then recorded from the ipsilateral primary motor cortex at different interstimulus intervals (ISIs) ranging between 2 and 15 ms. Results showed that in healthy subjects, a conditioning TMS pulse applied over the ipsilateral PPC at 90%, but not at 110%, of RMT intensity was able to increase the excitability of the right M1. This functional interaction peaked at ISI = 6 ms. Conversely, in AD patients the facilitatory pattern of parieto-motor connections was evident only when TMS was delivered at an intensity of 110% of RMT with a peak at ISI = 8 ms. Moreover in AD patients, treatment with cholinesterase inhibitors did not induce any significant modification in the strength of the connection. In subsequent analyses, we found that, in AD patients, the effects induced by PPC conditioning at 110% RMT correlated with neuropsychological measures of episodic memory and executive functions, implying that patients with better cognitive performance had less impaired connectivity. Our findings reveal that parieto-frontal cortico-cortical functional connectivity is altered in AD patients, providing further evidence for a disconnection-based interpretation of AD symptoms.

Objective: The aim of the present study was to investigate the qualitative characteristics of semantic impairment in patients with mild to moderate Alzheimer's disease (AD). In particular, we wanted to verify if subordinate and distinctive concept features are affected earlier than superordinate or shared ones and whether sensory features are more vulnerable than nonsensory ones. Also, we investigated if feature correlation and level of feature occurrence in concept description (dominance) influence the resilience of concept features to degenerative damage., Methods: We administered a feature-listing task to nine mild and 10 moderate AD patients and 19 matched healthy controls. The concepts utilized were taken from a normative database, which allowed quantifying semantic indexes of the concepts representation, that is, feature type, distinctiveness, correlation, and dominance., Results: Data confirmed that although semantic knowledge of concepts is overall impoverished in AD patients, (a) superordinate knowledge is better preserved than other types of knowledge, (b) nonsensory information is more preserved than sensory information, and (c) highly shared features are less affected than distinctive ones. Furthermore, patients' feature production was influenced by dominance and by age of acquisition., Conclusions: These data are in line with theories postulating that among the dimensions along which feature-based semantic representations may vary, those relative to type and distinctiveness are most sensitive to the differential effect of AD. Results also showed a preserved implicit knowledge about how informative a given feature is in these patients and highlighted the importance of early acquisition of concept knowledge for resilience to degenerative damage.

This study investigates the differential contribution of gray matter (GM) atrophy and deafferentation through white matter (WM) damage in the clinical progression of Alzheimer's disease (AD). Thirty-one patients with probable AD, 23 with amnestic mild cognitive impairment (a-MCI), and 14 healthy subjects underwent MRI scanning at 3T. Voxel-based morphometry was used to assess regional GM atrophy in AD and a-MCI patients. Diffusion tensor-MRI tractography was used to reconstruct the cingulum bilaterally, and to quantify, voxel-by-voxel, its fractional anisotropy (FA) and mean diffusivity (MD) (measures of microscopic WM integrity). Atrophy of the cinguli was also assessed by means of jacobian determinants (JD) of local transformations. In AD patients, four clusters of reduced GM were found nearby the cinguli, in the posterior (PCC) and anterior cingulate cortex, and in the hippocampal/parahippocampal areas. Widespread areas of reduced FA and increased MD were found in the cinguli of both, AD and a-MCI patients. A region of macroscopic atrophy was detectable in AD patients only. Strong associations were found between local GM densities in the four identified clusters, and measures of micro- and (to a lesser extent) macroscopic damage of patients' cinguli. Linear regression analyses revealed that MD in the cinguli predicts patients' measures of episodic memory in combination with GM density of hippocampal/parahippocampal areas, and measures of global cognition in combination with GM density of the PCC. This study indicates that brain deafferentation though the cingulum is likely to play a remarkable role in progressive development of cognitive impairment in AD., (Copyright © 2011 Wiley-Liss, Inc.)

This study investigates the patho-physiological implications of the uncinate fasciculus (UF) in the two most common forms of dementia, namely Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Forty-five consecutive patients diagnosed with either probable AD or DLB, and 16 individuals with amnesic mild cognitive impairment (a-MCI) were investigated using diffusion tensor MRI. Thirteen healthy subjects (HS) were also studied as controls. In each subject, the UF was bilaterally reconstructed by probabilistic tractography. From each UF, macroscopic volume and correspondent fractional anisotropy (FA) (an index of microscopic white matter integrity) were derived for the whole tract, and for the frontal and temporal portion of the UF. No significant between-group volumetric differences were found. In contrast, FA values from the UF were reduced bilaterally in patients with dementia (either AD or DLB) compared to HS. In addition, patients with AD showed reduced FA values compared to those with a-MCI. No significant FA difference was found between AD and DLB patients, nor between a-MCI and HS. Finally, in all patients, UF FA values were associated with neuropsychological scores at tests exploring memory and executive functions. This study indicates that the UF is remarkably damaged in patients at the stage of dementia, independently from the diagnostic form. Moreover, this UF damage seems to be driven by temporal involvement in AD, for which a prodromal stage (a-MCI) is defined.

Preliminary studies, based on a region-of-interest approach, suggest that quantitative magnetization transfer (qMT), an extension of magnetization transfer imaging, provides complementary information to conventional magnetic resonance imaging (MRI) in the characterisation of Alzheimer's disease (AD). The aim of this study was to extend these findings to the whole brain, using a voxel-wise approach. We recruited 19AD patients and 11 healthy subjects (HS). All subjects had an MRI acquisition at 3.0T including a T(1)-weighted volume, 12 MT-weighted volumes for qMT, and data for computing T(1) and B(1) maps. The T(1)-weighted volumes were processed to yield grey matter (GM) volumetric maps, while the other sequences were used to compute qMT parametric maps of the whole brain. qMT maps were warped to standard space and smoothed, and subsequently compared between groups. Of all the qMT parameters considered, only the forward exchange rate, RM(0)(B), showed significant group differences. These images were therefore retained for the multimodal statistical analysis, designed to locate brain regions of RM(0)(B) differences between AD and HS groups, adjusting for local GM atrophy. Widespread areas of reduced RM(0)(B) were found in AD patients, mainly located in the hippocampus, in the temporal lobe, in the posterior cingulate and in the parietal cortex. These results indicate that, among qMT parameters, RM(0)(B) is the most sensitive to AD pathology. This quantity is altered in the hippocampus of patients with AD (as found by previous works) but also in other brain areas, that PET studies have highlighted as involved with both, reduced glucose metabolism and amyloid β deposition. RM(0)(B) might reflect, through the measurement of the efficiency of MT exchange, some information with a specific pathological counterpart. Given previous evidence of a strict relationship between RM(0)(B) and intracellular pH, an intriguing speculation is that our findings might reflect metabolic changes related to mitochondrial dysfunction, which has been proposed as a contributor to neurodegeneration in AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Semantic priming paradigms have been used to investigate semantic knowledge in patients with Alzheimer's disease (AD). While priming effects produced by prime-target pairs with associative relatedness reflect processes at both lexical and semantic levels, priming effects produced by words that are semantically related but not associated should reflect only semantic activation processes. This study was aimed at further investigating automatic semantic priming effects in AD patients when semantically related concepts with little to no lexical association are used. Twenty patients with mild to moderate AD and 20 matched controls (NCs) performed a lexical decision task on 30 concept pairs (15 in the living and 15 in the non-living domain) in an automatic semantic priming paradigm. In order to investigate the relationship between priming alteration and semantic damage, we chose concepts from a database. This allowed us to quantify semantic indexes relative to the structural representation at the feature level. No priming was found in NCs or mild AD patients, probably because feature similarity was insufficient in the concept pairs used. Similar to the hyperpriming observed in previous studies, the appearance of priming in the moderate AD group suggests early semantic damage in which attribute knowledge is partially affected. Furthermore, the finding that priming was predicted by the level of sharing (in the semantic system) of features common to the two concepts in the pairs indicates that the level of redundancy of attribute information is the main factor responsible for resiliency to neurological damage in AD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cognitive reserve (CR), for which formal education represents a proxy index, has been claimed as a factor mitigating the clinical manifestations of Alzheimer disease (AD). The aim of this study was to assess the impact of formal education in modifying the relationship between cerebral grey matter (GM) damage and clinical manifestations in a large cohort of patients with AD or amnesic mild cognitive impairment (a-MCI). We recruited 22 patients with AD and 23 with a-MCI, and we classified them in subjects with high (HEL) or low educational level (LEL). All patients underwent a neuropsychological assessment and magnetic resonance imaging (MRI) scanning at 3T. T1-weighted volumes were analyzed, using voxel-based morphometry, for GM investigation. A 1-year clinical follow-up was available for part of the a-MCI patients. There were no between-groups differences in clinical features, memory, and language functions. Conversely, HEL subjects performed better in all tests assessing visuo-spatial abilities. GM volumes of LEL compared with HEL patients were reduced in the supramarginal gyrus bilaterally and in the right posterior cingulate/precuneus and frontal opercular cortex. Conversely, HEL compared with LEL patients showed reduced GM volumes in the entorhinal cortices and temporal poles, regions typically affected by AD pathology. These results remained unchanged when including in the analysis of only patients with clinically proven AD (AD and a-MCI converters). This study suggests that CR produces selective GM changes that mitigate the clinical impact of AD. Moreover, it supports the idea that CR is based on several "brain reserves" rather than on a generalized increase of brain plasticity.

Aim of the present review paper was to evaluate the hypothesis (included in the proposal of new research criteria for Alzheimer's disease; Dubois et al., Lancet Neurology, 6, 734-746, 2007) that a neuropsychological tool which provides support for the semantic encoding of memorandum at the time of study and supplies category cues at the time of retrieval (i.e. the Grober-Buschke paradigm) is more effective than traditional measures of free recall in 1) differentiating patients affected by the amnestic form of Mild Cognitive Impairment (MCI) or by mild to moderate forms of Alzheimer's disease (AD) from healthy matches, 2) predicting the conversion of individuals with MCI to AD, and 3) differentiating AD patients from individuals affected by other forms of dementia. Results of the review are controversial regarding the superiority of the Grober-Buschke procedure in differentiating individuals affected by AD or MCI from healthy individuals. The only study that evaluated this issue directly found that the Grober-Buschke procedure was more sensitive and specific than more traditional memory tests in predicting the conversion of MCI patients to AD. Finally, two studies reported that patients affected by AD or other forms of dementia showed different performance patterns in the free and cued recall tasks of the Grober-Buschke procedure. In conclusion, although encouraging results are reported in the few studies that investigated the ability of this procedure to predict the evolution of individuals with amnestic MCI and to differentiate AD patients from patients with other forms of cortical and subcortical dementia, more experimental work is needed to confirm these positive findings.

Previous studies suggest that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimer's disease (AD) at different clinical stages., Methods: Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis., Results: Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD., Conclusions: This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

Patients with Alzheimer's disease (AD) have heterogeneous rates of disease progression. The aim of the current study is to investigate whether neuropsychiatric disturbances predict cognitive and functional disease progression in AD, according to failure theory. We longitudinally examined 177 memory-clinic AD outpatients (mean age = 73.1, SD = 8.1; 70.6% women). Neuropsychiatric disturbances at baseline were categorized into five syndromes. Patients were followed for up to two years to detect rapid disease progression defined as a loss of ≥ 1 abilities in Activities of Daily living (ADL) or a drop of ≥ 5 points on Mini-Mental State Examination (MMSE). Hazard ratios (HR) were calculated with Gompertz regression, adjusting for sociodemographics, baseline cognitive and functional status, and somatic comorbidities. Most patients (74.6%) exhibited one or more neuropsychiatric syndromes at baseline. The most common neuropsychiatric syndrome was Apathy (63.8%), followed by Affective (37.3%), Psychomotor (8.5%), Manic (7.9%), and Psychotic (5.6%) syndromes. The variance between the observed (Kaplen Meier) and predicted (Gompertz) decline for disease progression in cognition (0.30, CI = 0.26-0.35), was higher than the variance seen for functional decline (0.22, CI = 0.18-0.26). After multiple adjustment, patients with the Affective syndrome had an increased risk of functional decline (HR = 2.0; CI = 1.1-3.6), whereas the risk of cognitive decline was associated with the Manic (HR = 3.2, CI = 1.3-7.5) syndrome. In conclusion, specific neuropsychiatric syndromes are associated with functional and cognitive decline during the progression of AD, which may help with the long-term planning of care and treatment. These results highlight the importance of incorporating a thorough psychiatric examination in the evaluation of AD patients.

Objectives: Neuropsychiatric symptoms are common in patients with Alzheimer disease (AD). Treatment for both AD and psychiatric disturbances may affect the clinical observed pattern and comorbidity. The authors aimed to identify whether particular neuropsychiatric syndromes occur in untreated patients with AD, establish the severity of syndromes, and investigate the relationship between specific neuropsychiatric syndromes and AD disease severity., Design: Cross-sectional, multicenter, clinical study., Participants: A total of 1,015 newly diagnosed, untreated outpatients with AD from five Italian memory clinics were consecutively enrolled in the study from January 2003 to December 2005., Measurements: All patients underwent thorough examination by clinical neurologists/geriatricians, including neuropsychiatric symptom evaluation with the Neuropsychiatric Inventory., Results: Factor analysis revealed five distinct neuropsychiatric syndromes: the apathetic syndrome (as unique syndrome) was the most frequent, followed by affective syndrome (anxiety and depression), psychomotor (agitation, irritability, and aberrant motor behavior), psychotic (delusions and hallucinations), and manic (disinhibition and euphoria) syndromes. More than three quarters of patients with AD presented with one or more of the syndromes (N = 790, 77.8%), and more than half exhibited clinically significant severity of symptoms (N = 603, 59.4%). With the exception of the affective one, all syndromes showed an increased occurrence with increasing severity of dementia., Conclusions: The authors' study supports the use of a syndrome approach for neuropsychiatric evaluation in patients with AD. Individual neuropsychiatric symptoms can be reclassified into five distinct psychiatric syndromes. Clinicians should incorporate a thorough psychiatric and neurologic examination of patients with AD and consider therapeutic strategies that focus on psychiatric syndromes, rather than specific individual symptoms.

Introduction: The closing-in phenomenon, first described by Mayer Gross (1935) as a tendency to close in on models while performing a constructional task, occurs with a relatively high frequency in patients with dementia. The phenomenon may appear in several tasks, but it is more usually observed in tests of copying drawings. In the present study we examined the hypothesis that in patients with Alzheimer's disease (AD) the phenomenon may be related to particularly severe visuo-spatial dysfunction., Methods: Thirty-nine of an overall sample of 382 patients consecutively admitted to an AD unit exhibited closing-in in their copying drawings performance. The presence of closing-in was diagnosed when, in at least one of three drawings, the copy touched, in one or more parts, the model., Results: With respect to another group of 39 AD patients with constructional apraxia but who showed no closing-in behaviour, patients with closing-in showed more severe impairment on several tests of visuo-spatial abilities. The two groups did not differ in the frequency of neurological primitive reflexes or performance on tests of executive functioning., Conclusions: The present study supports the interpretation that the closing-in phenomenon in patients with AD is a compensatory strategy to overcome basic visuo-spatial dysfunctions involved in the preliminary visuo-perceptual analysis and/or in the on-line maintenance of the visual representation of the model while performing a copying drawing task. Possible limits in the conclusions of the present study are related to the retrospective nature of the present study and to the choice of considering only overlap-type forms of closing behaviour., ((c) 2009 Elsevier Srl. All rights reserved.)

There is now a large body of evidence suggesting that color and photographic detail exert an effect on recognition of visually presented familiar objects. However, an unresolved issue is whether these factors act at the visual, the semantic or lexical level of the recognition process. In the present study, we investigated this issue by having Alzheimer's patients and normal controls name figures in four presentation displays (PDs): black and white and colored line drawings, and black and white and color photographs. We also collected image agreement (IA) values (a measure of the extent to which the presented figure matches the stored structural description of the depicted object) for the same stimuli and compared the effects of PD on IA and naming accuracy. Our results suggest that color acts on naming by assisting semantic processing of the stimuli to be recognized; by contrast, photographic detail seems to benefit visual processing by increasing IA., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

This study investigates abnormalities of grey (GM) and white matter (WM) in Alzheimer's disease (AD), by modeling the AD pathological process as a continuous course between normal aging and fully developed dementia, with amnesic mild cognitive impairment (aMCI) as an intermediate stage. All subjects (9 AD, 16 aMCI patients, and 13 healthy controls) underwent a full neuropsychological assessment and an MRI examination at 3 Tesla, including a volumetric scan and diffusion tensor (DT)-MRI. The volumes were processed to perform a voxel-based morphometric analysis of GM and WM volume, while DT-MRI data were analyzed using tract based spatial statistics, to estimate changes in fractional anisotropy and mean diffusivity data. GM and WM volume and mean diffusivity and fractional anisotropy were compared across the three groups, and their correlation with cognitive functions was investigated. While AD presented a pattern of widespread GM atrophy, tissue loss was more subtle in patients with aMCI. WM atrophy was mainly located in the temporal lobe, but evidence of WM microscopic damage, assessed by DT-MRI, was also observable in the thalamic radiations and in the corpus callosum. Memory and executive functions correlated with either GM volume or fractional anisotropy in fronto-temporal areas. In conclusion, this study shows a comprehensive assessment of the brain tissue damage across AD evolution, providing insights on different pathophysiological mechanisms (GM atrophy, Wallerian degeneration, and brain disconnection) and their possible association with clinical aspects of cognitive decline.

Background and Aims: Alzheimer's disease (AD) is a neurodegenerative disorder in which the patients can exhibit some behavioural disturbances in addition to cognitive impairment. The aims of the present study were to investigate the relationship between severity and rate of decline of the cognitive and behavioural impairment in patient with AD., Methods: 54 AD patients were assessed at baseline and after 12 months with the Mental Deterioration Battery (MDB), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) and the Neuropsychiatric Inventory (NPI-10)., Results: MDB was more accurate than ADAS-Cog in the early diagnosis of AD. Conversely, ADAS-Cog was more sensitive at revealing the progression of cognitive decline. Depression, Apathy and Anxiety are the most frequent and severe behavioural disturbances at baseline. At follow-up Delusions and Irritability increased significantly. Significant correlations were observed between severity of cognitive impairment and behavioural disorders both at baseline and in the progression rate passing from T0 to T12., Conclusions: Severity and progression rate of behavioural and cognitive alterations in patients with AD are significantly associated.

Behavioral and psychological symptoms of dementia (BPSD) are commonly observed over the course of Alzheimer's disease (AD). However, it is unclear whether BPSD are part of AD neuropathology or rather represent a psychological reaction to cognitive disabilities. Using voxel-based-morphometry (VBM), we aimed to clarify this issue by investigating patients with AD at different clinical stages. Twenty-seven patients with AD (12 early [ADe] and 15 moderate [ADm]), 19 with amnestic mild cognitive impairment (a-MCI), and 23 healthy controls underwent MRI scanning at 3T. Assessment of BPSD was done in each patient using the Neuropsychiatric Inventory-12 (NPI-12). VBM was used to investigate changes in grey matter (GM) atrophy across groups, and associations between regional GM volumes and occurrence and severity of BPSD in patients. Mood disorders, anxiety, and agitation were present in both a-MCI and AD, while psychotic symptoms were observed mainly in AD. As expected, VBM showed only limited areas of GM atrophy in a-MCI patients, with a progressive extension in ADe and ADm patients (PFWE-corrected-values < 0.05). Disinhibition was strongly associated with GM volume in bilateral cingulate and right middle frontal gyri, while delusions were associated with GM volume in right hippocampus (PFWE-corrected-values < 0.05). This study confirms that BPSD are present since the earliest AD stages. Interesting associations were found in regions traditionally implicated by AD neuropathology. This suggests that BPSD are likely to represent clinical features of AD and should be regarded for their diagnostic and prognostic value.

Background: Alzheimer disease (AD) has heterogeneous clinical manifestations. Different neuropsychological profiles in AD patients might be indicative of the diffusion of the pathological process and might be associated with differences in rates of disease progression., Methods: We studied 154 newly diagnosed AD patients (65.6% women; mean age: 73 years). Performance in memory, executive functions, praxis and language domains was categorized into mild, moderate and severe impairment. The time-dependent probability of losing 5 points on the Mini-Mental State Examination (MMSE) over 2 years was considered as disease progression and evaluated by survival analysis., Results: One fourth of the patients decreased by ≥ 5 MMSE points over the 2-year follow-up. Rapid disease progression was more frequent in more educated patients and in those with moderate severity of global cognitive impairment. In univariate analysis, more severe memory and executive functioning impairment were associated with higher probabilities of progression. The association with memory was explained by differences in executive function impairment that remained statistically significant in multivariate analyses., Conclusions: Patients with more severe executive functioning impairment have a worse prognosis over 2 years. This might be due to involvement of the prefrontal cortex by the pathological process of AD in patients with severe executive deficits., (Copyright © 2010 S. Karger AG, Basel.)

Rates of disease progression differ among patients with Alzheimer's disease, but little is known about prognostic predictors. The aim of the study was to assess whether sociodemographic factors, disease severity and duration, and vascular factors are prognostic predictors of cognitive decline in Alzheimer's disease progression. We conducted a longitudinal clinical study in a specialized clinical unit for the diagnosis and treatment of dementia in Rome, Italy. A total of 154 persons with mild to moderate Alzheimer's disease consecutively admitted to the dementia unit were included. All patients underwent extensive clinical examination by a physician at admittance and all follow-ups. We evaluated the time-dependent probability of a worsening in cognitive performance corresponding to a 5-point decrease in Mini-Mental State Examination (MMSE) score. Survival analysis was used to analyze risk of faster disease progression in relation to age, education, severity and duration of the disease, family history of dementia, hypertension, hypercholesterolemia, and type 2 diabetes. Younger and more educated persons were more likely to have faster Alzheimer's disease progression. Vascular factors such as hypertension and hypercholesterolemia were not found to be significantly associated with disease progression. However, patients with diabetes had a 65% reduced risk of fast cognitive decline compared to Alzheimer patients without diabetes. Sociodemographic factors and diabetes predict disease progression in Alzheimer's disease. Our findings suggest a slower disease progression in Alzheimer's patients with diabetes. If confirmed, this result will contribute new insights into Alzheimer's disease pathogenesis and lead to relevant suggestions for disease treatment.

Episodic long-term, short-term, and implicit memory were investigated in 79 elderly subjects who fulfilled criteria for the amnestic form of mild cognitive impairment (a-MCI; i.e., by having an idiopathic amnestic disorder with absence of impairment in cognitive areas other than memory and without confounding medical or psychiatric conditions) and who developed Alzheimer's disease (AD) after 2 years as well as in 111 subjects affected by a-MCI who did not develop dementia. Results document a memory profile in a-MCI subjects characterized by preserved short-term and implicit memory and extensive impairment of episodic long-term memory. In virtually all episodic memory indexes examined (learning, forgetting, recognition abilities), a-MCI subjects who converted to AD were more severely impaired than were subjects who did not become demented. This memory profile, which closely resembles that exhibited by amnestic patients with bilateral mesial-temporal lobe lesions, confirms a precocious phase in preclinical AD characterized by selective involvement of mesial-temporal areas and worsening of the memory impairment as atrophic changes progress in hippocampal structures. In this context of pervasive episodic memory impairment, tests assessing the free recall of verbal material following a delay interval demonstrated the greater sensitivity to memory deficits of a-MCI subjects who developed AD., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

A category-specific naming effect penalizing living things has often been reported in patients suffering from Alzheimer's disease (AD) and in other brain damaged populations, while the opposite dissociation (i.e., lower accuracy in naming nonliving than living things) is much rarer. In this study, we investigated whether the use of line drawings (rather than color photographs) in picture-naming tasks could be a relevant factor in the emergence of a category effect penalizing living things and found evidence in favor of this hypothesis. We administered the same naming tasks comprising living and nonliving items to 10 subjects suffering from AD and 10 normal controls. Once the stimuli were line drawings and once color photographs. A reliable Group x Semantic domain interaction, indicating a disproportionate impairment for living things in the AD group, was only found when line drawings were presented. Results are discussed with reference to two competing approaches to category-specificity in brain damaged people. One assumes that category effects are due to the differential involvement of dedicated neural subsystems, the other emphasizes the role of cross domains imbalances in processing demands. We conclude that our findings lead support to the latter approach.

Cognitive and functional decline in Alzheimer's disease (AD) may show different, yet correlated, rates of progression. Over a 2-year period we investigated the predictive role of neuropsychological and behavioural variables on the cognitive and functional decline of 43 patients with AD. Slow and fast decliners were defined on the basis of cognitive and functional indexes of disease progression. We found that cognitive decline was predicted by diffuse cognitive impairment and functional progression by visuospatial deficits. Psychotic symptoms predicted faster disease progression in both cognitive and functional dimensions.

A semantic battery comprising items from living and nonliving categories was administered to a sample of subjects suffering from probable Alzheimer's type dementia (n=20). The results were analyzed to test the role of semantic distance in predicting group accuracy and its possible causal link with the phenomenon of a category-specific deficit for living things in the experimental population. Our findings confirm a category effect favoring nonliving items (over and above the role of confounding variables) in patients with Alzheimer's disease and support the major role of an imbalance of semantic distance in the testing material in the genesis of this phenomenon.

The aim of this study was to investigate whether a brief neuropsychological battery consisting of a limited number of cognitive tests and an evaluation of the behavioural domains intended to discriminate between frontotemporal dementia (fv-FTD) and Alzheimer's disease (AD), constitutes a useful instrument for making a differential clinical diagnosis between these two pathologies. Nineteen fv-FTD and 39 AD patients were compared on cognitive tasks (assessing memory, executive functions, language and constructional praxis) and on the NPI behavioural assessment. A stepwise discriminant analysis was performed to identify the linear combination of cognitive and behavioural measures able to best discriminate between the two groups. One test for each of the investigated cognitive domains (Delayed Prose Recall, FAS verbal fluency, Boston naming test, Rey's Figure A Copy) and the four subscales of the Neuropsychiatry Inventory (NPI) which best differentiated between fv-FTD and AD patients (apathy, disinhibition, euphoria, aberrant motor behaviour) were used. The analysis selected Rey's Figure A Copy, FAS verbal fluency and NPI apathy subscale as the best discriminants between fv-FTD and AD patients. The final equation assigned 73.7% of the fv-FTD patients and 94.7% of the AD patients to the correct diagnostic group. A validation study conducted on a new independent sample of 11 fv-FTD and 22 AD patients confirmed the high sensitivity (82.6 %) and specificity (81.8%) of the diagnostic equation in assigning fv-FTD and AD patients to the correct dementia group. Although both cognitive and behavioural differences exist between FTD and AD, previous studies have aimed at differentiating the two pathologies by considering the two aspects separately and discriminant analyses were focused only on neuropsychological or neuropsychiatric evaluations. The present results emphasise the importance of rating both cognitive and behavioural clinical features of the two syndromes as objectively as possible to improve differential diagnostic accuracy.

In this study, we investigated whether alterations in the pattern of caspase activation could be found at the level of peripheral blood mononuclear cells (PBMCs) in patients with Alzheimer's disease (AD). The results showed that in experimental conditions resembling a physiological stimulation, there was a statistically significant increase in the enzymatic activity of caspase-3, caspase-8, and caspase-9 in PBMCs from a small, but well-characterized, cohort of sporadic AD patients compared to those from a comparable control group of aged adults (AA). This was accompanied by a parallel, early increase in the cleavage activity of the same caspases. The higher level of caspase activity in PBMCs from AD compared to AA was not associated with quantitative differences in cell subset profiles. Moreover, no increase in apoptosis level, in the same experimental conditions, was found in PBMCs from this cohort of AD patients compared to those from AA. Conversely, the higher proneness to caspase activation in PBMCs from AD patients in comparison with that from AA was associated with a higher proliferative response to PHA or CD3. These data show a new dysfunction in AD patients at the PBMCs level and suggest that increased proneness to caspase activation in lymphocytes could reflect an ongoing systemic response in neurodegenerative disease with pathogenetic implications.