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Background Sleep disturbances are common non-motor symptoms of Parkinson’s Disease (PD). Methods The aim of this study was to investigate the polysomnographic correlates of sleep changes, as investigated by the Parkinson’s Disease Sleep Scale-2 (PDSS-2), in a cohort of sixty-two consecutive de novo, drug naïve PD patients (71.40 ± 7.84 y/o). Results PDSS-2 total score showed a direct correlation with stage shifts (p = 0.008). Fragmented sleep showed an inverse correlation with sleep efficiency (p = 0.012). Insomnia symptoms showed an inverse correlation with wake after sleep onset (p = 0.005) and direct correlation with periodic leg movements (p = 0.006) and stage shift indices (p = 0.003). Motor Symptoms showed a direct correlation with Apnoea-Hypopnoea (AHI; p = 0.02) and awakenings indices (p = 0.003). Dream distressing showed a direct correlation with REM without atonia (RWA, p = 0.042) and an inverse correlation with AHI (p = 0.012). Sleep quality showed an inverse correlation with RWA (p = 0.008). Conclusion PDSS-2 features are significantly correlated with polysomnography objective findings, thus further supporting its reliability to investigate sleep disturbances in PD patients.

Theory of mind (ToM) deficit is a frequent finding in subjects with neurological and psychiatric conditions. While a number of brain regions play a role in ToM, to date the contribution of the diffuse projection systems is less understood. Here, we explored the topographical and neurochemical bases of ToM using multi-tracer molecular imaging and quantitative electroencephalography (qEEG) in a group of 30 drug-naive, de novo Parkinson's Disease (PD) patients (mean age 73.39 ± 8.93 years, 11 females). ToM was assessed using the “Reading the Mind in the Eyes Task” (RMET), while general cognition with the MMSE. We acquired FDG-PET images (as a marker of regional neurodegeneration), I-123 Ioflupane Single Photon Emission Computed Tomography (123 I-FP-CIT-SPECT, as a marker of dopaminergic impairment in the basal ganglia and in the cortex and as a proxy marker of serotoninergic deafferentation in the thalamus), and qEEG recordings (using the Theta/Alpha power ratio as marker of cholinergic deafferentation). PD presented with a significantly worse RMET score compared to 60 controls (20.7 ± 5.5 vs 27.5 ± 3.0 p = .001) while there was no difference between the two groups in age, education or MMSE. The voxel-wise analysis of total RMET score and regional metabolism showed a positive correlation in the superior temporal gyrus and in the insula. Among the proxy markers of dopaminergic degeneration, serotoninergic and cholinergic deafferentation, ToM presented only an inverse correlation with 123 I-FP-CIT thalamic specific binding ratio (SBR) values -a proxy serotoninergic marker-which remained significant after correction for FDG metabolism in the areas associated with ToM. On the other hand, MMSE only correlated with qEEG posterior Theta/Alpha power. These findings point to the presence of a specific cortical and neurochemical signature of ToM in PD, to the independence of ToM from general cognition, and suggest possible therapeutic targets to treat social cognition deficits.

BACKGROUND Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)-sleep behavior disorder (iRBD). However, it might be used as a second-line stratification tool in clinical trials, because it is expensive and mini-invasive. OBJECTIVE Aim of the study is to investigate whether other cost-effective and non-invasive biomarkers may be proposed as first-line stratification tools. METHODS Forty-seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT-SPECT. All patients underwent 6 month-based clinical follow-up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk. RESULTS Seventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non-displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS-AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox-regression analysis, only putamen SBR and NPS-AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9-19.8). At post-hoc analysis, the trail-making test B (TMT-B) was the single most efficient first-line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT-B and DAT-SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47). CONCLUSION The TMT-B seems to be a cost-effective and efficient first-line screening tool, to be used to select patients that deserve DAT-SPECT as second-line screening tool for disease-modifying clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Purpose: FDG-PET is an established supportive biomarker in dementia with Lewy bodies (DLB), but its diagnostic accuracy is unknown at the mild cognitive impairment (MCI-LB) stage when the typical metabolic pattern may be difficultly recognized at the individual level. Semiquantitative analysis of scans could enhance accuracy especially in less skilled readers, but its added role with respect to visual assessment in MCI-LB is still unknown. Methods: We assessed the diagnostic accuracy of visual assessment of FDG-PET by six expert readers, blind to diagnosis, in discriminating two matched groups of patients (40 with prodromal AD (MCI-AD) and 39 with MCI-LB), both confirmed by in vivo biomarkers. Readers were provided in a stepwise fashion with (i) maps obtained by the univariate single-subject voxel-based analysis (VBA) with respect to a control group of 40 age- and sex-matched healthy subjects, and (ii) individual odds ratio (OR) plots obtained by the volumetric regions of interest (VROI) semiquantitative analysis of the two main hypometabolic clusters deriving from the comparison of MCI-AD and MCI-LB groups in the two directions, respectively. Results: Mean diagnostic accuracy of visual assessment was 76.8 ± 5.0% and did not significantly benefit from adding the univariate VBA map reading (77.4 ± 8.3%) whereas VROI-derived OR plot reading significantly increased both accuracy (89.7 ± 2.3%) and inter-rater reliability (ICC 0.97 [0.96-0.98]), regardless of the readers' expertise. Conclusion: Conventional visual reading of FDG-PET is moderately accurate in distinguishing between MCI-LB and MCI-AD, and is not significantly improved by univariate single-subject VBA but by a VROI analysis built on macro-regions, allowing for high accuracy independent of reader skills.

Background Late Life Bipolar Disorder (LLBD) is associated with a high prevalence of cognitive impairments, but few studies have examined their risk factors and clinical correlates Methods Participants with bipolar disorder older than 60 ( n = 86) were recruited from psychiatric outpatient and inpatients units. Patients were assessed with various instruments, including the Clinical Dementia Rating scale, the Montreal Cognitive Assessment and the Cumulative Illness Rating Scale. The distribution of disorder-specific and general risk factors was compared between patients with LLBD plus cognitive impairments (mild cognitive impairment or dementia) and those with LLBD but no cognitive impairment. Analyses were first conducted at the bivariate level, then using multiple regression. The association with disability, aggressive behavior and suicidal ideation was also explored. Results Cognitive impairments in LLBD were associated with a diagnosis of type 1 bipolar disorder (OR = 6.40, 95%CI: 1.84 – 22.31, p = 0.004), fewer years of education (OR = 0.79, 95%CI: 0.69 – 0.91, p = 0.001) and higher severity of physical diseases (OR 26.54, 95%CI: 2.07 – 340.37, p = 0.01). Moreover, cognitive impairments were associated with an increased likelihood of disability and recent aggressive behavior, but not suicidal ideation. Limitations retrospective design, conflation of MCI and dementia, not all subjects were in euthymia Conclusions In LLBD, the presence of cognitive impairments was associated with a diagnosis of type I bipolar disorder, lower education and more severe physical comorbidities. In turn, MCI or dementia were associated with increased disability and aggressive behavior. These findings may aid the identification of patients at risk for cognitive deterioration in everyday clinical practice.

Cognitive decline is a common trait of neurodegenerative diseases of central nervous system and one of the major risk factors associated with faster phenoconversion from prodromal stages. In the transition to full-blown clinical syndromes, increased phase synchronization in the theta, alpha or beta EEG rhythms is thought to reflect the activation of compensatory mechanisms that may counterbalance the cognitive decline of patients affected by Mild Cognitive Impairment (MCI). Patients suffering from idiopathic Rapid eye-movement sleep Behavior Disorder (iRBD) have high risk of developing Parkinson Disease (PD) or Dementia with Lewy Bodies (DLB) and cognitive impairment is among the strongest risk factors together with motor symptoms. Here we wanted to investigate whether altered phase synchronization and amplitude couplings of the brain oscillations could be linked to the balancing of cognitive decline in a longitudinal cohort (N=18) of iRBD patients. We measured high-density Electroencephalographic (HD-EEG) activity at baseline and follow-up and quantified power distribution, orthogonalized amplitude correlation and weighted phase lag index. Despite the overt neurodegenerative progression (three patients converted to PD and one to DLB), cognitive decline was not evident from Mini Mental State Examination (MMSE) or neuropsychological tests. On the other hand, alpha phase synchronization and delta amplitude correlations were significantly different at follow-up compared to baseline. In particular, alpha synchrony was enhanced while delta amplitude coupling was reduced. Those differences were more pronounced among central-posterior channels while frontal channels showed a reduced number of significant edges with respect to surrogates. Both large-scale amplitude and phase coupling significantly correlated with cognitive or neuropsychological scores but not with sleep quality indices. Altogether, these results suggest that increased alpha phase-synchronization and reduced delta amplitude correlation may be considered as electrophysiological signs of an active compensatory mechanism of the cognitive impairment in RDB patients. Large-scale functional modifications could thus be used as significant biomarker in the characterization of prodromal stages of PD.Statement of SignificanceCognitive impairment and RBD emerge much earlier than the better-known motor symptoms distinctive of synucleinopathies. An improved investigation of RBD may constitute an important biomarker for an early diagnosis of the actual neurodegenerative diseases. For the first time, this preliminary study aims to quantify the large-scale network couplings as electrophysiological manifestation of the compensatory mechanism to the cognitive impairment in a longitudinal study of idiopathic RBD patients. Unfortunately, the small number of the subjects limits the generalizability of our observations, but this is only preliminary works in a larger project that aims to investigate advanced electrophysiological markers for an early diagnosis of the synucleinopathies.

Objective To investigate clinical and dopaminergic pre-synaptic brain imaging characteristics of subjects with idiopathic rapid eye movement (REM) behavior disorder (iRBD) and mild cognitive impairment (MCI), and to evaluate the combined predictive value of risk factors for short-term conversion to synucleinopathy. Method In sum, 44 polysomnography (PSG)-confirmed iRBD patients (68.5 ± 7.2 years; 38 males) underwent 123I-FP-CIT-SPECT, comprehensive neuropsychological evaluation, clinical examination and clinical follow-up every six months (30.6 ± 21.5 months). Step-wise logistic regression was applied to identify those features discriminating iRBD patients with (iRBD-MCI; n = 14) and without MCI (normal cognition [NC], iRBD-NC; n = 30). The risk of neurodegeneration was estimated with Kaplan–Meier analysis. Predictors of phenoconversion were assessed with Cox proportional-hazards analysis, adjusting for age, gender and education. A generalized linear model (GLM) was applied to define the best combination of risk factors predicting conversion at follow-up. Results At baseline, patients with iRBD-MCI showed reduced striatal dopamine transporter (DAT) specific to non-displaceable binding ratio (SBR) and more constipation compared with iRBD-NC patients (p Conclusions iRBD-MCI patients showed a more severe dopaminergic neuroimaging and clinical phenotype. Combining clinical and neuroimaging markers allowed to achieve excellent ability in identifying iRBD patients at high risk of developing a synucleinopathy within about three years from diagnosis.

Study Objectives Increased phase synchronization in electroencephalography (EEG) bands might reflect the activation of compensatory mechanisms of cognitive decline in people with neurodegenerative diseases. Here, we investigated whether altered large-scale couplings of brain oscillations could be linked to the balancing of cognitive decline in a longitudinal cohort of people with idiopathic rapid eye-movement sleep behavior disorder (iRBD). Methods We analyzed 18 patients (17 males, 69.7 ± 7.5 years) with iRBD undergoing high-density EEG (HD-EEG), presynaptic dopaminergic imaging, and clinical and neuropsychological (NPS) assessments at two time points (time interval 24.2 ± 5.9 months). We thus quantified the HD-EEG power distribution, orthogonalized amplitude correlation, and weighted phase-lag index at both time points and correlated them with clinical, NPS, and imaging data. Results Four patients phenoconverted at follow-up (three cases of parkinsonism and one of dementia). At the group level, NPS scores decreased over time, without reaching statistical significance. However, alpha phase synchronization increased and delta amplitude correlations decreased significantly at follow-up compared to baseline. Both large-scale network connectivity metrics were significantly correlated with NPS scores but not with sleep quality indices or presynaptic dopaminergic imaging data. Conclusions These results suggest that increased alpha phase synchronization and reduced delta amplitude correlation may be considered electrophysiological signs of an active compensatory mechanism of cognitive impairment in people with iRBD. Large-scale functional modifications may be helpful biomarkers in the characterization of prodromal stages of alpha-synucleinopathies.

Background Degeneration of the nigrostriatal dopaminergic (DA) and the raphe-thalamic serotonergic (SE) systems is among the earliest changes observed in Parkinson's disease (PD). The consequences of those changes on brain metabolism, especially regarding their impact on the cortex, are poorly understood. Objectives Using multi-tracer molecular imaging, we assessed in a cohort of drug-naive PD patients the association between cortical metabolism and DA and SE system deafferentation of either striatum or thalamus, and we explored whether this association was mediated by either striatum or thalamus metabolism. Methods We recruited 96 drug-naive PD patients (aged 71.9 ± 7.5 years) who underwent [123 I]ioflupane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) and brain [18 F]fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET). We used a voxel-wise analysis of [18 F]FDG-PET images to correlate regional metabolism with striatal DA and thalamic SE innervation as assessed using [123 I]FP-CIT-SPECT. Results We found that [123 I]FP-CIT specific to nondisplaceable binding ratio (SBR) and glucose metabolism positively correlated with one another in the deep gray matter (thalamus: P = 0.001, r = 0.541; caudate P = 0.001, r = 0.331; putamen P = 0.001, r = 0.423). We then observed a direct correlation between temporoparietal metabolism and caudate DA innervation, as well as a direct correlation between prefrontal metabolism and thalamus SE innervation. The effect of caudate [123 I]FP-CIT SBR values on temporoparietal metabolism was mediated by caudate metabolic values (percentage mediated: 89%, P-value = 0.008), and the effect of thalamus [123 I]FP-CIT SBR values on prefrontal metabolism was fully mediated by thalamus metabolic values (P Conclusions These data suggest that the impact of deep gray matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in drug-naive PD. © 2021 International Parkinson and Movement Disorder Society.

Bipolar disorder (BD) is a chronic and disabling psychiatric condition that is linked to significant disability and psychosocial impairment. Although current neuropsychological, molecular, and neuroimaging evidence support the existence of neuroprogression and its effects on the course and outcome of this condition, whether and to what extent neuroprogressive changes may impact the illness trajectory is still poorly understood. Thus, this selective review was aimed toward comprehensively and critically investigating the link between BD and neurodegeneration based on the currently available evidence. According to the most relevant findings of the present review, most of the existing neuropsychological, neuroimaging, and molecular evidence demonstrates the existence of neuroprogression, at least in a subgroup of BD patients. These studies mainly focused on the most relevant effects of neuroprogression on the course and outcome of BD. The main implications of this assumption are discussed in light of specific shortcomings/limitations, such as the inability to carry out a meta-analysis, the inclusion of studies with small sample sizes, retrospective study designs, and different longitudinal investigations at various time points.

To investigate brain functional correlates of mild cognitive impairment (MCI) in idiopathic REM sleep behavior disorder (iRBD). Thirty-nine consecutive iRBD patients, 17 with (RBD-MCI, 73.6±6.5 years), and 22 without (RBD-NC, 69.6±6.1 years) MCI underwent neuropsychological assessment, 18F-FDG-PET, and 123I-FP-CIT-SPECT as a marker of nigro-striatal dopaminergic function. Forty-two healthy subjects (69.6±8.5 years) were used as control for 18F-FDG-PET analysis. Brain metabolism was compared between the three groups by univariate analysis of variance. Post hoc comparison between RBD-MCI and RBD-NC was performed to investigate the presence of an MCI-related volume of interest (MCI-VOI). Brain functional connectivity was explored by interregional correlation analysis (IRCA), using the whole-brain normalized MCI-VOI uptake as the independent variable. Moreover, the MCI-VOI uptake was correlated with 123I-FP-CIT-SPECT specific-to-non displaceable binding ratios (SBR) and neuropsychological variables. Finally, the MCI-VOI white matter structural connectivity was analyzed by using a MRI-derived human atlas. The MCI-VOI was characterized by a relative hypometabolism involving precuneus and cuneus (height threshold p

BACKGROUND AND PURPOSE To explore the feasibility of a neuroprotection trial in prodromal synucleinopathy, using idiopathic rapid eye movement sleep behavior disorder (iRBD) as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression. METHODS Consecutive iRBD patients were randomly assigned to a treatment arm receiving selegiline and symptomatic rapid eye movement sleep behavior disorder treatment, or to a control arm receiving symptomatic treatment only. Selegiline was chosen because of a demonstrated neuroprotection effect in animal models. Patients underwent 123 I-FP-CIT-SPECT at baseline and after 30 months on average. The clinical outcome was the emergence of parkinsonism and/or dementia. A repeated-measures general linear model (GLM) was applied using group (control and treatment) as "between" factor, and both time (baseline and follow-up) and regions (123 I-FP-CIT-SPECT putamen and caudate uptake) as the "within" factors, adjusting for age. RESULTS Thirty iRBD patients completed the study (68.2 ± 6.9 years; 29 males; 21% dropout rate), 13 in the treatment arm, and 17 in the control arm. At follow-up (29.8 ± 9.0 months), three patients in the control arm developed dementia and one parkinsonism, whereas two patients in the treatment arm developed parkinsonism. Both putamen and caudate uptake decreased over time in the control arm. In the treatment arm, only the putamen uptake decreased over time, whereas caudate uptake remained stable. GLM analysis demonstrated an effect of treatment on the 123 I-FP-CIT-SPECT uptake change, with a significant interaction between the effect of group, time, and regions (p = 0.004). CONCLUSIONS A 30-months neuroprotection study for prodromal synucleinopathy is feasible, using iRBD as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression.

Background Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. Objective The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). Methods We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. Results Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. Conclusion In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

BACKGROUND Cognitive impairment is a frequent and disabling feature of Parkinson's disease. Identifying the factors able to predict cognitive worsening since the early stage may improve disease management. The objective of this study was to define the best predictors of future cognitive worsening in a group of patients with newly diagnosed PD and to propose cutoff values potentially useful at the individual level. METHODS Fifty-four consecutive drug-naive patients with de novo PD were prospectively evaluated by clinical and neuropsychological assessment, resting EEG, and 123 I-FP-CIT-SPECT and clinically classified into mainly motor, diffuse/malignant, and intermediate PD subtypes; they were then followed up for an average of 5 years. Cognitive outcome was defined by identifying cognitively stable or worsened patients. RESULTS Step-wise logistic regression selected the posterior qEEG mean frequency and 123 I-FP-CIT-SPECT uptake at caudate level (P < 0.0001). The posterior qEEG mean frequency (cut point, 8.3 Hz) and the caudate 123 I-FP-CIT-SPECT uptake (cut point, 2.3, specific to nondisplaceable binding ratio) achieved 82% and 80% of accuracy, respectively, in predicting cognitive outcome. Survival analysis showed decreasing expected time to cognitive worsening associated with scores below the established thresholds for qEEG and 123 I-FP-CIT-SPECT and with the presence of a malignant clinical phenotype. CONCLUSIONS Resting EEG and 123 I-FP-CIT-SPECT are good predictors of future cognitive worsening, in de novo drug-naive PD patients. Wherever available, these biomarkers could add valuable prognostic information to classification into different clinical phenotypes. © 2017 International Parkinson and Movement Disorder Society.

Elderly patients with mild cognitive impairment (MCI) may develop a Lewy body disease; their neuroimaging features at presentation are largely unknown. We present an intriguing group of 13 patients with MCI preceding (2.9 ± 1.9 years) parkinsonism (MCI-P), and eventually dementia 4.6 ± 1.6 years later (6 patients), whereas 7 patients remained dementia free after 4.7 ± 2.7 years. Neuropsychological tests, dopamine transporter (DAT) single photon emission computed tomography, and 18F-fluorodeoxyglucose positron emission tomography were compared with healthy controls and with cognitively normal patients with Parkinson's disease (PD-MOT). Compared to controls, MCI-P but not PD-MOT showed significant posterior temporo-parieto-occipital hypometabolism. Basal ganglia DAT uptake was similar between MCI-P and PD-MOT. Patients who converted to dementia were older, tended to have higher movement disorder society-unified Parkinson's disease rating scale scores and developed at least another clinical core feature fulfilling the criteria for probable dementia with Lewy bodies (DLB). Concurrent impairment of Corsi span and semantic verbal fluency, or of temporal lobe hypometabolism at baseline and reduced putamen-to-caudate ratio on DAT-SPECT at parkinsonism onset, both predicted (p < 0.001) the evolution to dementia. The constructs of Park cognitive subtype and prodromal Lewy body dementia partially overlap; functional imaging and neuropsychology may help in characterizing the patients and in tracking the risk toward dementia.

PURPOSE: Mild cognitive impairment (MCI) is a transitional pathological stage between normal ageing (NA) and Alzheimer's disease (AD). Although subjects with MCI show a decline at different rates, some individuals remain stable or even show an improvement in their cognitive level after some years. We assessed the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not. METHODS: FDG PET was performed in 42 NA subjects, 27 MCI patients who had not converted to AD at 5 years (nc-MCI; mean follow-up time 7.5 ± 1.5 years), and 95 MCI patients who converted to AD within 5 years (MCI-AD; mean conversion time 1.8 ± 1.1 years). Relative FDG uptake values in 26 meta-volumes of interest were submitted to ANCOVA and support vector machine analyses to evaluate regional differences and discrimination accuracy. RESULTS: The MCI-AD group showed significantly lower FDG uptake values in the temporoparietal cortex than the other two groups. FDG uptake values in the nc-MCI group were similar to those in the NA group. Support vector machine analysis discriminated nc-MCI from MCI-AD patients with an accuracy of 89% (AUC 0.91), correctly detecting 93% of the nc-MCI patients. CONCLUSION: In MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume-based analysis identified those who converted with an accuracy of 89%. However, further analysis is needed in patients with amnestic MCI who convert to a dementia other than AD.

Purpose: We aimed to identify the cortical regions where hypometabolism can predict the speed of conversion to dementia in mild cognitive impairment due to Alzheimer's disease (MCI-AD). Methods: We selected from the clinical database of our tertiary center memory clinic, eighty-two consecutive MCI-AD that underwent 18F-fluorodeoxyglucose (FDG) PET at baseline during the first diagnostic work-up and were followed up at least until their clinical conversion to AD dementia. The whole group of MCI-AD was compared in SPM8 with a group of age-matched healthy controls (CTR) to verify the presence of AD diagnostic-pattern; then the correlation between conversion time and brain metabolism was assessed to identify the prognostic-pattern. Significance threshold was set at p < 0.05 False-Discovery-Rate (FDR) corrected at peak and at cluster level. Each MCI-AD was then compared with CTR by means of a SPM single-subject analysis and grouped according to presence of AD diagnostic-pattern and prognostic-pattern. Kaplan-Meier-analysis was used to evaluate if diagnostic- and/or prognostic-patterns can predict speed of conversion to dementia. Results: Diagnostic-pattern corresponded to typical posterior hypometabolism (BA 7, 18, 19, 30, 31 and 40) and did not correlate with time to conversion, which was instead correlated with metabolic levels in right middle and inferior temporal gyri as well as in the fusiform gyrus (prognostic-pattern, BA 20, 21 and 38). At Kaplan-Meier analysis, patients with hypometabolism in the prognostic pattern converted to AD-dementia significantly earlier than patients not showing significant hypometabolism in the right middle and inferior temporal cortex (9 versus 19 months; Log rank p < 0.02, Breslow test: p < 0.003, Tarone-Ware test: p < 0.007). Conclusion: The present findings support the role of FDG PET as a robust progression biomarker even in a naturalist population of MCI-AD. However, not the AD-typical diagnostic-pattern in posterior regions but the middle and inferior temporal metabolism captures speed of conversion to dementia in MCI-AD since baseline. The highlighted prognostic pattern is a further, independent source of heterogeneity in MCI-AD and affects a primary-endpoint on interventional clinical trials (time of conversion to dementia).

Brain connectivity has been assessed in several neurodegenerative disorders investigating the mutual correlations between predetermined regions or nodes. Selective breakdown of brain networks during progression from normal aging to Alzheimer disease dementia (AD) has also been observed. Methods: We implemented independentcomponent analysis of 18F-FDG PET data in 5 groups of subjects with cognitive states ranging from normal aging to AD--including mild cognitive impairment (MCI) not converting or converting to AD--to disclose the spatial distribution of the independent components in each cognitive state and their accuracy in discriminating the groups. Results: We could identify spatially distinct independent components in each group, with generation of local circuits increasing proportionally to the severity of the disease. AD-specific independent components first appeared in the late-MCI stage and could discriminate converting MCI and AD from nonconverting MCI with an accuracy of 83.5%. Progressive disintegration of the intrinsic networks from normal aging to MCI to AD was inversely proportional to the conversion time. Conclusion: Independent-component analysis of 18F-FDG PET data showed a gradual disruption of functional brain connectivity with progression of cognitive decline in AD. This information might be useful as a prognostic aid for individual patients and as a surrogate biomarker in intervention trials.

Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.

Background In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. Objective To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). Methods A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1–42 (Aβ42), tau and p‐tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting‐state and auditory oddball event‐related potential (AO‐ERP) paradigm) biomarkers were evaluated. Results Prodromal AD was found in 55 aMCI patients defined by low Aβ42 in the cerebrospinal fluid (Aβ positive). Compared to the aMCI group with high Aβ42 levels (Aβ negative), Aβ positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO‐ERP (P = 0.03). Conclusion These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Introduction The association between Parkinson Disease (PD) and REM sleep behavior disorder (RBD) has been related to a specific, malignant clinical phenotype. Definite RBD diagnosis requires video-polysomnography that is often unfeasible. A malignant clinical PD-RBD phenotype could be expected also in PD patients with probable RBD. Aim of this cross-sectional study was to evaluate whether a more severe neuropsychological and functional neuroimaging phenotype can be identified in PD patients with probable RBD. Methods Thirty-eight de novo , drug naive PD patients underwent a first-line clinical assessment and a second-line multimodal assessment, including neuropsychological evaluation, 123 I-FP-CIT-SPECT and 18 F-FDG-PET, which were compared between PD patients with (PD + RBD+) and without (PD + RBD-) probable RBD. Results On first-line assessment, PD + RBD + patients had significantly more constipation (p = 0.02) and showed worse olfaction (p = 0.01) compared with PD + RBD-while the two groups were similar as for age, presence of orthostatic hypotension, UPDRS-III and MMSE scores. On second-line assessment, PD + RBD + patients showed a worse neuropsychological test profile, more severe nigro-striatal dopaminergic impairment, mainly at caudate level in the less affected hemisphere (p = 0.004) and impaired brain glucose metabolism, with relative hypometabolism in posterior cortical regions and relative hypermetabolism mainly in anterior regions of the more affected hemisphere (p = 0.015). Conclusions PD patients with probable RBD are likely to have a more severe neuropsychological and functional brain-imaging phenotype already at the time of diagnosis.

Purpose The diagnosis of behavioural variant frontotemporal dementia (bvFTD) is challenging during the predementia stage when symptoms are subtle and confounding. Morphological and functional neuroimaging can be particularly helpful during this stage but few data are available. Methods We retrospectively selected 25 patients with lateonset probable bvFTD. Brain structural MRI and FDG PET were performed during the predementia stage (mean MMSE score 27.1± 2.5) on average 2 years before. The findings with the two imaging modalities were compared (SPM8) with those in a group of 20 healthy subjects. The bvFTD patients were divided into two subgroups: those with predominant disinhibition (bvFTD+) and those with apathy (bvFTD-). Results Hypometabolism exceeded grey matter (GM) density reduction in terms of both extension and statistical significance in all comparisons. In the whole bvFTD group, hypometabolism involved the bilateral medial, inferior and superior lateral frontal cortex, anterior cingulate, left temporal and right parietal cortices and the caudate nuclei. GM density reduction was limited to the right frontal cortex and the left medial temporal lobe. In bvFTD+ patients hypometabolism was found in the bilateral medial and basal frontal cortex, while GM reduction involved the left anterior cingulate and left inferior frontal cortices, and the right insula. In bvFTD- patients, atrophy and mainly hypometabolism involved the lateral frontal cortex and the inferior parietal lobule. Conclusion These findings suggest that hypometabolism is more extensive than, and thus probably precedes, atrophy in predementia late-onset bvFTD, underscoring different topographic involvement in disinhibited and apathetic presentations. If confirmed in a larger series, these results should prompt biomarker operationalization in bvFTD, especially for patient selection in therapeutic clinical trials.

Aim: To unveil a brain single photon emission computed tomography (SPECT) pattern in Alzheimer’s disease (AD) patients, showing a reversed clock drawing test (CDT) phenomenon. Patients and Methods: Among 1,005 consecutive subjects, 9 AD patients who drew a reversed CDT (AD-R) underwent SPECT, which was analysed (SPM2) versus a group of 10 AD patients performing the CDT correctly (AD+) and versus 15 controls (CTR). Brain SPECT in 11 AD patients who mistook the CDT in a common way (AD–) was compared with AD+ and CTR groups. Results: Relative hypoperfusion was found in AD-R versus CTR in right medial frontal, parahippocampal and subcallosal gyri, and in left insula and superior temporal gyrus. Hypoperfusion was found in AD-R versus AD+ in the right uncus, superior temporal and parahippocampal gyri. In the AD– versus CTR comparison, hypoperfusion was found in left hippocampus, parahippocampal gyrus and superior parietal lobule. In AD-R versus AD+ and CTR merged together, the analysis showed hypoperfusion in the right parahippocampus, medial frontal gyrus, superior temporal gyrus and uncus, in the left insula and superior temporal gyrus. Conclusion: Fronto-temporal dysfunction, especially in the right hemisphere, plays a role in the reversed CDT phenomenon in AD patients, whereas matched AD patients mistaking the CDT in a common way show left posterior temporo-parietal hypoperfusion.

The purpose of this study was to investigate cortical dysfunction in Parkinson's disease (PD) patients with amnestic deficit (PD-MCI). Perfusion single photon emission computed tomography was performed in 15 PD-MCI patients and compared (statistical parametric mapping [SPM2]) with three groups, i.e., healthy subjects (CTR), cognitively intact PD patients (PD), and common amnestic MCI patients (aMCI). Age, depression, and UPDRS-III scores were considered as confounding variables. PD-MCI group (P < 0.05, false discovery rate-corrected for multiple comparisons) showed relative hypoperfusion in bilateral posterior parietal lobe and in right occipital lobe in comparison to CTR. As compared to aMCI, MCI-PD demonstrated hypoperfusion in bilateral posterior parietal and occipital areas, mainly right cuneus and angular gyrus, and left precuneus and middle occipital gyrus. With a less conservative threshold (uncorrected P < 0.01), MCI-PD showed hypoperfusion in a left parietal region, mainly including precuneus and inferior parietal lobule, and in a right temporal-parietal-occipital region, including middle occipital and superior temporal gyri, and cuneus-precuneus, as compared to PD. aMCI versus PD-MCI showed hypoperfusion in bilateral medial temporal lobe, anterior cingulate, and left orbitofrontal cortex. PD-MCI patients with amnestic deficit showed cortical dysfunction in bilateral posterior parietal and occipital lobes, a pattern that can be especially recognized versus both controls and common aMCI patients, and to a lesser extent versus cognitively intact PD. The relevance of this pattern in predicting dementia should be evaluated in longitudinal studies.

Objective: To investigate quantitative EEG (qEEG) in anorexia nervosa (AN) and bulimia nervosa (BN) in comparison with healthy controls. Methods: Resting EEG was recorded in 30 healthy females (age: 27.1 ± 5.5), 16-AN females (age: 26.4 ± 9.5) and 12-BN females (age: 27.0 ± 6.3). Cortical EEG sources (delta, theta, alpha 1, alpha 2, beta 1, beta 2) were modeled by LORETA solutions. The statistical analysis was performed considering the factors Group, power Band, and region of interest (central, frontal, parietal, occipital, temporal, limbic). Results: Alpha 1 sources in central, parietal, occipital and limbic areas showed a greater amplitude in Controls versus AN and BN groups. Alpha 2 sources in parietal, occipital and limbic areas showed a greater amplitude in Controls than in both AN and BN groups. Alpha 1 sources in temporal area showed a greater amplitude in Controls compared to both the BN and AN groups as well as in the BN group compared to AN group. Central alpha 1 source correlated significantly with BMI in patients. Conclusions: These results support the hypothesis that eating disorders are related to altered mechanisms of cortical neural synchronization, especially in rolandic alpha rhythms. Significance: To our knowledge this is the first study by LORETA able to detect modifications of cortical EEG activity in eating disorders.

Background/Aims: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer’s disease (AD). Methods: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer’s Disease Consortium were collected. Principal component analysis was used for factor analysis. Results: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. Conclusion: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

In Parkinson’s disease (PD) degeneration of mesocortical dopaminergic projections may determine cognitive and behavioral symptoms. Choice reaction time task is related to attention, working memory, and goal-directed behavior. Such paradigm involves frontal cortical circuits receiving mesocortical dopamine which are affected early in PD. The aim of this study is to characterize the role of dopamine on the cognitive processes that precede movement in a reaction time paradigm in PD. We enrolled 16 newly diagnosed and untreated patients with PD without cognitive impairment or depression and 10 control subjects with essential tremor. They performed multiple-choice reaction time task with the right upper limb and brain18F-DOPA PET/CT scan. A significant inverse correlation was highlighted between average reaction time and18F-DOPA uptake in the left lateral orbitofrontal cortex. No correlations were found between reaction time and PD disease severity or between reaction time and18F-DOPA uptake in controls. Our study shows that in PD, but not in controls, reaction time is inversely related to the levels of dopamine in the left lateral orbitofrontal cortex. This novel finding underlines the role of dopamine in the lateral orbitofrontal cortex in the early stages of PD, supporting a relation between the compensatory cortical dopamine and movement preparation.

The purpose of the study was to evaluate the Von Restorff effect in normal ageing and in Alzheimer's disease (AD). A shortened paradigm was administered to three groups of subjects: young volunteers, elderly volunteers and patients with early-stage AD (MMSE>20). Each subject was presented with 25 lists of 10 words each, the target word appearing in double font size. A free recall phase followed the presentation of each list; after completion of the battery, a size recognition test was administered and subjects were inquired regarding the strategy employed and perception of target words. The total number of recalled words differed significantly among the three groups (young volunteers 144.4+/-38.6, elderly volunteers 86.5+/-17.6, patients 44.2+/-14.6). A significant difference in percentage of recall was found between target and non-target words in young (60.0+/-13.8% vs. 45.7%+/-15.0%, p

Forty-nine consecutive, drug naive outpatients with de novo Parkinson's disease (PD) and 12 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) underwent clinical examination and dopamine transporter single photon emission computed tomography with [(123)I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane as a biomarker of nigro-striatal function. PD patients were grouped into rapid eye movement sleep behavior disorder (RBD) negative (PD-RBD-) and RBD positive (PD-RBD+). Repeated measures and univariate analysis of variance were used to compare dopaminergic and clinical impairment among groups. The variations of dopamine transporter-single photon emission computed tomography specific binding ratios (SBR) as a function of group belonging were significantly different (p = 0.0013) at caudate with respect to putamen level. Indeed, putamen SBR progressively decreased from iRBD to PD-RBD- and PD-RBD+ groups while caudate SBR were higher in PD-RBD- group than in PD-RBD+ and even than in iRBD group. Motor impairment was more severe in PD patients with RBD than in those without RBD. Our data suggest that a more severe nigro-caudate dopaminergic deafferentation is related to RBD, both in its idiopathic form and in PD patients.

This article describes the unusual case of a 60-year-old woman suffering from pure progressive aphemia. The fusion of multimodal neuroimaging (MRI, perfusion SPECT) implicated the right frontal lobe, especially the inferior frontal gyrus. This area also showed the greatest functional MRI activation during the performance of a covert phonemic fluency task. Results are discussed in terms of bihemispheric language representation. The fusion of three sets of neuroimages has aided in the interpretation of the patient's cognitive brain dysfunction.

Objective: In this prospective study we evaluate the effects of high-dose recombinant human erythropoietin (rHuEPO) on quality of life (QOL) and brain function in patients with low-risk myelodysplastic syndromes (MDS) (

Background : The recent introduction of acetylcholinesterase inhibitors (AChEIs) therapy for Alzheimer's Disease (AD) has led to the need to assess the brain's response to the therapy on an objective, neurophysiological basis. Brain perfusion single photon emission computed tomography (SPECT) was used in an open-label study to evaluate the effect of chronic Donepezil administration to a group of patients affected by mild to moderate AD, compared to a group of AD patients not receiving AChEIs and kept under observation for a similar period. Methods : Twenty-five consecutive patients with probable AD (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria) (19 women, 6 men; mean age: 74.2±7.2; mean Mini-Mental State Examination score, MMSE: 19.8±3.5) underwent ( t 0 ) brain SPECT with 99m Tc-hexamethylpropylene-amine-oxime by a brain-dedicated, high-resolution camera and were re-evaluated ( t 1 ) after 11±2.6 months of chronic Donepezil administration (5 mg/day) (treated group). Thirteen AD patients (9 women, 4 men, mean age: 71.4±5.7, MMSE score: 20.6±3.5) were not treated with AChEIs and served as controls (untreated group). They were subjected to the same evaluation after 13±1.4 months as the treated group. Statistical parametric mapping (SPM) was employed to analyse SPECT findings. Results : The MMSE score declined significantly ( P t 0 to t 1 both in untreated (from 20.6±3.5 to 17.8±4.4) and in treated (from 19.8±3.5 to 17.8±4.1) group. At t 0 , the untreated group showed higher regional cerebral blood flow (rCBF) than the treated group in a frontal and a frontal-parietal region of the left hemisphere. Between t 0 and t 1 , significant rCBF reduction was observed in the temporal lobe and occipital-temporal cortex of the left hemisphere in the untreated group, whereas no significant change was observed in the treated group. The rCBF of the two groups did not significantly differ at t 1 . By covariate SPM analysis between t 0 and t 1 in treated patients, MMSE score changes correlated significantly with rCBF changes in a large left frontal-temporal region. Conclusions : Brain perfusion is preserved in AD patients undergoing chronic Donepezil therapy while it is reduced in untreated patients. SPECT is a promising tool with which to assess the impact of AChEI therapy on brain functioning of AD patients.

Subtle cognitive impairment is recognized in the first stages of Parkinson's disease (PD), including executive, memory and visuospatial dysfunction, but its pathophysiological basis is still debated.Twenty-six consecutive, drug-naïve, de novo PD patients underwent an extended neuropsychological battery, dopamine transporter (DAT) and brain perfusion single photon emission computed tomography (SPECT). We previously reported that nigrocaudate impairment correlates with executive functions, and nigroputaminal impairment with visuospatial abilities. Here perfusion SPECT was first compared between the PD group and age-matched controls (CTR). Then, perfusion SPECT was correlated with both DAT SPECT and four neuropsychological factors by means of voxel-based analysis (SPM8) with a height threshold of p0.005 at peak level and p0.05 false discovery rate-corrected at cluster level. Both perfusion and DAT SPECT images were flipped in order to have the more affected hemisphere (MAH), defined clinically, on the same side.Significant hypoperfusion was found in an occipital area of the MAH in PD patients as compared to CTR. Executive functions directly correlated with brain perfusion in bilateral posterior cingulate cortex and precuneus in the less affected hemisphere (LAH), while verbal memory directly correlated with perfusion in the precuneus, inferior parietal lobule and superior temporal gyrus in the LAH. Furthermore, positive correlation was highlighted between nigrocaudate and nigroputaminal impairment and brain perfusion in the precuneus, posterior cingulate and parahippocampal gyri of the LAH.These data support the evidence showing an early involvement of the cholinergic system in the early cognitive dysfunction and point to a more relevant role of parietal lobes and posterior cingulate in executive functions in PD.

Objective The aim of this preliminary study was to investigate the physiologic substrate of executive function in anorexia nervosa (AN) by assessing the relation between brain perfusion and Stroop interference task (SIT). Method The classical SIT test and brain single-photon emission tomography (SPET) were evaluated in 16 AN females (mean age = 23.69 ± 8.68 years; mean body mass index [BMI] = 16.19 ± 1.53 kg/m2). The relation between the two examinations was searched by statistical parametric mapping (SPM 99) with a height threshold of p = .001. Results An abnormally low or a borderline SIT value was found in 25% of patients. A significant correlation between the SIT score and brain perfusion was found in the superior frontal gyrus of both hemispheres (Brodmann's area [BA] 6 in both hemispheres and BA 8 in the right hemisphere). No correlation was found in the anterior cingulate gyrus. Conclusion BA 6 and BA 8 and the anterior cingulate are believed to be the basis of both error detection and immediate correction. Activity of BA 6 and BA 8 reflects this executive task in AN patients as well, whereas the lack of correlation in the anterior cingulate may suggest its blunted activity in AN patients, similarly to what is shown in other conditions characterized by impaired executive function, such as patients with depression, patients with schizophrenia, and abstinent drug abusers. However, these findings should still be quoted as preliminary, given some limitations of the study design, such as the lack of a control group, and the unfeasibility of controlling some relevant confounding variables, such as psychiatric comorbidity, medication, and the time interval between examinations, mainly deriving from the relatively few patients studied. © 2005 by Wiley Periodicals, Inc.

Twenty patients affected with probable mild-to-moderate Alzheimer’s disease (AD; NINCDS-ADRDA criteria; 14 women and 6 men, mean age 75.2 ± 7.1 years) who regularly received an oral acetylcholinesterase inhibitor (AChEI; donepezil 5 mg/day; Dz group) were compared with a control group of 11 AD patients (6 women and 5 men, mean age 73.5 ± 6.0 years) diagnosed and followed up in the pre-AChEIs era (C group). At basal evaluation (t₀), the 2 groups were comparable for age, education, and severity of disease (Global Deterioration Scale). All patients underwent quantitative EEG (qEEG, average reference, 10–20 International System), and were reexamined about 1 year later (t1; i.e., after 12.3 ± 3.6 months the Dz group, and after 13.7 ± 3.9 months the C group). Log-transformed values of two qEEG bands, i.e. 2–6 and 6.5–12 Hz, were averaged between adjacent channels (frontal F3 and F7, F4 and F8; parietotemporal P3 and T7, P4 and T8) to obtain a qEEG ratio (6.5–12/2–6 Hz.) from one frontal and one temporoparietal region in each hemisphere. Neuropsychological impairment was summarized by the Mini-Mental Status Examination (MMSE). At t₀, both the MMSE score and the qEEG ratio values were somewhat higher in the C than in the Dz group, although nonsignificantly. Between t₀ and t1, the MMSE score decreased significantly (p < 0.01) more in the C group (–4.36 ± 2.25) than in the Dz group (–1.45 ± 2.16), as did the qEEG ratio in the right frontal region (p < 0.01), whereas in the left frontal region the significance level was not reached (p = 0.02). Between t₀ and t1, the qEEG ratio difference in both frontal regions and in the right temporoparietal region significantly correlated with the MMSE difference (p < 0.01), but neither with time between examinations nor with the difference on the Visual Search Test score. Long-term treatment with Dz led to a lesser deterioration of qEEG, paralleling a milder neuropsychological decline. The effect was significant in frontal regions, possibly because they are relatively spared during the mild-to-moderate phases of the disease.

The present investigation reports the application of regional cerebral blood flow (rCBF; 133Xe method) to prognostic purposes in a consecutive series of 76 patients (mean age 68.4 ± 8.7 years) with probable Alzheimer’s disease (AD; NINCDS-ADRDA criteria). The likelihood that rCBF from a posterior temporal-inferior parietal area in each hemisphere at the first visit may predict timing of achievement of three endpoints (i.e. loss of activity of daily living, ADL, incontinence and death due to end-stage AD) was tested by the ‘lifereg’ procedure of the Statistical Analysis System package. With respect to baseline evaluation, 32 patients lost ADL 20.6 ± 17.4 months later, 31 developed incontinence 27.1 ± 19.0 months later, and 16 patients died after 40.9 ± 23.8 months of follow-up. Baseline rCBF significantly predicted all end-points: the loss of ADL (left hemisphere: p = 0.04; righth hemisphere: p = 0.02), incontinence (p = 0.02 in both hemispheres) and death (p = 0.01 in both hemispheres). Statistical significance was maintained for the loss of ADL and incontinence both in a subgroup of mildly demented patients, in whom death was not considered due to the low number of patients who died, and in a multivariate analysis including patient age, age at onset, sex, duration of illness, Mini-Mental State Examination score and presence of extrapyramidal signs and psychotic symptoms at the first visit. This study shows that rCBF measurement in a posterior temporal-inferior parietal area may give prognostic information on timing of evolution of AD, whenever performed during the course of the disease, and may be utilized both in clinical practice and for social planning.

Perfusion and metabolic studies in patients with Alzheimer's disease (AD) have so far yielded conflicting results on the functional status of the hippocampal region, whose deep location in the brain makes it critical to optimize the image-reconstruction technique employed in emission tomography. We used a brain-dedicated device (CERASPECT) to perform single photon emission computed tomography (SPECT) studies with 99mTc-hexamethylpropylene-amine-oxime in 22 consecutive patients (mean age: 74+/-6.5 years) with mild [mini-mental status examination (MMSE) score > or =15, mean 20.8+/-3.2], probable AD. The control subjects were 11 healthy elderly people (mean age: 70.5+/-6.5 years). In patients, the total score on the selective reminding test (SRT) was used as an index of memory function. Counts from a hippocampal and a temporoparietal region of interest in each hemisphere were referred to the average thalamic counts. To optimize SPECT images, we used conventional filtered back-projection (FBP) reconstruction and a new iterative method of conjugate gradients (CG), which takes into account the geometrical and physical characteristics of the gamma-camera. Hippocampal perfusion in the two hemispheres was significantly lower in patients than in control subjects, regardless of which reconstruction method was used, and correlated with the MMSE score. The correlation between hippocampal perfusion and the SRT score was significantly (bootstrap procedure) higher with the CG method than with the FBP method (CG: r=0.52 and 0.54; FBP: r=0.39 and 0.47, for the right and left hemisphere, respectively). These results show hippocampal hypoperfusion in patients with mild AD, a correlation between hippocampal perfusion and the severity of cognitive impairment, and enhanced identification of these subtle perfusional changes with the use of an alternative image-reconstruction method that improves the spatial resolution of SPECT images.