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The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of non-invasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD.

Background A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer’s and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres. Methods The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer’s disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment. Results Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up. Conclusions Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.

Since the late ninety, research on Alzheimer's disease has been focused on the search of drugs able to modify the disease course. Patients and caregivers waiting for news on this topic, received enthusiastically the advice of the approval of Aducanumab-anti-amyloid β monoclonal antibody-by the FDA, and that of its rejection by the EMA with even greater disappointment. To estimate the number of patients that we would be able to treat-hypothesizing a possible future approval by EMA- in the memory clinic of the IRCCS S. Giovanni di Dio FBF of Brescia, we analyzed 1561 patients undergone a first geriatric visit in January 1st to December 31st 2019. Applying the EMERGE and ENGAGE studies criteria, only 15 of them (1%) could be eligible for Aducanumab. The communication of scientific news should be transparent, more balanced and less sensationalistic, to avoid the rise of false hopes and consequent disillusionment.

Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer&rsquo, s Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. Purpose. To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. Methods. AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. Results. APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, &ldquo, Psychosis&rdquo, and &ldquo, Hyperactivity&rdquo, resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and &ldquo, genexgene&rdquo, interactions. Conclusions. We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the &ldquo, interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms.

Age at symptom onset (AAO) underlies different Alzheimer's disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.

In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone, through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The oxigen-ozone (O2-O3) therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention working in absence of side effects for cognitive frailty.

Introduction Dementia is one of the major causes of disability and dependency among older people worldwide, and hospitalization occurs frequently in demented patients. The present study examined the course of behavioural symptoms and functional conditions in hospitalised older people with dementia. Materials and methods Prospective cohort study of 179 demented patients (age > 64 years) admitted to four geriatric units, evaluated at admission, discharge and at 6 months after discharge. An analysis of predictors of functioning improvement was performed. Results Patients with no symptoms at NeuroPsychiatric Inventory baseline assessment did not show any changes at both discharge and follow-up, while patients with symptoms at baseline showed an improvement in every subscale from admission to discharge. Using Barthel Index as a measure of functioning, we found a significant improvement in both "admission-discharge" and "discharge-follow-up" timeframe for the most impaired patients. However, for the less impaired patients, no significant changes emerged from admission to discharge, while a significant worsening occurred from discharge to follow-up. The significant associated variables with improvement in Barthel Index from discharge to follow-up were age and Blaylock Risk Assessment Screening Score at admission. Conclusion Interesting trends in the course of hospitalized older patients with dementia have been found, and they were associated to different levels of functional impairment at admission. Further research is still needed to understand the predictors of improvement and worsening in such hospitalized patients.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aβ)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aβ in cognitive decline, we analyzed the whole panel of CSF Aβ isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aβ peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aβ species while in sporadic AD Aβ1-42 was the only peptide reduced. A significant independent association between Aβ1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aβ and the most abundant Aβ1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aβ1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.

Cortical sources of resting eyes-closed alpha rhythms are typically abnormal in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. Here we tested the hypothesis of a progressive impairment of cortical alpha reactivity to eye-opening across amnesic MCI and mild AD subjects, reflecting another aspect of the impairment of cortical neural synchronization. Resting electroencephalography (EEG) data were recorded in 36 normal elderly subjects (Nold), 91 amnesic MCI, and 31 mild AD subjects during eyes-closed and -open conditions. EEG sources were estimated by LORETA software. In the eye-closed condition, posterior alpha 1 (8-10.5 Hz) sources were lower in MCI and AD than Nold subjects. The opposite was true for occipital delta sources (2-4 Hz). Reactivity to the eyes-open condition showed posterior alpha 1 and alpha 2 (10.5-13 Hz) sources was high in the Nold, intermediate in the MCI, and low in the AD subjects. Furthermore, occipital alpha 1 reactivity across MCI and AD subjects was correlated to the cognitive impairment as revealed by Mini-Mental State Examination score. In conclusion, at least at group level, the continuum across amnesic MCI and mild AD status is related to an impaired reactivity of cortical neuronal synchronization to eyes opening at alpha rhythms.

Aim of this study was to investigate the functional compensation mechanism in incipient Alzheimer's disease (AD). Seventeen elderly healthy subjects and nine amnestic MCI patients with incipient AD underwent brain MR scan and 99mTc ECD SPECT. We processed all images with SPM2, we created t maps, showing the wholebrain GM atrophy and functional changes, and we properly masked them with each other in order to assess relatively preserved perfusion or depression. Incipient AD showed GM atrophy in the medial temporal and temporoparietal lobes, in the insula and in the retrosplenial cortex, and GM hypoperfusion in the medial temporal and temporoparietal lobes. Relatively preserved perfusion, we could hypothesize to be compensatory in the setting of neuronal loss, was found in the posterior cingulate, in the head of the hippocampus, in the amigdala, and in the insula bilaterally, while functional depression occurred in bilateral parahippocampal gyri. In AD, a perfusional compensatory mechanism takes place in the neocortex, while perfusional depression occurs in the medial temporal lobe. These results help understand the reactive phenomena induced by the brain to try and counteract the pathological changes of AD.

Diffusion tensor MRI‐based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico‐cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto‐occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimer's disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas‐based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto‐occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico‐cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico‐cortical association pathways in aMCI and AD patients. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Objective: Revised research criteria for the diagnosis of Alzheimer disease have been proposed to capture patients presenting with mild and not yet disabling symptoms, and currently classified as mild cognitive impairment (MCI). We describe 2 very mild cases of MCI and their clinical outcome. Methods: The 2 cases were selected as they had unequivocal preservation of daily activities and normal global cognitive performance (Mini-Mental State Examination 29/30) and were positive to all 3 markers. Cognitive profile was assessed with an extensive neuropsychologic battery, medial temporal atrophy with hippocampal volumetry, hypometabolism on 18 F-deoxyglucose positron emission tomography and voxel-based statistical parametric mapping analysis, and tau and amyloid beta-42 in the cerebrospinal fluid with enzyme-linked immunosorbent assay. Results: Both patients had a poor performance in 2 out of 11 neuropsychologic tests. Both had hippocampal volumes at or below the first percentile of the age-specific distribution, retrosplenial glucose hypometabolism, and inversion of tau/amyloid beta-42 cerebrospinal fluid ratio. Both showed progression of the cognitive deficit over the following 12 months. Conclusions: These 2 patients with progressive MCI and positivity to all Alzheimer markers predicated by the new research criteria provide preliminary support to their validity. Future work will characterize the marker profile of the vast majority of patients with incomplete marker positivity.

Background We propose a completely automated methodology to investigate the relationship between magnetic resonance image (MRI) features and changes in cognitive estimates, applied to the study of Mini-Mental State Examination (MMSE) changes in mild cognitive impairment (MCI). Subjects A reference group composed of 75 patients with clinically probable Alzheimer's Disease (AD) and 75 age-matched controls; and a study group composed of 49 MCI, 20 having progressed to clinically probable AD and 29 having remained stable after a 48 month follow-up. Methods We created a pathology-specific reference space using principal component analysis of MRI-based features (intensity, local volume changes) within the medial temporal lobe of T1-weighted baseline images for the reference group. We projected similar data from the study group and identified a restricted set of image features highly correlated with one-year change in MMSE, using a bootstrap sampling estimation. We used robust linear regression models to predict one-year MMSE changes from baseline MRI, baseline MMSE, age, gender, and years of education. Results All experiments were performed using a leave-one-out paradigm. We found multiple image-based features highly correlated with one-year MMSE changes (|r| > 0.425). The model for all N = 49 MCI subjects had a correlation of r = 0.31 between actual and predicted one-year MMSE change values. A second model only for MCI subjects with MMSE loss larger than 1 U had a pairwise correlation r = 0.80 with an adjusted coefficient of determination r2 = 0.61. Findings Our automated MRI-based technique revealed a strong relationship between baseline MRI features and one-year cognitive changes in a sub-group of MCI subjects. This technique should be generalized to other aspects of cognitive evaluation and to a wider scope of dementias.

The aim of this study was to assess the changes of intrahemispheric and interhemispheric linear spectral electroencephalography (EEG) coherence associated with increasing hippocampal atrophy (HA) and white matter hyperintensities (WMHs) in patients with mild cognitive impairment (MCI). Eighty-five MCI patients underwent clinical and neuropsychologic assessment, EEG recordings, and magnetic resonance imaging. Intrahemispheric (fronto-temporal, temporo-parietal, and fronto-parietal) and interhemispheric (frontal, temporal, and parietal) linear EEG coherence was computed. MCI patients were categorized into classes of increasing HA and WMHs on the basis of tertile distribution of volume loss (high, mid, and low). Neuropsychologic tests were also gathered and compared in MCI subgroups. As expected, MCI patients with high WMHs had poorer performance on visuospatial and cognitive flexibility, whereas those with high HA failed on memory tests. Significant differences of EEG functional coupling were present in the fronto-temporal network in patients with high WMHs and high HA, but without a different pattern. In high WMHs the EEG coherence in low frequencies was increased (with the exception of alpha1 band), whereas coherence in the fast frequencies was decreased proportional to increasing damage. In high HA a change of coherence was present in the delta and alpha2 frequency bands that was not proportional to HA, fast frequencies being unaffected. Our results show a lateralization (right hemisphere for cerebrovascular disease and left hemisphere for hippocampal atrophy) of the pathologic modifications of functional coupling.

Background New marker-based criteria for the diagnosis of Alzheimer's disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic. Methods Visual ratings of hippocampal atrophy and of cortical glucose hypometabolism in magnetic resonance imaging and positron emission tomography, and concentrations of total tau and Aβ1-42 in cerebrospinal fluid were assessed in 12 patients with subjective memory complaints (SMCs) (Mini-Mental State Examination [MMSE] score, 28.0 ± 1.1 [mean ± SD]), 37 with mild cognitive impairment (MCI) (MMSE, 25.1 ± 3.6), 55 with AD (MMSE, 21.1 ± 3.5), and 40 with non-AD dementia (MMSE, 21.6 ± 5.5). Results The sensitivity for AD of each individual biomarker was higher (65% to 87%) than for MCI (18% to 50%). Each biomarker's specificity for SMC and non-AD dementias was good to moderate (83% and 53%). Positivity for at least one marker increased the probability 38 times of belonging to the AD group ( P Conclusion The new diagnostic criteria can be operationalized in clinical routines, but longitudinal studies of MCI patients will need to assess the criteria's prognostic value.

Does impairment of cholinergic systems represent an important factor in the development of amnesic mild cognitive impairment (aMCI), as a preclinical stage of Alzheimer's disease (AD)? Here we tested the hypothesis that electroencephalographic (EEG) rhythms, known to be modulated by the cholinergic system, may be particularly affected in aMCI patients with lesions along the cholinergic white‐matter tracts. Eyes‐closed resting EEG data were recorded in 28 healthy elderly (Nold) and 57 aMCI patients. Lesions along the cholinergic white‐matter tracts were detected with fluid‐attenuated inversion recovery sequences on magnetic resonance imaging. The estimation of the cholinergic lesion was performed with a validated semi‐automatic algorithm pipeline after registration to a stereotactic template, image integration with stereotactic masks of the cholinergic tracts, and normalization to intracranial volume. The aMCI patients were divided into two groups of high (MCI Ch+; N = 29; MMSE = 26.2) and low cholinergic damage (MCI Ch−; N = 28; MMSE = 26.6). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). Cortical EEG generators were estimated by LORETA software. As main results, (i) power of occipital, parietal, temporal, and limbic alpha 1 sources was maximum in Nold, intermediate in MCI Ch−, and low in MCI Ch+ patients; (ii) the same trend was true in theta sources. These results are consistent with the hypothesis that damage to the cholinergic system is associated with alterations of EEG sources in aMCI subjects. Hum Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.

Aim of the study was to assess the added diagnostic value of neuropsychologic tests and structural neuroimaging (computed tomography or magnetic resonance) in the routine clinical assessment of demented patients in Italian expert centers. Nine centers were involved, located across the whole country (3 in Northern, 3 in Central, and 3 in Southern Italy). Diagnostic pathways were tracked for 474 patients with an expert diagnosis of neurodegenerative or vascular dementia (age 76+/-8; 62% females; Mini-Mental State Examination 17.70+/-5.7). The contribution of neuropsychology and structural neuroimaging to diagnosis was estimated as "number needed to test" (NNT), denoting the number of patients who need to undergo such procedures to improve expert diagnosis of 1 unit. Expert physicians reached their diagnosis without resorting to structural imaging examinations and neuropsychologic tests in 93% of Alzheimer disease (AD) and 76% of non-AD dementias. The completion of the extended assessment led to improvement of diagnostic accuracy in both cases: the NNT was 15.3 (95% confidence interval: 10.4-29.1) and 4.1 (3.0 to 6.5) for AD and non-AD diagnoses. The added value of structural imaging and neuropsychologic testing in the routine clinical assessment of demented patients is substantial in both AD and non-AD cases.

To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI).56 MCI patients (age = 69.3 +/- 7.0, 32 females) underwent brain MR scan and (99m)Tc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates.MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus.MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.

Objectives Morphological abnormalities have been reported for the hippocampi and amygdalae in young schizophrenia patients, but very little is known about the pattern of abnormalities in elderly schizophrenia patients. Here we investigated local structural differences in the hippocampi and amygdalae of elderly schizophrenia patients compared with healthy elderly subjects. We also related these differences to clinical symptom severity. Design 20 schizophrenia patients (mean age: 67.4 ± 6.2 years; Mini-Mental State Exam: 22.8 ± 4.4) and 20 healthy elderly subjects (70.3 ± 7.5 years; 29.0 ± 1.1) underwent high resolution magnetic resonance imaging of the brain. The Radial Atrophy Mapping technique was used to reconstruct the 3D shape of the amygdala and the hippocampus. Local differences in tissue reductions were computed between groups and permutation tests were run to correct for multiple comparisons, in statistical maps thresholded at p = 0.05. Results Significant tissue reduction was observed bilaterally in the amygdala and hippocampus of schizophrenia patients. The basolateral-ventral-medial amygdalar nucleus showed the greatest involvement, with over 30% local tissue reduction. The centro-medial, cortical, and lateral nuclei were also atrophic in patients. The hippocampus showed significant tissue loss in the medio-caudal and antero-lateral aspects of CA1, and in medial section of its left head (pre- and para-subiculum). In the left amygdala and hippocampus, local tissue volumes were significantly correlated with negative symptoms. Conclusions Tissue loss and altered morphology were found in elderly schizophrenia patients. Tissue loss mapped to amygdalo-hippocampal subregions known to have bidirectional and specific connections with frontal cortical and limbic structures and was related to clinical severity.

The diagnosis of mild cognitive impairment (MCI) is clinically unhelpful, as many patients with MCI develop dementia but many do not.To identify clinical instruments easily applicable in the clinical routine that might be useful to predict progression to dementia in patients with MCI assessed in the outpatient facility of a memory clinic.52 dementia-free patients (mean (standard deviation) age 70 (6) years; 56% women) with MCI, and 65 healthy controls (age 69 (6) years; 54% women) underwent brain magnetic resonance scan with standardised visual assessment of medial temporal atrophy (MTA) and subcortical cerebrovascular lesions (SVLs). Follow-up assessment occurred 15.4 (SD 3.4) months after baseline to detect incident dementia and improvement, defined as normal neuropsychological performance on follow-up.Patients were classified into three groups according to the presence of memory disturbance only (MCI Mem), other neuropsychological deficits (MCI Oth) or both (MCI Mem+). MCI Mem and Mem+ showed MTA more frequently (31% and 47% v 5% and 14% of controls and MCI Oth, p0.001). 11 patients developed dementia (annual rate 16.5%) and 7 improved on follow-up. The only independent predictor of progression was MTA (odds ratio (OR) 7.1, 95% confidence interval (CI) 1.4 to 35.0), whereas predictors of improvement were the absence of memory impairment (OR 18.5, 95% CI 2.0 to 171.3) and normal MRI scan (OR 10.0, 95% CI 1.7 to 60.2).Neuropsychological patterns identify groups of patients with MCI showing specific clinical features and risk of progression to dementia. MTA clinically rated with a visual scale is the most relevant predictor of progression and improvement.

Background and aims: To test the agreement of a visual rating scale of medial temporal lobe atrophy (MTA) with linear and volumetric assessments, and to test its accuracy in discriminating between Alzheimer’s disease (AD) patients and controls. Methods: Participants were 28 patients with AD and 29 healthy controls. MTA was evaluated according to Scheltens’ five-point scale. Its accuracy in distinguishing AD patients from controls was evaluated as a stand-alone measure and in association with linear [width of the temporal horn (WTH)] and volumetric [hippocampal volume (HV)] measures. Results: The agreement of this visual rating scale with the other MTA measures was statistically significant (vs WTH and vs HV, p for trend

The validity of a computed tomography (CT)-based rating scale that separately rates leukoaraiosis, patchy lesions, and lacunes was tested using neuropathological findings collected on 87 subjects enrolled in the Oxford Project to Investigate Memory and Ageing. The CT-based score (range 0–64) was associated with both small vessel disease (p = 0.015) and microinfarcts (p = 0.002) on pathology. A sum score of subcortical cerebrovascular disease (CVD) on pathology was computed, 0 indicating absent/mild small vessel CVD and no microinfarcts, 1 moderate small vessel CVD or microinfarcts, and 2 and higher both conditions or severe small vessel CVD. Subjects with a sum score of 0 were decreasing with increasing severity of CT-based score (64, 46, and 25% in those with CT-based scores of 0, 1–38, and 39 and higher), while those with a sum score of 2 and higher were increasing (0, 14, and 44%; p = 0.002). A standardized assessment of subcortical CVD on CT films can be compounded into a unique score that is in good agreement with neuropathology. This supports the validity of the CT-based visual rating scale as a valid tool to detect subcortical vascular changes in elderly persons.

Background Small vessel cerebrovascular disease (svCVD) causes cognitive impairment and predicts poorer outcomes in elderly persons. The demonstration of svCVD by structural imaging such as computed tomography (CT) is central to the clinical diagnosis but its accuracy is uncertain. Objective The aim of this study was to assess the validity of CT to detect pathologically verified svCVD. Methods Leukoaraiosis, patchy lesions, and lacunes were assessed separately in different cerebral regions on CT scans of 87 elderly persons with Mini-Mental State Examination scores between 0 and 30 enrolled in the OPTIMA project. We rated small vessel disease on pathology separately in the white matter and basal ganglia as absent/mild, moderate, and severe. The presence of microinfarcts was also noted. Results The severity of all types of CT lesions was associated with pathological findings. Subjects with absent/mild leukoaraiosis on CT decreased and those with severe leukoaraiosis increased with increasing severity of subcortical small vessel ratings on pathology (31, 18 and 0%; 17, 23 and 50%, respectively; p = 0.028). A similar association was present for patchy lesions (73, 59 and 17%; 7, 18 and 33%, respectively; p = 0.004) and lacune (83, 77 and 50%; 0, 4 and 17%, respectively; p = 0.023). Leukoaraiosis, patchy lesions, and lacunes on CT were associated also with microinfarcts on pathology (p

OBJECTIVES: To identify subjects with minimal or mild nonamnestic cognitive impairment with parkinsonian stance and gait and investigate vascular correlates of this condition. DESIGN: First wave of an epidemiological longitudinal study (InCHIANTI) on factors predicting loss of mobility in older persons. SETTING: The Chianti geographic area (Tuscany, Italy). PARTICIPANTS: Five hundred fifty-six subjects aged 70 to 90 with Mini-Mental State Examination (MMSE) scores greater than 23 of 30, of the 1,260 persons aged 65 and older randomly selected from the population registry of Greve in Chianti and Bagno a Ripoli, two small towns near Florence. METHODS: Low cognitive performance (LCP) was defined as an age- and education-adjusted MMSE below the 50th percentile for the InCHIANTI population. Subcortical features were plastic rigidity on neurological examination (parkinsonism), gait disturbance (small-step gait or parkinsonian gait), and dysexecutive features. Two hundred forty-three participants had high cognitive performance, 166 had LCP without subcortical features, and 75 had LCP with subcortical features. Vascular risk factors were hypertension, atrial fibrillation or pathological findings on electrocardiogram (ECG), low serum high-density lipoprotein (HDL) or high low-density lipoprotein cholesterol, diabetes mellitus, obesity, and heavy smoking. RESULTS: Three main vascular risk factors were significantly more prevalent in LCP with subcortical features: hypertension (P = .02), atrial fibrillation or ECG changes (P = .04), and low HDL cholesterol (P = .001). LCP with subcortical features was significantly associated with cerebrovascular risk factors (P = .001). CONCLUSION: Gait disturbance and nonamnestic cognitive symptoms might be the consequence of subcortical vascular damage.

The use of an electronic memory aid (EMA) for patients with mild-to-moderate probable Alzheimer disease is examined in five outpatients aged 58-79 years. The ability to remember to carry out seven tasks at a particular time was evaluated in three experimental conditions: recall without an external memory aid, recall with a written list and recall with support available from an EMA. The use of an EMA significantly improved patients' prospective memory, while the written list and free recall were not useful. Future research that examines the value of using an EMA to help with tasks that are associated with prospective memory with a larger sample of patients within their own home context is suggested.

Objective: To compare patterns of brain atrophy in fronto-temporal dementia (FTD) and Alzheimer’s disease (AD) since atrophy in individual areas may not be sufficiently specific as diagnostic marker. Methods: Frontal, temporal and hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27 controls. Corrected atrophy and asymmetry were computed (W-scores). Results: FTD had mild atrophy in the hippocampus (average W-score =− 1.3), severe in the frontal (W-score =− 2.4) and very severe in the temporal lobes (W-score =− 2.9). AD had moderate atrophy in the hippocampus and temporal lobes (W-score =− 1.8 and −1.9, respectively), and very mild frontal atrophy (W-score =− 0.9). Atrophy was more asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the temporal lobes. A discriminant function including the asymmetry values of frontal and temporal regions could separate FTD from AD with 90% sensitivity and 93% specificity. Conclusions: FTD is characterized by a specific pattern of atrophy, more useful than atrophy of single regions in the differential diagnosis. © 2002 Elsevier Science Inc. All rights reserved.

Objectives: Subcortical ischemic vascular disease (SIVD) is frequently associated with cognitive impairment. Rating scales to grade cerebrovascular disease are available, but their sensitivity to the clinical features of mild SIVD is unclear. The aim of the study is to devise and validate a computed tomography (CT)-based visual rating scale sensitive to SIVD in patients with mild cognitive deterioration. Methods: Subjects were 122 consecutive outpatients of a memory clinic (mean age ± SD 77 ± 8 years, 71% females, mean ± SD score of mental state exam 22 ± 3, 61% with clinical dementia rating of 0.5 and 39% of 1). Diffuse leukoaraiosis, fuzzy and patchy lesions, and lacunes were assessed on ordinary CT films and weights were computed based on clinical indicators of SIVD. A continuous score and an ordinal class (0–3) with higher values indicating higher vascular damage were derived. Results: Intraclass correlation coefficients for intra- and interrater reliability of the subcortical vascular score and class ranged from 0.84 to 0.88. Convergent validity versus the scale of Wahlund et al. was good (Spearman’s correlation coefficient between 0.53 and 0.73, p < 0.0005). Known-group validity was assessed versus clinical diagnoses of degenerative (mild cognitive impairment determined by Petersen et al. and NINCDS-ADRDA probable Alzheimer’s disease; n = 58), mixed (possible Alzheimer’s disease with cerebrovascular disease; n = 21), and vascular cognitive impairment (criteria of Erkinjuntti et al. for subcortical vascular dementia and cognitive impairment; n = 43). Patients with degenerative cognitive impairment were more often in the lower subcortical vascular classes (43% in class 0, 43% in class 1, 14% in class 2, and 0% in class 3), while patients with mixed (0, 24, 24, and 52%) and vascular cognitive impairment were in increasingly higher subcortical vascular classes (0, 12, 35, 53%; p < 0.00005). Criterion-related validity was assessed versus clinical indicators of cerebrovascular disease. Hypertension, platelet aggregation inhibitor use, balance, gait, and bradykinesia increased linearly with increasing subcortical vascular class (p for trend Conclusions: This rating scale is valid and sensitive to capture different degrees of SIVD associated with mild cognitive deterioration.

Crude and corrected amygdaloid volumes were computed from magnetic resonance scans in ten patients with frontotemporal dementia (FTD), 25 patients with Alzheimer's disease (AD) and 27 controls. Amygdaloid atrophy was present in FTD (P

Objectives: To identify non-demented individuals with cognitive impairment due to a cerebrovascular etiology among those coming to observation of a memory clinic and to describe their clinical features and outcome. Methods: Patients were enrolled in a prospective study on early cognitive impairment carried out in a Memory Clinic. Mild cognitive impairment of the vascular type (MCI-V) was defined based on modified criteria for subcortical vascular dementia (SVD) by Erkinjuntti and colleagues. Twenty-nine patients with MCI-V (age 78 ± 7, Mini Mental State Exam (MMSE) 24 ± 3) were compared with 14 with mild cognitive impairment of degenerative etiology (MCI) based on the Mayo Clinic criteria (age 72 ± 9, MMSE 25 ± 2), and to 21 patients with frank SVD (age 80 ± 6, MMSE 21 ± 3). Patients were followed over time for 32 ± 8 months. Results: MCI-V patients had a neuropsychological profile characterized by poor performance on frontal tests (Wisconsin card sorting and word fluency) and neurological features of parkinsonism without tremor (impairment of balance and gait). Of those followed for at least 40 months, 50 % of patients with MCI-V and SVD had died, while all MCI patients were still alive (P = 0.03). Of those alive, 68 % of the MCI-V, 52 % of the SVD, and 17 % of the MCI patients had reached one of the following outcomes at 40 months: nursing home placement, functional loss, and cognitive deterioration (P = 0.02). Conclusions: Patients with MCI-V have a distinctive clinical picture and can be identified in a clinical setting. Because of the high frequency of adverse outcomes, very early preventive measures need to be devised.

Behavioral disturbances in Alzheimer's (AD) patients might be caused by environmental factors. The authors tested the hypothesis that delusions in AD might be a result of caregiver's distress. Participants were 22 delusional and 21 nondelusional mild AD patients and their caregivers. Those who cared for nondelusional patients, compared with the delusional patients' caregivers, reported higher levels of distress because of behavioral disturbances other than delusions. When patients were stratified into 2 groups according to median distress value, 64% of the delusional patients and 33% of the nondelusional patients showed a high level of caregiver's distress, chi2(1, N = 43) = 3.94, p = .047. Although final conclusions about the causal direction of the association cannot be drawn, these findings are consistent with the hypothesis that distressed caregivers might use inappropriate coping strategies that, in turn, might favor the development of delusions.

Whether and which genetic factors affect human longevity is unclear. This study assesses the association between the epsilon2 allele of apolipoprotein E (APOE), a putative longevity gene, and extremely old age.This study is based on all centenarians living in Finland in 1991. Subjects were 179 persons (28 men and 151 women) aged 100 years and older (response rate, 97%).The percentages of epsilon2-allele carriers in persons aged 100 to 101, 102 to 103, and 104 years and older were 9% (10/117), 21% (9/42), and 25% (5/20; gender-adjusted p for trend = .01), respectively. The effect was particularly strong in women: 8% (8/100), 18% (6/33), and 28% (5/18; p for trend = .01) by age group, respectively. Low cell numbers prevented clear conclusions being drawn for men. Seventeen percent (30/179) of the adult Finnish population were carriers of the epsilon4 allele, a figure lower than expected, and stable by age group.Carriers of the epsilon2 allele of APOE might be predisposed to reach extremely old age.

Objective—To test the hypothesis that delusions are associated with asymmetric involvement of the temporal lobe regions in Alzheimer’s disease. Methods—Temporal lobe atrophy was assessed with a linear measure of width of the temporal horn (WTH) taken from CT films. Temporal asymmetry was computed as the right/left (R/L) ratio of the WTH in 22 non-delusional and 19 delusional patients with Alzheimer’s disease. Delusional patients had paranoid delusions (of theft, jealousy, persecution). None of the patients had misidentifications or other delusions of non-paranoid content. Results—The R/L ratio indicated symmetric temporal horn size in the nondelusional (mean 1.05 (SD 0.20), and right greater than left temporal horn in the delusional patients (mean 1.30, (SD 0.46); t=2.27,df=39,p=0.03).When patients were stratified into three groups according to the R/L ratio, 47% of the delusional (9/19) and 14% of the non-delusional patients (3/21; ˜ 2 =5.6, df=1, p=0.02) showed right markedly greater than left WTH. Conclusions—Predominantly right involvement of the medial temporal lobe might be a determinant of paranoid delusions in the mild stages of Alzheimer’s disease. (J Neurol Neurosurg Psychiatry 2000;69:187‐191)

Asymmetry of brain structures is common to many species and is even present in utero. Some developmental, pathological, and dementing diseases are associated with alterations in normal anatomical asymmetries. Anatomical asymmetries, however, have been only superficially studied in Alzheimer's disease. Recent evidence indicates that the allele epsilon4 of the apolipoprotein E (ApoE), a well known risk factor for Alzheimer's disease, might play a part in determining some brain morphological changes both in normal carriers and in patients with Alzheimer's disease. This study evaluated the effect of the ApoE genotype on hippocampal asymmetry in patients with Alzheimer's disease carrying 0, 1, and 2 copies of the allele. Volumetric right-left differences of the hippocampi were computed in 28 right handed patients with Alzheimer's disease (14 -/-, 9 epsilon4/-, and 5 epsilon4/4) and 30 controls without detectable cognitive deficit. In controls, the right hippocampus was larger than the left, whereas in patients with Alzheimer's disease this asymmetry was progressively reduced with increasing gene dose of the epsilon4 allele, and the asymmetry was reversed in the epsilon4/4 Alzheimer's disease group. The mean right-left volume differences were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, epsilon4/-, and epsilon4/4 patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose dependent effect of the ApoE epsilon4 allele on hippocampal volume asymmetry in Alzheimer's disease.

Ageing trends in populations are common amongst most European countries. One of the consequences of this trend is the increase of hospitalisation of elderly patients. To better manage the elderly population hospitalisation, it is crucial to obtain a better understanding of this population's clinical and functional conditions and their hospitalisation outcome predictors. The present prospective observational cohort study aimed at studying the variables considered predictive of the length of stay, of destination at discharge, of re-hospitalisation, and of mortality at 6 months of elderly (age64 years, N = 329) admitted to ten geriatric units, having different missions (e.g., cognitive impairment and dementia; movement disorders; bone fractures and immobilisation syndrome; or stroke), of the St. John of God Order during a 4-month-long index period.The patients were monitored from the first day of hospitalisation through the discharge. Researchers filled in a "Patient Schedule" based on a comprehensive set of socio-demographic and clinical variables and standardised assessment tools. We used a standardised telephone interview to re-assess patients at the 6-month follow-up.The BRASS score proved to be a better reliable predictor of length of stay (F = 3.9, p = 0.04) among all variables associated with higher risks of prolonged hospital stay and post-discharge problems. In addition, discharge destination was also predicted by the use of the Tinetti Scale score (OR = 0.95, 95 % CI 0.90-0.99), the Mini Mental State Examination (MMSE) score (OR = 0.1.07, 95 % CI 1.01-1.13) and by independence in daily activity as measured by the IADL scale (OR = 4.09, 95 % CI 1.46-11.44). Motor functioning resulted as a reliable predictor (OR = 2.67, 95 % CI 1.27-5.59) of re-hospitalisation in all the medical units. Lastly, female gender (OR = 0.28, 95 % CI 0.11-0.71) resulted as the only reliable variable associated with a lower mortality risk after discharge.The variables related to the clinical and functional status were reliable predictors for length of stay, for discharge destination, and for re-hospitalisation among older patients admitted to ten geriatric units in Italy. Further research is needed to establish valid and reliable predictors of mortality risk, to develop effective preventive strategies in those vulnerable populations.

The aims of this study were to (i) describe the typology of patients admitted to the day hospital for cognitive disorders of the Alzheimer's Disease Unit, Brescia, Italy, and (ii) describe the diagnostic, therapeutic and rehabilitative interventions carried out. Data are presented on the first 102 consecutive patients admitted to the day hospital. Seventy-five per cent of patients had not previously received an appropriate diagnostic evaluation. The mean length of stay in the day hospital was 5 days for patients receiving diagnostic evaluation only, 2 weeks for those also receiving treatment for medical disorders or behavioural disturbance, and 1 month for cognitive rehabilitation. Though the effectiveness and usefulness of a day hospital service remains largely undemonstrated in terms of user satisfaction and quality of care, the present study suggests a day hospital may have a role in the diagnosis of cognitive disorder.

Sleep symptoms, cognitive, psychic, and physical health variables were assessed in a sample of 449 community-dwelling elders aged 75 and over. The subjects were in a good cognitive and functional condition. Three night sleep symptoms were evaluated: difficulty falling asleep, waking up frequently in the night, and early morning awakenings. For each symptom, respondents were asked to estimate the frequency of the symptom during the past month on a five-point scale. White-collar workers reported the best, and blue-collar workers the poorest quality of sleep: the difference in the difficulty of falling asleep between the two groups was 0.86, of waking up frequently in the night 0.93, of early morning awakenings 1.01 (corresponding to 3 days/month, 5 days/month, and 3.5 days/month, respectively), and of total sleep symptoms 2.81. These unadjusted differences were reduced, respectively, to 0.57, 0.42, 0.54, and 1.53 after adjustment for other factors. Of these, only waking up frequently in the night was not statistically significant. These data show more frequent sleep symptoms in socially disadvantaged occupational groups, suggesting that social factors can significantly affect the quality of sleep in the elderly.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aβ)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aβ in cognitive decline, we analyzed the whole panel of CSF Aβ isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aβ peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aβ species while in sporadic AD Aβ1-42 was the only peptide reduced. A significant independent association between Aβ1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aβ and the most abundant Aβ1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aβ1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.