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

Effects of dog-assisted therapies on cognitive mnemonic capabilities in people affected by Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of dementia in humans and, currently, a valid treatment is lacking. Our goal is to demonstrate the importance and benefits of the relationship with companion animals (considered as co-therapists), intended as a means of facilitating social relations and promoting evident wellbeing in AD patients. The study involved 30 randomly chosen patients with Alzheimer’s disease (group T) and three dogs. The group participated in a total of 24 animal-assisted interventions (AAIs) sessions over a span of 12 weeks, using the Mini-Mental State Examination (MMSE), Wellness and Cognitive Ability Questionnaire (Brief Assessment Cognition or BAC), and Alzheimer’s Disease Assessment Scale (ADAS) as assessment tests. A second group (group C), consisting of 10 people with AD, was enrolled as control group and underwent the same assessment tests but did not benefit from the presence of the dogs. Tests were carried out at time T0 (before starting sessions), T1 (end of sessions), and T2 (two months after last session). People belonging to group T achieved an overall improvement in their perceived state of wellbeing, even on a cognitive and mnemonic plane. However, two months after the end of the sessions, the test results in people suffering from AD decreased towards the baseline (T0). The study shows how such progress can be achieved through activities based on the relationship with an animal, as long as the animal is a steady presence in the life of the patient receiving the intervention. Dogs involved in other dog-assisted therapies have been found suitable also for assisting patients with AD

The Qualitative Scoring MMSE Pentagon Test (QSPT): A New Method for Differentiating Dementia with Lewy Body from Alzheimer's Disease

The differential diagnosis across different variants of degenerative diseases is sometimes controversial. This study aimed to validate a qualitative scoring method for the pentagons copy test (QSPT) of Mini-Mental State Examination (MMSE) based on the assessment of different parameters of the pentagons drawing, such as number of angles, distance/intersection, closure/opening, rotation, closing-in, and to verify its efficacy to differentiate dementia with Lewy Body (DLB) from Alzheimer's disease (AD). We established the reliability of the qualitative scoring method through the inter-raters and intra-subjects analysis. QSPT was then applied to forty-six AD and forty-six DLB patients, using two phases statistical approach, standard and artificial neural network respectively. DLB patients had significant lower total score in the copy of pentagons and number of angles, distance/intersection, closure/opening, rotation compared to AD. However the logistic regression did not allow to establish any suitable modeling, whereas using Auto-Contractive Map (Auto-CM) the DLB was more strongly associated with low scores in some qualitative parameters of pentagon copying, i.e. number of angles and opening/closure and, for the remaining subitems of the MMSE, in naming, repetition and written comprehension, and for demographic variables of gender (male) and education (6–13 years). Twist system modeling showed that the QSPT had a good sensitivity (70.29%) and specificity (78.67%) (ROC-AUC 0.74). The proposed qualitative method of assessment of pentagons copying used in combination with non-linear analysis, showed to be consistent and effective in the differential diagnosis between Lewy Body and Alzheimer's dementia

Recovery from Transient Global Amnesia Following Restoration of Hippocampal and Fronto–Cingulate Perfusion

A patient who suffered a transient global amnesia (TGA) attack underwent regional cerebral blood flow (rCBF) SPECT imaging and neuropsychological testing in the acute phase, after one month and after one year. Neuropsychological testing in the acute phase showed a pattern of anterograde and retrograde amnesia, whereas memory was within age normal limits at follow up. SPECT data were analysed with a within subject comparison and also compared with those of a group of healthy controls. Within subject comparison between the one month follow up and the acute phase detected increases in rCBF in the hippocampus bilaterally; further rCBF increases in the right hippocampus were detected after one year. Compared to controls, significant hypoperfusion was found in the right precentral, cingulate and medial frontal gyri in the acute phase; after one month significant hypoperfusion was detected in the right precentral and cingulate gyri and the left postcentral gyrus; after one year no significant hypoperfusion appeared. The restoration of memory was paralleled by rCBF increases in the hippocampus and fronto-limbic-parietal cortex; after one year neither significant rCBF differences nor cognitive deficits were detectable. In conclusion, these data indicate that TGA had no long lasting cognitive and neural alterations in this patient

Brief practical clinical diagnostic criteria for the neurodegenerative diseases in the elderly

In the literature there is need of clinical and instrumental characterization of all neurodegenerative diseases. Particular attention deserves the timing of the onset of motor or cognitive symptoms, which is extremely useful issue giving the frequent overlapping between neurodegenerative diseases. Aim of this review is to provide a description of typical clinical and imaging features of all neurodegenerative diseases, especially idiopathic Parkinson's disease (PD) and Alzheimer's disease (AD). Particular attention will be devoted to the cluster of symptoms at the moment of the diagnosis. Based on early starting symptoms (cognitive or extrapiramidal) we will introduce criteria to differentiate AD from fronto-Temporal Dementia (FTD), Lewy bodies dementia (DLB) and Vascular dementia (VaD), and between PD, Vascular Parkinsonism (VP) and DLB. All these diseases are characterized by cognitive deficits. PD will be suspected if cognitive impairment occurs at least one year after the onset of the motor symptoms while VP and DLB are more likely if cognitive deficits and motor symptoms appear simultaneously. Finally, we will focus on parkinsonian signs plus other motor symptoms at the time of the diagnosis. The presence of cerebellar or pyramidal signs, with falls and autonomic dysfunction, with or without cognitive deficit should help to consider potential causes of atypical parkinsonism including cortical-basal degeneration (CBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP)

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

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

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

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

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.