Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration.

OBJECTIVE: To examine the relationship between empathy and cognition in frontotemporal lobar degeneration (FTLD). BACKGROUND: Theoretical models suggest empathy has multiple cognitive and affective subcomponents, and recent studies suggest that performance on specific cognitive tests may predict empathy. Qualitative behavioral studies of patients with FTLD suggest empathy loss may occur directly as a result of damage to frontal and temporal structures. METHOD: First-degree relatives used the Interpersonal Reactivity Index (IRI), a measure of cognitive and emotional empathy, to rate 18 patients with frontotemporal dementia (FTD), 19 patients with semantic dementia (SD), 16 patients with Alzheimer disease (AD), and 10 age-matched healthy control subjects (NC). Subjects also underwent cognitive testing. RESULTS: Both FTD and SD groups showed significantly lower levels of empathy than either ADs or NCs. SDs showed disruption of both emotional and cognitive empathy, whereas FTDs showed only disruption of cognitive empathy. Regressions controlling for general cognitive impairment showed 32% of the variance in Perspective Taking score was predicted by Category Fluency (P < 0.001), and 25% of the variance in Fantasy score was accounted for by Phonemic Fluency (P < 0.001). CONCLUSIONS: Although cognitive empathy is at least partly reliant on frontal structures, the emotional components of empathy are likely mediated by structures in the temporal lobes.     

Portraits of artists: emergence of visual creativity in dementia

As a uniquely human talent that has evolved from prehistoric cave paintings, art draws on many brain areas responsible for various cognitive processes. The pattern of degeneration in dementia leads to predictable changes in art. The visuospatial deficits in Alzheimer disease lead to less precision and attention to spatial relationships. In some cases of frontotemporal dementia, artistic creativity appears anew as the disease develops. The artwork is approached in a compulsive manner and is often realistic or surrealistic in style. Art in the context of dementia provides a unique window into the cognitive processes of various brain regions and an opportunity for rehabilitation.     

Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline

OBJECTIVES: To define the cognitive characteristics of Pick disease (PcD), and to determine which features distinguish PcD from Alzheimer disease (AD), in a cross-sectional and longitudinal study. METHODS: The participants were 44 patients with PcD (10 pathologically verified), 121 patients with AD (14 pathologically verified), and 60 normal control subjects. We obtained information regarding the initial symptom of dementia from each patient's caregiver, estimated global dementia severity by the Blessed Dementia Scale and the Activities of Daily Living Scale, and assessed specific cognitive domains by administering 10 tests of memory, language, visuospatial, and reasoning abilities and selective attention. RESULTS: Among initial symptoms reported by caregivers, personality change and language impairment were significantly more common in PcD than AD; deficits in memory were common in both groups but more prevalent in AD (P<.001). At initial cognitive testing, the scores of patients with PcD were inferior to those of normal controls on all tests, except on a measure of visuospatial function; the scores of patients with AD were inferior to those of controls on all tests. Patients with PcD were superior to patients with AD on measures of explicit memory (P<.001) and visuospatial function (P = .001) but had greater impairments on the Activities of Daily Living Scale (P<.05). During the course of illness, patients with PcD declined significantly faster than those with AD on language tests and on global measures of dementia severity (P<.05), whereas measures of explicit memory and visuospatial and reasoning abilities worsened equally in both patient groups. CONCLUSIONS: There is a characteristic cognitive profile and course of dementia in PcD. Nonetheless, cognitive test performance does not clearly distinguish PcD from AD.     

Posed facial emotional expression in brain-damaged patients

Posed emotional facial expression was examined in brain-damaged adults with right (RBD) or left (LBD) hemisphere cerebrovascular lesions and in matched normal controls (NC). Subjects were videotaped while posing eight facial expressions (positive and negative) under two elicitation conditions (verbal command and visual imitation). Expressions were rated by four na?ve judges for intensity, category accuracy, and valence accuracy. RBDs were significantly more impaired than LBDs or NCs on category and valence accuracy, while LBDs posed expressions with significantly more intensity than RBDs or NCs. These findings held for positive emotions only. The results for category accuracy replicate an earlier report (Borod et al., 1986) which utilized a different rating procedure. Finally, expressions posed to visual imitation were rated as more intense and more accurate than those posed to verbal command.     

Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia

BACKGROUND: The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. OBJECTIVE: To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. DESIGN: Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. MAIN OUTCOME MEASURE: Plasma levels of sRAGE. RESULTS: Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). CONCLUSIONS: Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.     

A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis

BACKGROUND: Early-onset familial Alzheimer disease is caused by mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes. Phenotypic diversity has been reported to be associated with various mutations in PSEN1. Various mutations of PSEN1 have been reported in cases of early-onset Alzheimer disease with spastic paraparesis. OBJECTIVE: To describe a novel mutation in the PSEN1 gene associated with early-onset Alzheimer disease with spastic paraparesis. PATIENT AND METHODS: The patient was a 27-year-old man who developed early-onset dementia with spastic paraparesis. We examined sequences of the PSEN1, PSEN2, and APP genes from the patient and his family. To detect a possible mutation effect on the production of amyloid-beta peptide (Abeta), transfected HEK293 cells were examined for Abeta42 and Abeta40 production. RESULTS: We found a novel mutation (Leu85Pro) in PSEN1. This mutation influenced the production of Abeta, resulting in a 2-fold elevation of Abeta42 production and of the Abeta42/40 ratio. CONCLUSION: To our knowledge, this is the first report of very early-onset Alzheimer disease with spastic paraparesis and with the visual variant form of the disease, which is associated with visuospatial cognitive disorder. The Leu85Pro mutation in PSEN1 was pathogenic.     

Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia

BACKGROUND: There are inconsistencies in published reports regarding the profile of cognitive impairments in vascular dementia, and its differentiation from Alzheimer's disease. OBJECTIVES: To identify the overall profile of cognitive impairment in subcortical vascular dementia as compared with Alzheimer's disease; and the tests which best discriminate between these groups. METHODS: 57 subjects participated: 19 with subcortical vascular dementia, 19 with Alzheimer's disease, and 19 controls. The dementia groups were matched for age, education, and general levels of cognitive and everyday functioning. Subcortical vascular dementia was defined by clinical features (prominent vascular risk factors plus a previous history of transient ischaemic events or focal neurological signs) and substantial white matter pathology on magnetic resonance imaging. All subjects were given a battery of 33 tests assessing episodic and semantic memory, executive/attentional functioning, and visuospatial and perceptual skills. RESULTS: Despite a minimal degree of overall dementia, both patient groups had impairments in all cognitive domains. The Alzheimer patients were more impaired than those with vascular dementia on episodic memory, while the patients with vascular dementia were more impaired on semantic memory, executive/attentional functioning, and visuospatial and perceptual skills. Logistic regression analyses showed that the two groups could be discriminated with 89% accuracy on the basis of two tests, the WAIS logical memory--delayed recall test and a silhouette naming test. CONCLUSIONS: Subcortical vascular dementia and Alzheimer's disease produce distinctive profiles of cognitive impairment which can act as an adjunct to diagnosis. Many of the neuropsychological deficits thought to characterise Alzheimer's disease are also found in subcortical vascular dementia.     

Evaluating atypical dementia syndromes using positron emission tomography with carbon 11 labeled Pittsburgh Compound B

CONTEXT: A progressive decline in episodic memory affecting activities of daily living is the usual clinical presentation of Alzheimer disease. However, patients presenting with atypical or focal clinical symptoms such as language or visuospatial dysfunction often pose a diagnostic challenge. OBJECTIVE: To explore the presence and topography of beta amyloid (Abeta) as measured by carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) in patients with atypical presentations of dementia. DESIGN, SETTING, AND PARTICIPANTS: At a tertiary referral center for memory disorders, 15 healthy controls, 10 patients with Alzheimer disease, a patient with primary progressive aphasia (PPA), and a patient with posterior cortical atrophy (PCA) underwent (11)C-PiB positron emission tomographic studies. Retention of (11)C-PiB was compared between different groups using statistical parametric mapping. MAIN OUTCOME MEASURE: The topography of cortical (11)C-PiB binding in atypical vs typical Alzheimer disease. RESULTS: Cortical (11)C-PiB binding was higher in the group with Alzheimer disease and in the patients with PPA and PCA than the controls (P < .001). Both patients with atypical dementia had a similar (11)C-PiB binding pattern to Alzheimer disease although (11)C-PiB retention was higher on the left cerebral hemisphere in the patient with PPA (P < .01) and higher in the occipital cortex in the patient with PCA (P < .01). CONCLUSIONS: The presence of distinctive focal (11)C-PiB retention patterns was demonstrated in 2 patients with atypical onset of dementia. Pittsburgh Compound B has the potential to facilitate differential diagnosis of dementia and identify patients who could benefit from specific therapeutic strategies aimed at beta amyloid reduction.     

Neuropsychological differences between the dementias of Alzheimer's and Parkinson's diseases

The question of whether dementia of the Alzheimer type and dementia associated with Parkinson's disease are clinically separable is controversial. We examined possible neuropsychological differences in these two patient groups matched for overall severity of dementia. Patients with dementia of the Alzheimer type had more severe impairment on measurements of memory, language, and orientation, and, unlike patients with Parkinson's disease, there was evidence of apraxia. Patients with Parkinson's disease had more severe impairment related to speed of information processing, and, unlike patients with dementia of the Alzheimer type, they also had disturbance of mood. The nature of visuospatial abnormalities also differentiated the two groups. The pattern of neuropsychological differences is consistent with the cortical-subcortical hypothesis.     

Development and validation of a test for early diagnosis of dementia with differentiation from depression (TFDD)

Psychometric tests used for the early detection of dementia often are seen as too difficult or too complex. Classical neuropsychologic tests were not developed for this purpose. Sensitivity and specificity to discriminate "healthy" vs. "ill" are low. For measuring both dementive and depressive symptoms, so far no test has been published. The objective of this study was to develop a sensitive and specific test for dementia that is easy to administer and to evaluate. Moreover, it should discriminate dementia from depressive pseudodementia. With respect to former studies, items were selected that recognized patients in the beginning of the disease. Additionally, depressive symptoms were rated. With the items for dementia, 88 patients with dementia of the Alzheimer type, 52 patients with depressive disorder and 37 healthy elderly controls were investigated. In this group of already diagnosed patients, the test reached a sensitivity and specificity of 100 percent (healthy elderly controls vs. patients with Alzheimer's disease: n = 125, U = 0, p < 0.001; patients with depressive disorder vs. patients with Alzheimer's disease: n = 140, U = 0, p < 0.001; healthy elderly controls vs. patients with depressive disorder: n = 89, U = 485.5, p < 0.001). For the dementia items, the inter-rater-reliability was rs = 0.996 (p < 0.001, n = 18), for the depression items it was rs = 0.753 (n = 18, p < 0.001). The test-retest-reliability was rs = 0.868 (p < 0.001, n = 35) for the dementia items and rs = 0.7 (n = 8, p < 0.05) for the depression items. These validation data will make the test useful for practitioners. Its ability to discriminate patients suffering from dementia of the Alzheimer type from healthy controls is comparable to tests consuming more time.     

Exploring visuospatial short-term memory defect in Alzheimer's disease

Abstract

The present study aimed at controlling two variables that may affect the visuospatial short-term memory of Alzheimer patients: visuospatial coding efficiency and response modality. Thirty patients affected by Alzheimer-type dementia with relatively spared visuo-perceptual functions were tested under three conditions, all of which employed the same kind of stimuli (visuospatial patterns). At all memory tasks, patients achieved scores significantly lower than those of 30 age and education-matched normal subjects. Patients did not benefit from longer presentation time, nor did their performance improve with pointing response modality, although they performed perceptual pattern recognition as well as did controls. These data confirm that visuospatial immediate memory capacity is reduced in dementia.     

Cinguloparietal atrophy distinguishes Alzheimer disease from semantic dementia

BACKGROUND: Progressive brain atrophy is associated with Alzheimer disease (AD) and other dementias. Regional differences in brain atrophy may reflect clinical features of disease. OBJECTIVE: To identify regions of cerebral atrophy that are associated with AD vs other dementias. SETTING: University hospital dementia clinic. PARTICIPANTS: Eleven patients with AD and 11 with semantic dementia (SD), matched for age, sex, education, and degree of overall cognitive impairment and 15 normal controls. METHODS: Voxel-based morphometry was used to compare patterns of gray matter loss, measured on T1-weighted magnetic resonance images, between patients with AD or SD, a subtype of frontotemporal lobar degeneration, and controls. Statistically significant differences in regional gray matter concentration, after multiple-comparisons correction, between groups of subjects were identified. RESULTS: Patients with AD were more impaired than those with SD on tests of visuospatial function and on simple calculations. Consistent with these neuropsychological deficits, the most significant area of atrophy in the AD group was the left parietal cortex vs controls (z = 5.0; P =.04). Compared with SD, AD was associated with more atrophy in the left parietal lobe (z = 5.6; P =.04) and bilaterally in the posterior cingulate/precuneus (z = 5.1; P =.04). A discriminant function analysis demonstrated that the degree of atrophy of right posterior cingulate, left parietal lobe, right amygdala, and right anterior temporal lobe structures correctly classified 96% of the patients. CONCLUSION: Alzheimer disease is associated with a specific pattern of cortical atrophy compared with SD.     

The neuropsychology of de novo patients with idiopathic Parkinson's disease: the effects of age of onset

One hundred de novo patients with Parkinson's disease (PD) were classified into two groups according to age of onset of symptoms. Seventy two patients were under 70 years and 28 were 70 years and over. All patients were given neurological and neuropsychological assessments, and the severity of the signs was rated on a modified Columbia scale. The neuropsychological assessment was also administered to 50 age-and-education-matched controls. The neuropsychological test battery included tests of verbal learning, visual memory, verbal fluency, visuospatial skill, simple and choice reaction time, language and maze learning. The late-onset patients had significant impairment in nonverbal reasoning, auditory verbal learning, visual memory and choice reaction time in contrast to early-onset patients and controls. A relationship was found between bradykinesia and widespread cognitive impairment. Severity of tremor was found to be significantly correlated with impairment in auditory verbal learning, visual memory and increased choice reaction time, while rigidity was found to be associated with cognitive impairment in verbal fluency and visuospatial skill. Using DSM II criteria, 39% of the late-onset and 8% of the early-onset group were classified as demented. Dementia was more common in patients with bilateral symmetrical disease and in those patients with marked tremor and bradykinesia. The pattern of cognitive impairment in PD was consistent with that associated with a subcortical dementia. This study confirms that the expression of PD is markedly influenced by the age of onset.     

Remote memory for visuospatial information in patients with Alzheimer's disease

Remote memory for visuospatial information was studied in patients with dementia of the Alzheimer type (DAT) using a test of geographic knowledge previously employed in a study of patients with Huntington's disease. When asked to locate places on a map of the region of the United States in which they were born and raised or on a map of California where they currently resided, the DAT patients performed less accurately than controls. However, unlike controls, the performance of DAT patients in locating places was relatively more accurate using the map of the region in which they were born and raised than using the map of California. Thus, the DAT patients exhibited temporally graded retrograde amnesia for visuospatial knowledge, which parallels the pattern of retrograde amnesia reported for DAT patients when remote memory was assessed with tests requiring identification of famous persons or recall of past public events.     

Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type

Regional cerebral metabolic rates for glucose (rCMRglc), as measured with positron emission tomography, and neuropsychological function were studied longitudinally (range, 15 to 48 months) in 11 mildly impaired patients with dementia of the Alzheimer type (DAT) and compared with results from patients with moderate and severe DAT and from controls. At initial evaluation, association cortex metabolic asymmetries were greater in patients with DAT than in controls for all dementia severities and correlated significantly with neuropsychological discrepancies between visuospatial and language abilities in patients with moderate dementia. In mildly impaired patients, right-left metabolic asymmetries in the association cortices were directionally stable and became more pronounced over time. At initial evaluation, these patients had significant impairment, relative to controls, on tests of memory and attention to complex tasks but not on tests of language and visuospatial function. Memory, attention, language, and visuospatial impairments, however, all worsened significantly over time. In mildly impaired patients, correlations between right-left metabolic asymmetries and neuropsychological discrepancies were insignificant initially but were significant at last evaluation. These results demonstrate that heterogeneous nonmemory language and visuospatial impairments in early DAT are related to and predicted by the earlier-appearing distribution of metabolic reductions in the association neocortex.     

Gesture comprehension,knowledge and production in Alzheimer’s disease

Background and purpose: Although apraxia is a typical consequence of Alzheimer’s disease (AD), the profile of apraxic impairments is still subject to debate. Here, we analysed apraxia components in patients with AD with mild‐to‐moderate or moderately severe dementia. Methods: Thirty‐one patients were included. We first evaluated simple gestures, that is, the imitation of finger and hand configurations, symbolic gestures (recognition, production on verbal command and imitation), pantomimes (recognition, production on verbal command, imitation and production with the object), general knowledge and complex gestures (tool–object association, function–tool association, production of complex actions and knowledge about action sequences). Tests for dementia (Mini Mental State Examination and the Dementia Rating Scale), language disorders, visual agnosia and executive function were also administered. Results: Compared with controls, patients showed significant difficulties (P ≤ 0.01) in subtests relating to simple gestures (except for the recognition and imitation of symbolic gestures). General knowledge about tools, objects and action sequences was less severely impaired. Performance was frequently correlated with the severity of dementia. Multiple‐case analyses revealed that (i) the frequency of apraxia depended on the definition used, (ii) ideomotor apraxia was more frequent than ideational apraxia, (iii) conceptual difficulties were slightly more frequent than production difficulties in the early stage of AD and (iv) difficulties in gesture recognition were frequent (especially for pantomimes). Conclusion: Patients with AD can clearly show gesture apraxia from the mild–moderate stage of dementia onwards. Recognition and imitation disorders are relatively frequent (especially for pantomimes). We did not find conceptual difficulties to be the main problem in early‐stage AD.     

Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type

Patients with dementia of the Alzheimer type (DAT) received two tests of visual selective attention, together with tests of spatial and visual recognition memory and visuospatial conditional learning previously used to show deficits early in the course of DAT. One set of attentional tests compared visual discrimination learning along intra- and extra-dimensional shifts, using a "total change" design. In the 12 DAT patients capable of attempting the extra-dimensional shift (subgroup 1), performance was equivalent to that of controls. This subgroup was also unimpaired at simple and compound discrimination learning and reversal and an intra-dimensional shift. They were as accurate as controls on a visual search task requiring matching of stimuli on two dimensions with variable numbers of alternatives, but were significantly impaired in the tests of recognition memory and learning. By contrast, the other 13 patients showed marked impairments in the attentional tasks. This subgroup was also significantly worse than subgroup 1 in performance on the visual recognition and conditional learning tasks, and showed greater severity on most of the clinical ratings of dementia. The sparing of attentional shifting in patients early in the course of DAT is contrasted with the impairments previously described in patients with Parkinson's disease with only mild or absent memory loss. The implications of this double dissociation of deficits for understanding the neural bases of the cognitive deficits in these two neurodegenerative diseases are discussed and their significance for the staging of DAT is considered.     

Early neuropsychological detection and the characteristics of Parkinson's disease associated with mild dementia

Parkinson's disease (PD) may exhibit patterns of cognitive deficits, yet physicians are currently lacking operational criteria to define the clinical boundaries between PD and PD dementia (PDD). Therefore, we investigated the characteristics of the cognitive impairments in mild PDD. We recruited 30 PDD, 20 PD-MCI (PD with mild cognitive impairment without dementia) and 33 controls. All subjects were evaluated with detailed neuropsychological tests. Our results showed that visual memory, visuospatial functions, naming and calculation displayed more marked impairment than that of the other domains. Thus we suggest that adding cognitive dysfunctions of cortical type to the early cognitive deficits of PD-MCI can help predict the development of dementia.     

A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials

In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.     

Do visuospatial and constructional disturbances differentiate frontal variant of frontotemporal dementia and Alzheimer's disease? An experimental study of a clinical belief

BACKGROUND: In recent years several attempts have been made to distinguish frontotemporal dementia (FTD) from Alzheimer's disease (AD) on neuropsychological grounds; in particular, it has been suggested that FTD patients show spared spatial abilities with respect to AD patients. OBJECTIVE: We aimed at verifying whether patients with the frontal variant of frontotemporal dementia (fv-FTD) and AD patients perform differently on visuospatial and constructional tasks. METHODS: We assessed a wide range of visuospatial abilities and provided a qualitative analysis of constructional performances in 14 fv-FTD patients and 11 AD patients, matched for general cognitive abilities. RESULTS: The two groups of patients achieved similar scores on two copying tasks, presented similar drawing procedures in copying Rey complex figure and made a similar quantitative and qualitative pattern of errors in copying simple geometrical drawings. Moreover, no significant difference was found between fv-FTD and AD patients on a specific battery for visuospatial abilities. CONCLUSIONS: Our data and a review of the literature suggest that basic visuospatial and constructional skills cannot be taken as a reliable diagnostic criterion for distinguishing fv-FTD and AD at a mild to moderate disease stage and that the clinical belief of spared spatial abilities in fv-FTD has to be referred to the lack of topographic disorientation in comparison to AD.