The Dynamic Interplay between Loss of Semantic Memory and Semantic Learning Capacity: Insight from Neologisms Learning in Semantic Variant Primary Progressive Aphasia.

Semantic Variant of Primary Progressive Aphasia (svPPA) has often been considered as a loss of knowledge stored in semantic memory, but might also be due to a general disruption of mechanisms allowing the acquisition, storage, and retrieval of semantic memories. In order to assess any parallelism in svPPA patients between loss of semantic knowledge and inability to acquire new semantic information, we administered a battery of semantic learning tasks to healthy individuals and svPPA patients, where they were requested to learn new conceptual representations and new word forms, and to associate the former with the latter. A strong relation was found between loss of semantic knowledge and disruption of semantic learning: (a) patients with severe svPPA had the lowest scores in the semantic learning tasks; (b) significant correlations were found between scores obtained in semantic learning tasks and scores obtained in semantic memory disorders in svPPA patients.

Allochiria for spatial landmarks as the presenting feature of posterior cortical atrophy.

Allochiria refers to the mislocation of stimuli to the corresponding position on the opposite side of the body or hemispace. It is most often, although not exclusively, reported in the tactile modality and typically in association with unilateral neglect. We describe a patient presenting with a 2-year history of topographical disorientation without other cognitive complaints. We conducted a systematic exploration of his topographical problems to identify their cognitive substrate. Standard neuropsychological examination revealed no abnormalities. Notably, he performed well on perceptual, spatial, and constructional tasks. No signs of neglect were elicited. A tailored battery of tests was administered, involving road maps and landmarks, and designed to replicate the situations in which he experienced symptoms. The experimental tests showed no evidence of topographical agnosia or amnesia for landmarks and their spatial relationships and no hemispatial neglect. Nevertheless, the patient exhibited a systematic tendency to translocate topographical landmarks sited on the left to the right side. The phenomenon, consistent with representational allochiria, occurred exclusively for topographical landmarks, and was present along both personally familiar and new learned routes. Over the next two years more widespread visuoperceptual and spatial deficits emerged, with Balint and Gerstmann syndromes. Functional imaging revealed hypoperfusion of the occipito-parietal regions and amyloid PET the presence of amyloid plaques. A diagnosis was made of posterior cortical atrophy, the visual variant of Alzheimer's Disease. To our knowledge this is the first case of topographical disorientation presenting with selective representational allochiria and the first report of allochiria as an early sign of posterior cortical atrophy. The case sheds light on the cognitive basis of allochiria and on a puzzling clinical presentation of neurodegenerative brain disease.

Cerebrospinal Fluid α-Calcitonin Gene-Related Peptide: A Comparison between Alzheimer's Disease and Multiple Sclerosis.

Alzheimer's disease (AD) and Multiple Sclerosis (MS) represent an emerging health problem on a global scale, as they are responsible for a significant contribution to the burden of disability in Western countries. Limited numbers of cerebrospinal fluid (CSF) diagnostic markers are available for each disease (amyloid and tau deposition markers for AD and oligoclonal bands for MS) representing mostly state markers that provide few, if any, clues about the severity of the clinical phenotype. α-CGRP is a neuropeptide implied in nociception, vasodilation, synaptic plasticity and immune functions. This neuropeptide is expressed in encephalic regions connected to memory, attention, autonomic and behavioral functions and is also expressed by spinal motor neurons. The present work confronted α-CGRP levels between 19 AD, 27 MS and 17 control subjects using an ELISA/EIA assay. We measured higher CSF α-CGRP contents in control subjects with respect to AD, as shown in previous studies, as well as in MS patients in comparison to AD. The control subjects and MS patients did not significantly differ between each other. We did not observe a relationship between CSF protein content, albumin quotient and α-CGRP. We also describe, retrospectively, an association between higher CSF CGRP content and higher MRI overall lesion count in MS and between lower α-CGRP and worse attention and visuo-perceptual skills in AD. We speculate that α-CGRP could be differentially involved in both disabling diseases.

Association between homocysteine levels and cognitive profile in Alzheimer's Disease.

BACKGROUND: Growing evidence suggests that hyperhomocysteinemia (HHcy) constitutes a risk factor for Alzheimer's Disease (AD). The impact of HHcy on cognitive functions has mainly been investigated using screening neuropsychological tests that provide general, unspecific measures of cognitive level. Since an association between HHcy and temporo-mesial atrophy has been documented, we predicted that a fine-grained analysis of neuropsychological performance should show stronger Hcy effects on memory scores than on other cognitive scores. OBJECTIVE: To determine the influence of Hcy level on cognitive profile evaluated with specific, sensitive neuropsychological tests in a wide AD cohort. METHODS: 323 patients with AD were enrolled in a cross-sectional study and underwent a neuropsychological examination exploring several cognitive domains (memory, language, visuoperception, visuospatial abilities, executive function, constructional praxis, ideomotor praxis). The effects of Hcy levels and other risk factors (including cholesterol, smoking habits, triglycerides, apoEε4 allele) were analysed. RESULTS: Generalized Linear Model detected a significant drop in performance with increasing Hcy in 6/19 measures of cognitive functions, namely, in memory performance tasks as well as in Luria's motor planning test, with effect sizes ranging 1.4%-2.8% (Eta-squared), partialling out effects of other predictors. CONCLUSIONS: HHcy was associated with poor performance in short and long-term spatial and verbal memory more than with other cognitive dysfunctions. These results support the hypothesis that medial temporal networks might be vulnerable to HHcy, consistently with data from neuroimaging studies suggesting a link in AD between temporal atrophy and HHcy; the effect on Luria's motor planning task suggests further involvement of frontal structures.

Sleep actigraphic patterns and cognitive status.

We performed an actigraphic assessment of sleep characteristics in healthy subjects and patients with cognitive impairment. Thirty subjects were included and classified into controls (10 subjects), mild cognitive impairment (10 patients) and mild-to-moderate Alzheimer's disease (10 patients). Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Participants had a 7-day actigraphic record. Sleep parameters collected were time in bed, total sleep time, sleep efficiency, sleep latency, wakefulness after sleep onset, number of awakenings, and mean motor activity. Significant differences between mild cognitive impairment and controls patients were found for sleep latency (p = 0.05); Alzheimer's disease patients had significantly worse scores for Pittsburgh Sleep Quality Index (p = 0.01), time in bed (p = 0.001), total sleep time (p = 0.04), sleep latency, sleep efficiency, motor activity (p = 0.0001) and wakefulness after sleep onset (p = 0.001) compared to controls. When comparing Alzheimer's disease and mild cognitive impairment, differences were significant for sleep latency (p = 0.01), wakefulness after sleep onset (p = 0.004), sleep efficiency, number of awakenings and motor activity (p = 0.0001). In addition to showing a high prevalence of sleep alterations in subjects with cognitive impairment, our data suggest that they are evident from the earliest stages of cognitive decline. Further studies are needed to assess whether early correction of sleep alterations can positively influence the evolution of cognitive impairment. The opportunity to provide clinically meaningful information with a simple assessment of sleep characteristics based on actigraphy suggests that wider use of the approach in patients with cognitive decline should be considered.

The neural bases of discourse semantic and pragmatic deficits in patients with frontotemporal dementia and Alzheimer's disease.

Neuropsychological research on language has largely focused on how the brain processes single words and sentences whose meaning does not depend on the context or on the intentions of the speaker. Fewer studies have investigated the neurobiological bases of discourse semantics and pragmatics in patients and healthy individuals. We studied discourse semantic and pragmatic skills in patients with behavioral variant frontotemporal dementia (bvFTD) or Alzheimer's disease (AD) in comparison to healthy controls. Our goal was to assess whether and how the two patient groups differ in their cognitive and behavioral profiles, and whether these differences may be traced back to disease-specific patterns of neuronal hypometabolism. We combined PET imaging with standard neuropsychological assessment tools and a dedicated test battery designed to evaluate discourse semantics and pragmatics in patients with brain lesions or neurological disorders. We found that AD and bvFTD patients were both impaired compared to controls in discourse comprehension, but largely spared in single word comprehension. Importantly, we also found evidence for behavioral impairments specific to each disease, associated with different brain damage patterns. Compared to AD and controls, bvFTD patients had, behaviorally, more difficulty in evaluating whether certain inferences follow from discourse and in identifying humorous completions of stories; neurally, they had greater damage to medial and lateral regions of PFC. AD patients showed a different pattern of errors in a humor comprehension task than bvFTD patients and controls, and they showed greater posterior temporal and parietal cortical depletion. Both groups had comparable difficulties with understanding idioms and indirect requests. Finally, bvFTD-specific errors were correlated with the severity of hypometabolism in bvFTD. We discuss these results in light of previous research on the dementias as well as consequences for models of semantics and pragmatics in the brain.

Insight in frontotemporal dementia and progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) and behavioural variant frontotemporal dementia - (bv-FTD) share common neuropsychological features except for online monitoring awareness. Therefore, the aim of our study is to explore if this assessment could be used in standard clinical practice. MATERIALS AND METHODS: We retrospectively analyse 93 subjects (27 FTD, 25 PSP, 42 healthy controls). Neuropsychological and instrumental examinations were performed for each patient. RESULTS: FTD patients made fewer self-corrections than PSP patients despite a similar number of total errors. We also performed ROC curves: the area under the curve (AUC) is 0.79. A model for a logistic regression was also developed: the only significant predictor is the number of self-corrections (p = 0.004 ß = 1244). DISCUSSION AND CONCLUSIONS: In conclusion, our findings show online awareness is more compromised in FTD patients than in PSP patients. This difference could be useful for making a differential diagnosis between the two diseases: for each extra point in number of self-corrections the probability of suffering from PSP increases by about three and a half times (OR 3.47).

Inter-rater reliability of primitive signs in dementia.

OBJECTIVES: The aim of the present study is to explore inter-rater reliability of primitive signs in a group of patients assessed for dementia. PATIENTS AND METHODS: 97 patients admitted to our University Hospital for cognitive impairment were enrolled in the study. The mean age was 73.04 ±â€¯8.68 (53 females and 44 males). All patients were examined by two cognitive neurologists in a blind fashion. The grasp reflex, the snout reflex, the glabella tap reflex and the palmomental reflex were elicited according to the current literature. Moreover, we add a stretch reflexes (the masseter reflex) to our battery. RESULTS: The most frequent primitive reflex was the palmomental reflex followed by the glabella tap, snout, and grasp. The inter-rater reliability was measured for each primitive reflex: grasp reflex (0.884) have a strong correspondence; the glabella tap (0.556), the palmomental (0.516) and the snout reflex (0.445) have otherwise a weak correspondence. The masseter reflex reaches a moderate agreement (0.662). All the measurements reached statistical significance (p < 0.005). CONCLUSION: The results of the study show weak to substantial agreement for primitive signs and the masseter reflex as expressed by the low-to-high kappa values.

Selective associative phonagnosia after right anterior temporal stroke.

We report the case of a 48 year old men who developed a selective impairment in famous voice recognition after ischemic stroke in right subcortical structures (lenticular nucleus and head of the caudate) and right anterior temporal lobe. He underwent fibrinolytic treatment. During the following days he progressively recovered and was discharged without neurological focal sign. Patent foramen ovale was found. When he got back to his house he noticed that he was unable to recognize the voice of his favoured singers and needed to ask who was the singer to his relatives. Neuropsychological examination revealed a selective impairment in famous voice recognition in the absence of alteration of voice perception, face perception and famous face recognition. All other neuropsychological domains were spared. In particular language, memory and executive functions were intact. Neuroimaging carried out by means of PET and MRI revealed two small ischemic lesions in the right subcortical region, involving lenticular and caudate nuclei and in the right temporal pole. To our knowledge, this is the first case described in literature of a patient showing a selective associative phonagnosia after right anterior temporal stroke. The present case helps to clarify the brain circuits underlying famous voice recognition and adds evidence in favour of a right hemisphere involvement in processing knowledge of familiar voices. These findings are discussed in relation to current models of brain organization of person-specific and general semantic knowledge.

Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship.

BACKGROUND: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. OBJECTIVE: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. METHODS: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. RESULTS: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. CONCLUSIONS: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration.

Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation.

Famous faces and voices: Differential profiles in early right and left semantic dementia and in Alzheimer's disease.

BACKGROUND: Famous face and voice recognition is reported to be impaired both in semantic dementia (SD) and in Alzheimer's Disease (AD), although more severely in the former. In AD a coexistence of perceptual impairment in face and voice processing has also been reported and this could contribute to the altered performance in complex semantic tasks. On the other hand, in SD both face and voice recognition disorders could be related to the prevalence of atrophy in the right temporal lobe (RTL). OBJECTIVE: The aim of the present study was twofold: (1) to investigate famous faces and voices recognition in SD and AD to verify if the two diseases show a differential pattern of impairment, resulting from disruption of different cognitive mechanisms; (2) to check if face and voice recognition disorders prevail in patients with atrophy mainly affecting the RTL. MATERIALS: To avoid the potential influence of primary perceptual problems in face and voice recognition, a pool of patients suffering from early SD and AD were administered a detailed set of tests exploring face and voice perception. Thirteen SD (8 with prevalence of right and 5 with prevalence of left temporal atrophy) and 25 CE patients, who did not show visual and auditory perceptual impairment, were finally selected and were administered an experimental battery exploring famous face and voice recognition and naming. Twelve SD patients underwent cerebral PET imaging and were classified in right and left SD according to the onset modality and to the prevalent decrease in FDG uptake in right or left temporal lobe respectively. Correlation of PET imaging and famous face and voice recognition was performed. RESULTS: Results showed a differential performance profile in the two diseases, because AD patients were significantly impaired in the naming tests, but showed preserved recognition, whereas SD patients were profoundly impaired both in naming and in recognition of famous faces and voices. Furthermore, face and voice recognition disorders prevailed in SD patients with RTL atrophy, who also showed a conceptual impairment on the Pyramids and Palm Trees test more important in the pictorial than in the verbal modality. Finally, in 12SD patients in whom PET was available, a strong correlation between FDG uptake and face-to-name and voice-to-name matching data was found in the right but not in the left temporal lobe. DISCUSSION: The data support the hypothesis of a different cognitive basis for impairment of face and voice recognition in the two dementias and suggest that the pattern of impairment in SD may be due to a loss of semantic representations, while a defect of semantic control, with impaired naming and preserved recognition might be hypothesized in AD. Furthermore, the correlation between face and voice recognition disorders and RTL damage are consistent with the hypothesis assuming that in the RTL person-specific knowledge may be mainly based upon non-verbal representations.

Obstructive Sleep Apnea Syndrome: An Emerging Risk Factor for Dementia.

Epidemiological studies have suggested that obstructive sleep apnea syndrome (OSAS) may increase the risk of developing cognitive impairment. In patients with Alzheimer's disease (AD), the prevalence of OSAS is much higher than that expected in cognitively healthy subjects. A deeper knowledge of the pathophysiological link between OSAS and AD and the demonstration that OSAS may directly influence the development of cognitive alterations, would increase prevention and treatment strategies for AD patients. In this article, we discuss the evidence of the association between OSAS and dementia. Moreover, we present data about the functional and anatomic cerebral changes induced by OSAS and the possible effects on cognitive activities and on AD pathogenesis. The possibility to positively influence cognitive impairment by OSAS treatment will be also discussed.

Semantic fluency: cognitive basis and diagnostic performance in focal dementias and Alzheimer's disease.

Semantic fluency is widely used both as a clinical test and as a basic tool for understanding how humans extract information from the semantic store. Recently, major efforts have been made to devise fine-grained scoring procedures to measure the multiple cognitive processes underlying fluency performance. Nevertheless, it is still unclear how many and which independent components are necessary to thoroughly describe performance on the fluency task. Furthermore, whether a combination of multiple indices can improve the diagnostic performance of the test should be assessed. In this study, we extracted multiple indices of performance on the semantic fluency test from a large sample of healthy controls (n = 307) and patients (n = 145) suffering from three types of focal dementia or Alzheimer's Disease (AD). We found that five independent components underlie semantic fluency performance. We argue that these components functionally map onto the generation and application of a search strategy (component 2), to the monitoring of the overall sequence to avoid repetitions (component 3) and out-of-category items (component 4), and to the full integrity of the semantic store (component 5). The integrated and effective work of all these components would relate to a "general effectiveness" component (component 1). Importantly, while all the focal dementia groups were equally impaired on general effectiveness measures, they showed differential patterns of failure in the other components. This finding suggests that the cognitive deficit that impairs fluency differs among the three focal dementia groups: a semantic store deficit in the semantic variant of primary progressive aphasia (sv-PPA), a strategy deficit in the non-fluent variant of primary progressive aphasia (nfv-PPA), and an initiation deficit in the behavioural variant of fronto-temporal dementia (bv-FTD). Finally, we showed that the concurrent use of multiple fluency indices improves the diagnostic accuracy of semantic fluency both for focal dementias and for AD. More generally, our study suggests that a formal evaluation of fine-grained patterns of performance would improve the diagnostic accuracy of neuropsychological tests.