The treatment of Alzheimer's disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning.The present study provides important hints on the promising therapeutic use of rTMS in AD.

Dysregulation of cholesterol homeostasis in the CNS has been associated with various neurodegenerative disorders, including Parkinson's, Huntington's, and Alzheimer's disease (AD) (1). Evidence supporting this relationship derives, for example, from recent genomic-wide association studies that have identified several loci involved in lipid metabolism among the AD-susceptible genes (2, 3). For example, the 4 allele of the APOE gene encoding apoE is undoubtedly the most strong genetic risk factor, but recently other genes have been identified such as BIN1, CLU, PICALM, ABCA7, ABCA1, ABCG1, and SORL1 (4). However, the exact mechanisms linking cholesterol homeostasis derangement and AD pathogenesis are far from being understood and conflicting data have been released, describing both increased, decreased, or no change of cholesterol levels in different brain sections and the cerebrospinal fluid (CSF) of AD patients compared with control subjects (5). Approximately 30% of the total body cholesterol is present in the brain, where it plays a crucial role in the synaptogenesis and maintenance of neuronal plasticity and function (6). The brain relies on endogenous local cholesterol synthesis because it is isolated from other body compartments by the blood-brain barrier (7, 8). While cholesterol synthesis in neurons and glial cells is very high during embryogenesis, adult neurons progressively lose this capacity and most exclusively rely on cholesterol produced from other Abstract HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes toward the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer's disease (AD) by analyzing AD (n = 37) patients, non-AD dementia (non-AD DEM; n = 16) patients, and control subjects (n = 39). As expected, AD patients showed reduced CSF A 1-42, increased total and phosphorylated tau, and a higher frequency of the apo4 genotype. ABCA1-and ABCG1-mediated CSF-CEC was markedly reduced in AD (73% and 33%, respectively) but not in non-AD DEM patients, in which a reduced passive diffusion CEC (40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (24%) compared with controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apo4 status. ABCG1 CSF-CEC positively correlated with A 1-42 (r = 0.305, P = 0.025), while ABCA1 CSF-CEC inversely correlated with total and phosphorylated tau (r = 0.348, P = 0.018 and r = 0.294, P = 0.048, respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.

These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.

Background: The rate of cognitive and functional decline in Alzheimer’s disease (AD) changes across individuals.Objectives: Our purpose was to assess whether the concept of “fast decline” really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD.Methods: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into “fast decliners” (n = 62), defined by a loss ≥5 points on the MMSE score within the first year from the baseline; “intermediate decliners” (n = 37), by a loss ≥5 points after the first year and before the 18th month; or “slow decliners” (n = 225), composed of the remaining patients.Results: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis.Conclusions: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called “fast decliners”. This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.

Stereotypies are simple or complex involuntary/unvoluntary behaviors, common in fronto-temporal dementia (FTD), but not studied in other types of degenerative dementias. The aim was to investigate stereotypy frequency and type in patients with FTD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease with dementia (PDD) in a multicenter observational study; and to investigate the relation of stereotypies to cognitive, behavioral and motor impairment. One hundred fifty-five consecutive outpatients (45 AD, 40 FTD, 35 PSP and 35 PDD) were studied in four hospitals in northern Italy. Stereotypies were examined by the five-domain Stereotypy Rating Inventory. Cognition was examined by the Mini Mental State and Frontal Assessment Battery, neuropsychiatric symptoms by the Neuropsychiatric Inventory, and motor impairment and invalidity by the Unified Parkinson's Disease Rating Scale part III, and activities of daily living. Stereotypies were present in all groups. FTD and PDD had the greatest frequency of one-domain stereotypies; FTD also had the greatest frequency of two-or-more domain stereotypies; movement stereotypies were the most common stereotypies in all groups. AD patients had fewer stereotypies than the other groups. Stereotypies are not exclusive to FTD, but are also fairly common in PSP and PDD, though less so in AD. Stereotypies may be underpinned by dysfunctional striato-frontal circuits, known to be damaged in PSP and PDD, as well as FTD.