ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease.

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 Aß 1-42, increased total and phosphorylated tau, and a higher frequency of the apoε4 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 apoε4 status. ABCG1 CSF-CEC positively correlated with Aß 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.

A case of reversible anti-NMDA-receptor encephalitis: neuropsychological and neuroradiological features.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune encephalitis mainly affecting young women. We report a case of a mild paraneoplastic anti-NMDAR encephalitis in a 31-year-old female with an ovarian immature teratoma. The patient exhibited a severe short-term episodic memory impairment and psychiatric symptoms. A detailed diagnostic work-up including complete clinical and laboratory examinations, neuropsychological assessments, and neuroradiological investigations has been done at the onset and during follow-up. The amnestic syndrome and MRI medial-temporal abnormalities reversed after medical and surgical treatment. The present report indicates that the disease can be rapidly reversible if promptly diagnosed and treated. While the disease has already been described elsewhere, the course of neurospychological deficits in adults is not as much known. Usually, when the diagnosis of anti-NMDAR encephalitis is made, the severity of the disease makes the assessment of the neuropsycological profile particulary challenging. The present report is of interest because it describes the complete neuropsychological profile of a mild form of anti-NMDAR encephalitis.

Enhancing cognitive training effects in Alzheimer's disease: rTMS as an add-on treatment.

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.

The Role of Free and Cued Selective Reminding Test in Predicting [18F]Florbetaben PET Results in Mild Cognitive Impairment and Mild Dementia.

BACKGROUND: Free and Cued Selective Reminding Test (FCSRT) is a reliable cognitive marker for Alzheimer's disease (AD), and the identification of neuropsychological tests sensitive to the early signs of AD pathology is crucial both in research and clinical practice. OBJECTIVE: The study aimed to ascertain the ability of FCSRT in predicting the amyloid load as determined from amyloid PET imaging (Amy-PET) in patients with cognitive disorders. METHODS: For our purpose, 79 patients (71 MCI, 8 mild dementia) underwent a complete workup for dementia, including the FCSRT assessment and a [18F]florbetaben PET scan. FCSRT subitem scores were used as predictors in different binomial regression models. RESULTS: Immediate free recall and delayed free recall were the best predictors overall in the whole sample; whereas in patients <76 years, all models further improved with immediate total recall (ITR) and Index of Sensitivity of Cueing (ISC) resulting the most accurate in anticipating Amy-PET results, with a likelihood of being Amy-PET positive greater than 85% for ITR and ISC scores of less than 25 and 0.5, respectively. CONCLUSION: FCSRT proved itself to be a valid tool in dementia diagnosis, also being able to correlate with amyloid pathology. The possibility to predict Amy-PET results through a simple and reliable neuropsychological test might be helpful for clinicians in the dementia field, adding value to a paper and pencil tool compared to most costly biomarkers.

CSF biomarkers and amyloid PET: concordance and diagnostic accuracy in a MCI cohort.

Brain amyloid deposition is one of the main hallmarks of Alzheimer's disease (AD) and two approaches are available for assessing amyloid pathology in vivo: cerebrospinal fluid (CSF) biomarkers levels and amyloid load visualized by amyloid beta positron emission tomography imaging (Amy-PET) probes. We aimed to investigate the concordance between CSF biomarkers and Amy-PET in a memory clinic cohort. Moreover, using a proper clinical follow-up, we wanted to assess the diagnostic accuracy of CSF and PET biomarkers in predicting the progression of patients with mild cognitive impairment (MCI) to AD dementia. We included 31 MCI patients who underwent [18F]florbetaben PET and CSF sampling (Aß1-42, t-Tau, p-Tau). A semiquantitative visual scan assessment was used to quantify amyloid deposition in 5 brain regions, rating from 1 (negative), to 2 and 3 (positive). CSF biomarkers were considered abnormal if: Aß1-42 < 600 pg/ml, p-Tau/Aß1-42 > 0.08 and t-Tau/Aß1-42 > 0.52. We also applied less lenient cutoffs of 550 pg/ml and 450 pg/ml for Aß1-42. The concordance rate was 77% between Amy-PET and CSF Aß1-42 levels, and 89% between Amy-PET and p-Tau/Aß1-42 and t-Tau/Aß1-42. According to the clinical follow-up, Amy-PET (sensitivity [SE] 93.7%, specificity [SP] 80%) exhibited the best diagnostic accuracy in discriminating AD from non-AD, followed by p-Tau/Aß1-42 ratio and t-Tau/Aß1-42 ratio (SE 93.7%, SP 66.6%), and Aß1-42 levels (SE 81%, SP 60%). The regional uptake of [18F]florbetaben PET in the precuneus and the striatum showed the best SP (86.6%). In discordant cases, the clinical diagnosis was most often in agreement with PET results. In general, concordance between CSF biomarkers and Amy-PET was good, especially when the ratios between CSF amyloid and Tau biomarkers were used. However, Amy-PET proved to be superior to CSF Aß1-42 in terms of diagnostic accuracy for AD, with the possibility to further increase its specificity by focusing the analysis in specific areas such as the precuneus/posterior cingulate cortex and the striatum.

The Incremental Diagnostic Value of [18F]Florbetaben PET and the Pivotal Role of the Neuropsychological Assessment in Clinical Practice.

BACKGROUND: Amyloid pathology is a key feature of Alzheimer's disease (AD) and can be assessed in vivo with amyloid positron emission tomography (PET) imaging. OBJECTIVE: The objective of this study was to evaluate the incremental value of a PET scan with [18F]florbetaben, in terms of changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological assessment, including the Free and Cued Selective Reminding Test (FCSRT). METHODS: A total of 104 patients (69 mild cognitive impairment, 35 dementia), with diagnostic uncertainty after diagnostic workup, were recruited from our memory clinic. [18F]florbetaben PET scans were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating. Clinical diagnosis and diagnostic confidence for AD or non-AD dementia were rated before and after PET result disclosure, as was the impact of PET on the patient management plan. RESULTS: There were 69/104 (66%) [18F]florbetaben positive scans, 51/62 (82%) patients were suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to 83.5±9.1 (p < 0.001), with the greatest impact on diagnosis and confidence in PET negative patients with an initial diagnosis of AD (p < 0.01) and in early-onset patients (p = 0.01). CONCLUSION: Amyloid PET represents a source of added value in dementia diagnosis, with a significant effect on diagnosis and diagnostic confidence. However, the use of a complete neuropsychological assessment has an add-on value on limiting the amyloid PET influence on change of diagnosis, and the real impact of amyloid PET should always be weighed up together with an accurate standardized diagnostic workup.

Stereotypic behaviours in frontotemporal dementia and progressive supranuclear palsy.

INTRODUCTION: The behavioural variant of frontotemporal dementia (bvFTD), and the Richardson variant of progressive supranuclear palsy (PSP-RS) share several clinical signs and symptoms. Since stereotypic behaviours are fairly common in bvFTD, and are also described in other degenerative dementias including Alzheimer's disease, and parkinsonisms with dementia, we aimed to examine the extent to which stereotypies also characterise PSP-RS. METHODS: We compared 53 bvFTD patients with 40 demented PSP-RS patients, seen consecutively as outpatients at four Italian Hospitals. Patients were assessed by the Neuropsychiatric Inventory (NPI); Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive functions; Stereotypy Rating Inventory (SRI) for stereotypies; Unified Parkinson's Disease Rating Scale (UPDRS) for motor function; and Activities of Daily Living (ADL) to assess autonomy in daily life. RESULTS: The groups did not differ for age, illness duration, cognitive functions or total NPI score; PSP-RS had significantly more depressive symptoms and greater motor and autonomy compromise than bvFTD. The groups did not differ significantly on total SRI score, but bvFTD had significantly more cooking and eating stereotypies. Twenty-three (57.5%) PSP-RS and 43 (81%) bvFTD patients had at least one stereotypy; 16/23 (69.5%) PSP-RS and 9/43 (20.9%) bvFTD patients appeared aware of their stereotypies. CONCLUSION: Stereotypies were common in our demented PSP-RS patients. Further studies on earlier stage non-demented PSP patients are required to ascertain whether stereotypies are characteristic of PSP in general or are confined to PSP-RS, and whether they may be used to suggest a PSP diagnosis early in disease course.

Behavioral and Neurophysiological Effects of Transcranial Direct Current Stimulation (tDCS) in Fronto-Temporal Dementia.

Fronto-temporal dementia (FTD) is the clinical-diagnostic term that is now preferred to describe patients with a range of progressive dementia syndromes associated with focal atrophy of the frontal and anterior temporal cerebral regions. Currently available FTD medications have been used to control behavioral symptoms, even though they are ineffective in some patients, expensive and may induce adverse effects. Alternative therapeutic approaches are worth pursuing, such as non-invasive brain stimulation with transcranial direct current (tDCS). tDCS has been demonstrated to influence neuronal excitability and reported to enhance cognitive performance in dementia. The aim of this study was to investigate whether applying Anodal tDCS (2 mA intensity, 20 min) over the fronto-temporal cortex bilaterally in five consecutive daily sessions would improve cognitive performance and behavior symptoms in FTD patients, also considering the neuromodulatory effect of stimulation on cortical electrical activity measured through EEG. We recruited 13 patients with FTD and we tested the effect of Anodal and Sham (i.e., placebo) tDCS in two separate experimental sessions. In each session, at baseline (T0), after 5 consecutive days (T1), after 1 week (T2), and after 4 weeks (T3) from the end of the treatment, cognitive and behavioral functions were tested. EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed at the same time points in nine patients. The present findings showed that Anodal tDCS applied bilaterally over the fronto-temporal cortex significantly improves (1) neuropsychiatric symptoms (as measured by the neuropsychiatric inventory, NPI) in FTD patients immediately after tDCS treatment, and (2) simple visual reaction times (sVRTs) up to 1 month after tDCS treatment. These cognitive improvements significantly correlate with the time course of the slow EEG oscillations (delta and theta bands) measured at the same time points. Even though further studies on larger samples are needed, these findings support the effectiveness of Anodal tDCS over the fronto-temporal regions in FTD on attentional processes that might be correlated to a normalized EEG low-frequency pattern.

The Progression of Alzheimer's Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up.

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.

Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. OBJECTIVE: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4. METHODS: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aß42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. RESULTS: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ɛ4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454). CONCLUSION: 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.

Brain Metabolism Correlates of the Free and Cued Selective Reminding Test in Mild Cognitive Impairment.

Free and Cued Selective Reminding Test (FCSRT) measures immediate and delayed episodic memory and cueing sensitivity and is suitable to detect prodromal Alzheimer's disease (AD). The present study aimed at investigating the segregation effect of FCSRT scores on brain metabolism of memory-related structures, usually affected by AD pathology, in the Mild Cognitive Impairment (MCI) stage. A cohort of forty-eight MCI patients underwent FCSRT and 18F-FDG-PET. Multiple regression analysis showed that Immediate Free Recall correlated with brain metabolism in the bilateral anterior cingulate and delayed free recall with the left anterior cingulate and medial frontal gyrus, whereas semantic cueing sensitivity with the left posterior cingulate. FCSRT in MCI is associated with neuro-functional activity of specific regions of memory-related structures connected to hippocampal formation, such as the cingulate cortex, usually damaged in AD.

Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation.

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

Degenerative jargon aphasia: unusual progression of logopenic/phonological progressive aphasia?

Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction.