Using diffusion tensor imaging to detect cortical changes in fronto-temporal dementia subtypes.

Fronto-temporal dementia (FTD) is a common type of presenile dementia, characterized by a heterogeneous clinical presentation that includes three main subtypes: behavioural-variant FTD, non-fluent/agrammatic variant primary progressive aphasia and semantic variant PPA. To better understand the FTD subtypes and develop more specific treatments, correct diagnosis is essential. This study aimed to test the discrimination power of a novel set of cortical Diffusion Tensor Imaging measures (DTI), on FTD subtypes. A total of 96 subjects with FTD and 84 healthy subjects (HS) were included in the study. A "selection cohort" was used to determine the set of features (measurements) and to use them to select the "best" machine learning classifier from a range of seven main models. The selected classifier was trained on a "training cohort" and tested on a third cohort ("test cohort"). The classifier was used to assess the classification power for binary (HS vs. FTD), and multiclass (HS and FTD subtypes) classification problems. In the binary classification, one of the new DTI features obtained the highest accuracy (85%) as a single feature, and when it was combined with other DTI features and two other common clinical measures (grey matter fraction and MMSE), obtained an accuracy of 88%. The new DTI features can distinguish between HS and FTD subgroups with an accuracy of 76%. These results suggest that DTI measures could support differential diagnosis in a clinical setting, potentially improve efficacy of new innovative drug treatments through effective patient selection, stratification and measurement of outcomes.

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Functional Changes of Mentalizing Network in SCA2 Patients: Novel Insights into Understanding the Social Cerebellum.

In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II.The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients' social impairment in domain-specific complex and abstract forms of social functioning.

Age-related changes in brain deactivation but not in activation after motor learning.

It is poorly understood how healthy aging affects neural mechanisms underlying motor learning. We used blood-oxygen-level dependent (BOLD) contrasts to examine age-related changes in brain activation after acquisition and consolidation (24 h) of a visuomotor tracking skill. Additionally, structural magnetic resonance imaging and diffusion tensor imaging were used to examine age-related structural changes in the brain. Older adults had reduced gray matter volume (628 ±â€¯57 ml) and mean white matter anisotropy (0.18 ±â€¯0.03) compared with young adults (741 ±â€¯59 ml and 0.22 ±â€¯0.02, respectively). Although motor performance was 53% lower in older (n = 15, mean age 63.1 years) compared with young adults (n = 15, mean age 25.5 years), motor practice improved motor performance similarly in both age groups. While executing the task, older adults showed in general greater brain activation compared with young adults. BOLD activation decreased in parietal and occipital areas after skill acquisition but activation increased in these areas after consolidation in both age groups, indicating more efficient visuospatial processing immediately after skill acquisition. Changes in deactivation in specific areas were age-dependent after consolidating the motor skill into motor memory. Young adults showed greater deactivations from post-test to retention in parietal, occipital and temporal cortices, whereas older adults showed smaller deactivation in the frontal cortex. Since learning rate was similar between age groups, age-related changes in activation patterns may be interpreted as a compensatory mechanism for age-related structural decline.

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

Microstructural MRI Basis of the Cognitive Functions in Patients with Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.

Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral "nodes" in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.

The γ-parameter of anomalous diffusion quantified in human brain by MRI depends on local magnetic susceptibility differences.

Motivated by previous results obtained in vitro, we investigated the dependence of the anomalous diffusion (AD) MRI technique on local magnetic susceptibility differences (Δχ) driven by magnetic field inhomogeneity in human brains. The AD-imaging contrast investigated here is quantified by the stretched-exponential parameter γ, extracted from diffusion weighted (DW) data collected by varying diffusion gradient strengths. We performed T2* and DW experiments in eight healthy subjects at 3.0T. T2*-weighted images at different TEs=(10,20,35,55)ms and DW-EPI images with fourteen b-values from 0 to 5000s/mm2 were acquired. AD-metrics and Diffusion Tensor Imaging (DTI) parameters were compared and correlated to R2* and to Δχ values taken from literature for the gray (GM) and the white (WM) matter. Pearson's correlation test and Analysis of Variance with Bonferroni post-hoc test were used. Significant strong linear correlations were found between AD γ-metrics and R2* in both GM and WM of the human brain, but not between DTI-metrics and R2*. Depending on Δχ driven magnetic field inhomogeneity, the new contrast provided by AD-γ imaging reflects Δχ due to differences in myelin orientation and iron content within selected regions in the WM and GM, respectively. This feature of the AD-γ imaging due to the fact that γ is quantified by using MRI, may be an alternative strategy to investigate, at high magnetic fields, microstructural changes in myelin, and alterations due to iron accumulation. Possible clinical applications might be in the field of neurodegenerative diseases.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment.

Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.

Functional connectivity changes within specific networks parallel the clinical evolution of multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), the location of focal lesions does not always correlate with clinical symptoms, suggesting disconnection as a major pathophysiological mechanism. Resting-state (RS) functional magnetic resonance imaging (fMRI) is believed to reflect brain functional connectivity (FC) within specific neuronal networks. OBJECTIVE: RS-fMRI was used to investigate changes in FC within two critical networks for the understanding of MS disabilities, namely, the sensory-motor network (SMN) and the default-mode network (DMN), respectively, implicated in sensory-motor and cognitive functions. METHODS: Thirty-four relapsing-remitting (RR), 14 secondary progressive (SP) MS patients and 25 healthy controls underwent MRI at 3T, including conventional images, T1-weighted volumes, and RS-fMRI sequences. Independent component analysis (ICA) was employed to extract maps of the relevant RS networks for every participant. Group analyses were performed to assess changes in FC within the SMN and DMN in the two MS phenotypes. RESULTS: Increased FC was found in both networks of MS patients. Interestingly, specific changes in either direction were observed also between RR and SP MS groups. CONCLUSIONS: FC changes seem to parallel patients' clinical state and capability of compensating for the severity of clinical/cognitive disabilities.

Anatomical brain connectivity can assess cognitive dysfunction in multiple sclerosis.

BACKGROUND: Brain disconnection plays a major role in determining cognitive disabilities in multiple sclerosis (MS). We recently developed a novel diffusion-weighted magnetic resonance imaging (DW-MRI) tractography approach, namely anatomical connectivitity mapping (ACM), that quantifies structural brain connectivity. OBJECTIVE: Use of ACM to assess structural connectivity modifications in MS brains and ascertain their relationship with the patients' Paced-Auditory-Serial-Addition-Test (PASAT) scores. METHODS: Relapsing-remitting MS (RRMS) patients (n = 25) and controls (n = 25) underwent MRI at 3T, including conventional images, T1-weighted volumes and DW-MRI. Volumetric scans were coregistered to fractional anisotropy (FA) images, to obtain parenchymal FA maps for both white and grey matter. We initiated probabilistic tractography from all parenchymal voxels, obtaining ACM maps by counting the number of streamlines passing through each voxel, then normalizing by the total number of streamlines initiated. The ACM maps were transformed into standard space, for statistical use. RESULTS: RRMS patients had reduced grey matter volume and FA, consistent with previous literature. Also, we showed reduced ACM in the thalamus and in the head of the caudate nucleus, bilaterally. In our RRMS patients, ACM was associated with PASAT scores in the corpus callosum, right hippocampus and cerebellum. CONCLUSIONS: ACM opens a new perspective, clarifying the contribution of anatomical brain disconnection to clinical disabilities in MS.

Reserve mechanisms in neurodegenerative diseases: from bench to bedside and back again.

In the course of neurodegenerative disorders there are several mechanisms that may counteract the pathological process, mitigating the clinical manifestations of the disease. Usually referred as cognitive reserve hypothesis, this theoretical framework posits that individuals with enriched cognitive status (i.e. with higher educational and occupational levels and higher individual social achievement) may cope better with the occurrence of cognitive decline by a more efficient recruitment of neural networks sustaining higher-level functions. Cognitive reserve was initially studied in Alzheimer's disease, but this concept has been soon after extended also to other neurodegenerative disorders, such as Frontotemporal Dementia, Parkinson's disease, and Huntington's disease, suggesting a general applicability of cortical plasticity phenomena in contrasting neurodegeneration. The neural underpinnings of these dynamic compensatory mechanisms open the possibility for strategic interventions based on environmental approaches. In this continuously growing field, the aim of the present review is to explore new acquisitions, derived from basic research and clinical grounds, on cognitive reserve mechanisms and the potential application as novel therapeutic targets in neurodegenerative diseases.

Magnetic resonance imaging in Alzheimer's disease: from diagnosis to monitoring treatment effect.

Quantitative outcome variables in Alzheimer's disease (AD) are of interest because of their low longitudinal variability compared with that of repeated clinical and cognitive measurements. Conventional MR-based volumetry of structures within and beyond the medial temporal lobe has proven to be useful in the diagnostic work up of early AD patients, and measures of atrophy have the potential to monitor the efficacy of disease-modifying agents. The extensive application of new non-conventional MR-based techniques to the study of AD, such as proton magnetic resonance spectroscopy, diffusion tensor MRI, and functional MRI, has undoubtedly improved our understanding of the pathophysiology of the disease, and might lead to the identification of additional useful markers of disease progression. This review summarizes the main results obtained from the application of conventional and non-conventional MRI in AD patients, and supports their more extensive use in studies of disease evolution and clinical trials.

White matter damage along the uncinate fasciculus contributes to cognitive decline in AD and DLB.

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.

θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect.

OBJECTIVE: Cortico-cortical circuits originating from the posterior parietal cortex (PPC) of the intact left hemisphere (LH) may become hyperexcitable in patients with hemispatial neglect due to a right hemispheric (RH) stroke. METHODS: In the current randomized, double-blind, sham-controlled study, we investigated safety and efficacy of continuous theta-burst stimulation (cTBS) in 10 sessions over 2 weeks applied over the intact PPC of the LH in subacute ischemic stroke patients. Severity of neglect was assessed through the standardized Behavioral Inattention Test (BIT). We also measured, by means of bifocal transcranial magnetic stimulation (TMS), how cTBS modified the excitability of the parieto-frontal functional connections in the intact LH. RESULTS: We found that 2 weeks of cTBS, but not sham cTBS, were effective in improving neglect symptoms as measured by BIT score. BIT scores improved by 16.3% after 2 weeks of cTBS and 22.6% at 1 month follow-up. We also found that hyperexcitability of LH parieto-frontal circuits was reduced following treatment with real but not sham cTBS. CONCLUSION: These findings suggest that a 2-week course of cTBS over the LH PPC may be a potential effective strategy in accelerating recovery from visuospatial neglect in subacute stroke patients, possibly counteracting the hyperexcitability of LH parieto-frontal circuits. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that left posterior parietal cortex theta-burst stimulation improves hemispatial neglect for up to 2 weeks after treatment.

Regional grey matter loss and brain disconnection across Alzheimer disease evolution.

It is becoming increasingly clearer that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional grey matter (GM) damage, but also with abnormal integration between cortical brain regions by disconnection mechanism. This concept comes from the evidence that white matter (WM) damage (as assessed by diffusion MR imaging) can be observed in patients with AD since the early clinical stages, and it correlates with clinical measures of cognitive disability. In this perspective, several functional imaging studies, based on PET and resting state fMRI, have provided evidence that brain hypometabolism/disconnection may precede the occurrence of GM atrophy in certain regions of AD brains, such as the cingulate cortex. The cingulum represents the most prominent WM tract of the limbic system, being directly connected to the medial temporal lobe structures. Therefore, this structure likely contributes to changes in functional connectivity observed within the so called default-mode network of AD patients, and its damage is likely to play a remarkable role in the conversion from mild cognitive impairment (MCI) to dementia. Nowadays, the combination of several neuroimaging techniques that provide both, measures of regional GM loss and measures of functional and structural connectivity offer the opportunity to investigate in vivo the pathophysiological changes of brain tissue modifications across the clinical evolution of AD. This paper reviews the main MR based methods of investigation of brain tissue involvement in patients with AD and MCI, and the role they have played in clarifying the differential contribution of GM damage and brain disconnection to AD pathophysiology. This subject seems to be relevant for both, speculative aspects of neurology and application to clinical trials.

Anisotropic anomalous diffusion assessed in the human brain by scalar invariant indices.

A new method to investigate anomalous diffusion in human brain, inspired by the stretched-exponential model proposed by Hall and Barrick, is proposed here, together with a discussion about its potential application to cerebral white matter characterization. Aim of the work was to show the ability of anomalous diffusion indices to characterize white matter structures, whose complexity is only partially accounted by diffusion tensor imaging indices. MR signal was expressed as a stretched-exponential only along the principal axes of diffusion; whereas, in a generic direction, it was modeled as a combination of three stretched-exponentials. Indices to quantify the tissue anomalous diffusion and its anisotropy, independently of the experiment reference frame, were derived. Experimental results, obtained on 10 healthy subjects at 3T, show that the new parameters are highly correlated to intrinsic local geometry when compared with Hall and Barrick indices. Moreover, they offer a different contrast in white matter regions when compared with diffusion tensor imaging. Specifically, the new indices show a higher capability to discriminate among areas of the corpus callosum associated to different distribution in axonal densities, thus offering a new potential tool to detect more specific patterns of brain abnormalities than diffusion tensor imaging in the presence of neurological and psychiatric disorders.

Single domain amnestic MCI: a multiple cognitive domains fMRI investigation.

Amnestic mild cognitive impairment (a-MCI) is associated with the highest annual incidence of conversion to Alzheimer's disease (AD) (10-15%). a-MCI patients may have only a memory deficit (single domain: sd-a-MCI) or additional dysfunctions affecting other cognitive domains (multiple domain: md-a-MCI). Using functional magnetic resonance imaging (fMRI), we investigated brain activation in 16 sd-a-MCI patients and 14 controls during four different tasks assessing language, memory, attention and empathy functions. We found greater activation in sd-a-MCI compared with controls in the left inferior temporal gyrus (language), the right superior temporal gyrus (memory) and the right dorsal precentral gyrus (attention). Moreover, patients' activation correlated significantly with neuropsychological scores obtained at tests exploring the corresponding function. These findings indicate that fMRI is sensitive to detect early changes occurring in AD pathology and that individuals with sd-a-MCI show increased activation in multiple task-related brain regions. We suggest that these functional changes relate to the development of early compensatory mechanisms that reduce cognitive deficits associated with the progressive accumulation of brain damage.

Prospective memory in thalamic amnesia.

The contribution of the thalamus to the functioning of prospective memory (PM) is currently unknown. Here we report an experimental investigation of the performance of two patients with bilateral infarcts in the anterior-mesial regions of the thalami on an event-based PM paradigm. One patient, G.P., had a pervasive declarative memory impairment but no significant executive deficit. The other patient, R.F., had a memory deficit limited to verbal material with associated behavioral abnormalities (inertia and apathy); she performed poorly on tests of executive functions. Although both patients performed poorly on the PM task, a qualitative analysis of performance revealed different mechanisms at the base of their impaired PM. G.P. had reduced declarative memory for target words compared with normal controls; but, unforgotten words were normally able to elicit his recall of the prospective intention. Conversely, R.F.'s declarative memory for target words was as accurate as that of normal controls, but she presented a dramatically reduced ratio between the number of target words she recalled and the number of times she activated the prospective intention on the PM task, suggesting that her deficit consisted of difficulty in activating the intention despite normal declarative memory for the target events. In conclusion, results of the present study demonstrate that thalamic structures have an important role in PM processes. They also document that damage to the anterior-mesial regions of the thalami affects PM abilities by two different mechanisms, respectively based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved by the lesions. Indeed, while G.P.'s pervasive declarative memory deficit was underlain by bilateral involvement of the mammillo-thalamic tract, R.F.'s executive and behavioral abnormalities were likely related to bilateral damage of the midline, intralaminar, and medio-dorsal nuclei.