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Spatial localization is a unique aspect of selective attention that precedes and facilitates other aspects of sensory processing. A common model of spatial attention is an attentional spotlight that enlarges to fit attentional demands. It is unclear if this attentional spotlight expands to survey a blank field or to scan the spatial environment with a smaller attentional spotlight. Two tachistoscopic experiments with young adults investigated how attention is surveyed in a blank field. Exp. 1 consisted of single letters at two concentric regions and under different conditions of attentional demand. Reaction times were proportionally slower for stimuli occurring in a combination of the two regions located at different distances from the fixation point than for stimuli occurring in each region alone. This finding is not consistent with attentional spread to encompass the entire attentional field. The addition of more stimulus locations within each single region yielded significantly slower reaction times. Together these findings suggest that a small attentional spotlight serially monitors different regions of the visual field when there are anticipated locations to be attended.

The sense of empathy may be altered by brain disease. We report the drawing performance of four artists who developed frontotemporal dementia (FTD). The first three, but not the fourth, had a prominent decrease in empathy for others as well as alterations in their caricatures of people. Their drawings of faces became distorted, menacing, skeleton-like, or 'alien'. None of the four had facial recognition difficulties, problems in interpreting facial emotions, or a decreased appreciation of the distinction between animate and inanimate objects. Functional brain imaging in the patients revealed bilateral frontal hypometabolism or hypoperfusion, and the three with altered drawings had additional prominent involvement of the right temporal lobe. These FTD patients and the literature suggest that FTD, possibly with greater right temporal involvement, disrupts the sense of empathy from human faces.

Delusional thoughts are common in patients with Alzheimer's disease and contribute prominently to morbidity. The pathophysiologic underpinnings for delusions in Alzheimer's disease are not well understood. In this study the authors examined the relationship between delusional thoughts and regional cortical metabolism in patients with Alzheimer's disease.Twenty-five patients with probable Alzheimer's disease were included. None was taking psychotropic medication. Severity of delusions and other neuropsychiatric symptoms was assessed by using a semistructured interview and the Neurobehavioral Rating Scale just before the imaging procedure. [(18)F]Fluorodeoxyglucose positron emission tomography was used to measure resting cerebral glucose metabolic rates in the cortical lobes and in anatomically defined subregions of the frontal and temporal cortexes.A linear regression model, controlling for the effects of cognitive deficits, revealed a significant relationship between severity of delusional thought and the metabolic rates in three frontal regions: the right superior dorsolateral frontal cortex (Brodmann's area 8), the right inferior frontal pole (Brodmann's area 10), and the right lateral orbitofrontal region (Brodmann's area 47). Bivariate partial correlation analysis indicated that severity of delusions was associated with hypometabolism in additional prefrontal and anterior cingulate regions. Robust relationships with metabolism in regions of the temporal cortex were not apparent.Dysmetabolism in specific regions of the right prefrontal cortex may be associated with delusional thought in Alzheimer's disease. Delusions appear to reflect the pathophysiologic state of particular cortical regions. Activity across distributed neuronal networks and the specific content of delusional thoughts may modulate these relationships.

This review of pharmacotherapy for frontotemporal lobar degeneration describes the chemical rationale for agents used and reports observed responses to psychotropic medications. Paroxetine addressed anxiety and repetitive, ritualistic behaviors. Depression was resistant to treatment. Valproic acid and quetiapine calmed agitated subjects without exacerbating Parkinsonism. Donepezil has not emerged as a beneficial medication for this group of subjects. Behavioral disturbances can be alleviated pharmacologically, but further research might determine guidelines for management of this non-Alzheimer's dementia syndrome that could decrease the frequency of adverse drug events.

Background: Predominant and progressive complex visual disorders are often due to posterior cortical atrophy (PCA), a rare early-onset dementing syndrome presenting with visual complaints. In clinicopathological studies, PCA is most commonly considered a form of Alzheimer’s disease (AD); no prior study has evaluated clinical differences between PCA and AD. Methods: This study identified 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypoperfusion on SPECT. These patients were retrospectively compared on clinical variables with 30 patients with clinically probable AD matched for gender, age and duration of illness. Results: The PCA patients presented with alexia, elements of Balint’s syndrome, apperceptive visual agnosia, dressing apraxia and environmental disorientation along with elements of Gerstmann’s syndrome. Compared to the AD patients, the 15 PCA patients (mean age of onset 58 years, range 51–64) had significantly better verbal fluency, less memory difficulty, more depression and greater insight into their illness but similar familial and apolipoprotein E risk factors. In the PCA patients, MRI often showed occipitoparietal atrophy without detectable mesiotemporal atrophy. Conclusions: PCA is a distinct clinical syndrome and not just AD with prominent visual deficits. Compared to AD controls, PCA patients have better language and memory but more insight and depression and more posterior atrophy on MRI. These results indicate clinical criteria for the diagnosis of PCA and recommend specific interventions such as visual aids and antidepressant medications. Similar risk factors and course suggest that PCA is most commonly an early-onset posteriorly shifted AD variant.

Background:Caregivers report early disturbances in social behavior among patients with behavioral variant frontotemporal dementia (bvFTD); however, there are few direct observational studies of these social behavioral disturbances. This study aimed to identify social behavioral themes in bvFTD by direct observation in naturalistic interactions. The identification of these themes can help caregivers and clinicians manage the social behavioral disturbances of this disease.Methods:Researchers observed 13 bvFTD patients in their homes and community-based settings and recorded field notes on their interpersonal interactions. A qualitative analysis of their social behavior was then conducted using ATLAS.ti application and a constant comparison method.Results:Qualitative analysis revealed the following themes: (1) diminished relational interest and initiation, indicating failure to seek social interactions; (2) lack of social synchrony/intersubjectivity, indicating an inability to establish and maintain interpersonal relationships; and (3) poor awareness and adherence to social boundaries and norms. These themes corresponded with changes from caregiver reports and behavioral scales.Conclusion:This analysis indicates that real-world observation validates the diagnostic criteria for bvFTD and increases understanding of social behavioral disturbances in this disorder. The results of this and future observational studies can highlight key areas for clinical assessment, caregiver education, and targeted interventions that enhance the management of social behavioral disturbances in bvFTD.

Background Deep brain stimulation (DBS) improves motor symptoms in Parkinson9s disease (PD), but questions remain regarding neuropsychological decrements sometimes associated with this treatment, including rates of statistically and clinically meaningful change, and whether there are differences in outcome related to surgical target. Methods Neuropsychological functioning was assessed in patients with Parkinson9s disease (PD) at baseline and after 6 months in a prospective, randomised, controlled study comparing best medical therapy (BMT, n=116) and bilateral deep brain stimulation (DBS, n=164) at either the subthalamic nucleus (STN, n=84) or globus pallidus interna (GPi, n=80), using standardised neuropsychological tests. Measures of functional outcomes were also administered. Results Comparison of the two DBS targets revealed few significant group differences. STN DBS was associated with greater mean reductions on some measures of processing speed, only one of which was statistically significant in comparison with stimulation of GPi. GPi DBS was associated with lower mean performance on one measure of learning and memory that requires mental control and cognitive flexibility. Compared to the group receiving BMT, the combined DBS group had significantly greater mean reductions at 6-month follow-up in performance on multiple measures of processing speed and working memory. After calculating thresholds for statistically reliable change from data obtained from the BMT group, the combined DBS group also displayed higher rates of decline in neuropsychological test performance. Among study completers, 18 (11%) study participants receiving DBS displayed reliable decline by multiple indicators in two or more cognitive domains, a significantly higher rate than in the BMT group (3%). This multi-domain cognitive decline was associated with less beneficial change in subjective ratings of everyday functioning and quality of life (QOL). The multi-domain cognitive decline group continued to function at a lower level at 24-month follow-up. Conclusions In those with PD, the likelihood of significant decline in neuropsychological functioning increases with DBS, affecting a small minority of patients who also appear to respond less optimally to DBS by other indicators of QOL. Trial registration number NCT00056563 and NCT01076452.

Behavioral variant frontotemporal dementia (bvFTD) is a non-Alzheimer dementia characterized by difficulty in documenting social-emotional changes. Few investigations have used virtual reality (VR) for documentation and rehabilitation of non-Alzheimer dementias.Five bvFTD patients underwent insight interviews while immersed in a virtual environment. They were interviewed by avatars, their answers were recorded, and their heart rates were monitored. They were asked to give ratings of their stress immediately at the beginning and at the end of the session.The patients tolerated the head-mounted display and VR without nausea or disorientation, heart rate changes, or worsening stress ratings. Their insight responses were comparable to real world interviews. All bvFTD patients showed their presence in the VR environment as they moved their heads to face and respond to each avatar's questions. The bvFTD patients tended to greater verbal elaboration of answers with larger mean length of utterances compared to their real world interviews.VR is feasible and well-tolerated in bvFTD. These patients may have VR responses comparable to real world performance and they may display a presence in the virtual environment which could even facilitate assessment. Further research can explore the promise of VR for the evaluation and rehabilitation of dementias beyond Alzheimer's disease. Implications for Rehabilitation Clinicians need effective evaluation and rehabilitation strategies for dementia, a neurological syndrome of epidemic proportions and a leading cause of disability. Memory and cognitive deficits are the major disabilities and targets for rehabilitation in Alzheimer's disease, the most common dementia. In contrast, social and emotional disturbances are the major disabilities and targets for rehabilitation in behavioral variant frontotemporal dementia (bvFTD), an incompletely understood non-Alzheimer dementia. Virtual reality is a technology that holds great promise for the evaluation and rehabilitation of patients with bvFTD and other non-Alzheimer dementias, and preliminary evidence suggests that this technology is feasible in patients with bvFTD.

The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimer’s disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD.

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants – 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer’s disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted ‘rich club’ – a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia.

Background: Emotional blunting is a major clinical feature of behavioral variant frontotemporal dementia (bvFTD). Assessing the change in emotional blunting may facilitate the differential diagnosis of this disorder and can quantify a major source of distress for the patients' caregivers and families. Methods: We evaluated investigator ratings on the Scale for Emotional Blunting (SEB) for 13 patients with bvFTD versus 18 patients with early-onset Alzheimer's disease (AD). The caregivers also performed SEB ratings for both the patients' premorbid behavior (before dementia onset) and the patients' behavior on clinical presentation (after dementia onset). Results: Before the onset of dementia, the caregivers reported normal SEB scores for both dementia groups. After the onset of dementia, both caregivers and investigators reported greater SEB scores for the bvFTD patients compared to the AD patients. The patients were rated to be much more emotionally blunted by the bvFTD caregivers than by the investigators. A change of ≥15 in the caregiver SEB ratings suggests bvFTD. The change in caregiver SEB ratings was positively correlated with bifrontal hypometabolism on FDG-PET scans. Conclusions: Changes in the caregiver assessment of emotional blunting with dementia onset can distinguish patients with bvFTD from those with AD, and they may better reflect the impact of emotional blunting than similar assessments made by clinicians/investigators.

Background Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. Objective We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer's disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. Methods Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. Results The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. Conclusions Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.

Neuroleptic hypersensitivity is characteristic of dementia with Lewy bodies (DLB) but not of other dementias. The authors report 5 patients with psychotic mood disorders and long-standing antipsychotic drug therapy. As they reached 50 to 60 years of age, they unexpectedly developed hypersensitivity to these medications, with rigidity, muteness, or the neuroleptic malignant syndrome. Nearly coincident with this reaction, they developed progressive cognitive deficits consistent with frontotemporal dementia. These patients illustrate emergent neuroleptic hypersensitivity as an early manifestation of other dementias. The predisposition to neuroleptic hypersensitivity could result from depleted nigral dopaminergic neurons suggested by "smudging" of the substantia nigra pars compacta on magnetic resonance imaging.

Visuospatial deficits are characteristic of posterior cortical atrophy (PCA). A 58 year old woman had progressive dressing apraxia and environmental disorientation but continued to read voraciously. Positron emission tomography revealed hypometabolism of the occipitoparietal regions bilaterally, consistent with PCA. The symptoms suggested predominant dysfunction of the dorsal (“where”) stream with abnormalities in visual localization and visuospatial integration; however, the patient also had a less pronounced apperceptive object agnosia. Further analysis of her preserved reading ability was performed. Familiar irregular words were read rapidly, but nonsense words were read slowly in a letter-by-letter fashion. She had a word superiority effect for embedded words and words with obscured letters but had difficulty reading stylized script or printing in unusual fonts. These findings suggested a dissociation between reading routes. Although the patient had a phonological dyslexia, her visuospatial processing was sufficient for access to preserved visual word forms for efficient lexical reading.

Sirs Visual allesthesia is a condition in which visual images are transposed from one half of the visual field to the other. The most common cause is an acute right parietal stroke, but allesthesia can result from other lesions and mechanisms. We describe the unusual case of a man with continuous transposition of his right visual field into his left due to epilepsia partialis continua. A 57-year-old, right-handed man with a remote gunshot wound to the right parietal lobe presented with the complaint of seeing everything on his right-side moved to his left-side. He initially developed paroxysmal episodes that began with an awareness that visual objects were transposed from his right visual field to his left. The transposed objects were less distinct than the original, appeared further away, and involved background as well as foreground. The patient turned his eyes and his head to the left in order to capture the original left-sided images. The transposition persisted a few minutes after removal of the original visual stimulus and despite closing either or both eyes. About a minute into the transpositions, he experienced other sensory phenomena including a repetitive “clicking or crackling” sound on the left side and a numbness of his left hand. He would then recover with a residual “fogginess” and right-sided headache. The entire episodes usually lasted 3-4 min, but, at time of presentation, the visual transposition had increased in frequency to the point of becoming continuous. On past medical history, he had a penetrating head injury 18 years previously, post-traumatic seizures (simple motor involving his left upper extremity), mild glaucoma responsive to ophthalmic drops, and hearing loss. His epilepsy responded to phenytoin and then gabapentin, which he had discontinued 8 years previously. Afterwards, he continued with monthly episodes of left upper extremity numbness and weakness. Six months before presentation, he underwent MRI for evaluation of his hearing loss. He underwent examination during the ongoing visual transpositions. He reported that the examiner, standing on his right side, was seen on his left. When the examiner moved items on the right, the patient reported the movements on the left. He was otherwise alert, attentive, and oriented with fluent speech, normal auditory comprehension, and normal memory testing. The rest of his examination was normal except for diminished left hemi-body pinprick sensation, left hand astereognosia and agraphaesthesia, and a left upgoing toe. After resolution of his visual transpositions, he showed left hemifield extinction on double simultaneous stimulation, but no hemispatial neglect on line bisection and visual search tasks. On visual examination, he had visual acuity of OD 20/25 and OS 20/30 +2 and a left superior arcuate visual field deficit in his right eye attributed to glaucoma rather than to his right parietal predominant encephalomalacia (Fig. 1). Fig. 1 Magnetic resonance axial flair images at lower (a) and higher (b) levels. There is a large area of encephalomalacia along the right parietal lobe, extending from the sensory strip to the precuneus. There is a significant amount of gliosis in the white ... The patient’s presentation was consistent with partial simple seizures. On hospitalization, he had continuous clinical seizures lasting over an hour. Electroencephalogram taken on day 2 and 3 after hospitalization showed ictal focal episodes emanating from the right parieto-temporal region (Fig. 1). He was administered lorazepam 2 mg IV and loaded with levetiracetam 1,500 mg IV. His seizures gradually subsided, and he was discharged with only occasional partial seizures on levetiracetam 2,000 mg BID, divalproex 1,500 mg BID, and gabapentin 1,200 mg QID. This patient had ictal visual allesthesia, or the epileptogenic transfer of visual information from his right hemifield to his left hemifield [1, 2]. This was accompanied by palinopsia or the persistence of the transposed images [1]. Visual allesthesia usually results from right hemisphere lesions with left-sided neglect or extinction [2, 3]. In addition, investigators have reported ictal or post-ictal visual allesthesia in patients with right parieto-occipital or temporal-occipital arteriovenous malformations and in a patient with a right falcotentorial meningioma compressing the area around Brodmann’s areas 18 and 19 [1, 4, 5]. Visual allesthesia may result from interhemispheric transfer of vision from a normal right field to a partially impaired left field [1, 6, 7] associated with sustained neural activity in the contralateral parietal cortex [8]. This patient had a baseline attentional compromise of left hemi-space, and ongoing seizures shifted the normally attended right hemi-space into the left side. Visual allesthesia, along with palinopsia, differs from epileptic visual illusions and hallucinations from occipital and temporal lesions [9], and implicate a parietal localization.

Patients with dementia and leukoaraiosis may have either Alzheimer’s disease (AD) with cerebrovascular changes or a form of vascular dementia (VaD). The presence or absence of the characteristic AD pattern of bilateral temporoparietal hypometabolism on 18FDG-PET was used to differentiate 30 patients with progressive dementia and severe leukoaraiosis. Compared to 18 patients with the typical AD pattern (group I), the remaining 12 (group II) had better recognition memory, and greater difficulty with sustained attention and serial reversals. Better recognition memory, confluent periventricular leukoaraiosis, and poorer sustained attention distinguished all group II patients from group I. Dementia patients with severe leukoaraiosis and bilateral temporoparietal hypometabolism may have predominant AD; those who lack this pattern and have confluent leukoaraiosis may have a greater contribution from VaD.

Frontotemporal dementia (FTD) is a dementing syndrome characterized by the occurrence of neuropsychiatric features early in the clinical course. Patients with Alzheimer's disease (AD) also have neuropsychiatric symptoms, but these symptoms typically emerge later in the course after the development of memory and other cognitive impairment. The BEHAVE-AD, an instrument developed to evaluate neuropsychiatric features in dementia, may help characterize the behavioral features of FTD and differentiate FTD from AD. This study evaluated BEHAVEAD results of 29 patients with the diagnosis of FTD compared to those of 29 patients with the diagnosis of probable AD of similar dementia severity. The FTD patients had significantly worse global BEHAVE-AD scores compared to the AD patients. Verbal outbursts and inappropriate activity characterized the FTD patients, and three BEHAVE-AD subscales correctly classified 69% of the patients. The assessment of neuropsychiatric symptoms with a standardized scale or inventory can help distinguish dementia patients with FTD and AD.

We present the case report of a patient who manifested seizures due to malingering, and discuss the differential diagnosis. The characteristics typical of nonepileptic seizures not due to malingering and of seizures due to malingering are described. Methods of distinguishing nonepileptic seizures from epileptic seizures are outlined, and the differences between seizures due to malingering and other nonepileptic seizures are discussed.

Neuropsychiatric symptoms are common manifestations of temporolimbic lesions. These neuropsychiatric symptoms result from disturbances of specific temporolimbic networks, including medial limbic circuits, lateral limbic circuits, and the "extended" amygdala. Moreover, temporolimbic networks interface with multiple cortical and subcortical circuits that modulate emotional behavior and affect. This article not only reviews these behaviorally relevant aspects of temporolimbic neuroanatomy, but also describes positive, productive symptoms from the temporal lobes. The Klüver-Bucy syndrome, the Gastaut-Geschwind syndrome, emotional or mood disorders, delusions, anxiety and associative disorders, and neurovegetative symptoms are discussed, as well as amnesia, the signature temporolimbic disturbance of cognition. The temporolimbic lobe is a classic example of a widely distributed circuit within the brain that has behaviorally relevant manifestations.

Frontotemporal dementia (FTD) may be one of the most common neurodegenerative dementias with onset before age 65. Investigators have only recently characterized FTD, which encompasses Pick's disease as well as non-specific degeneration of the frontal lobes. Neuropsychiatric symptoms are the main features of FTD and include disinhibition, apathy, obsessive-compulsive behavior, and the Kluver-Bucy syndrome. We report a patient with FTD who developed prominent self-injurious behavior (SIB) consisting of persistent self-biting and hair-pulling. Stereotypical, repetitive SIB usually occurs in patients with autism or mental retardation; SIB is rarely discussed in patients with dementia. This report extends the neuropsychiatric spectrum of FTD to encompass SIB and discusses the potential mechanisms for SIB in these patients. The most likely contributing source for their self-injury is the development of obsessive-compulsive behaviors in the presence of coincident self-directed behaviors. Hyperorality fr...

This study evaluated information processing differences between 30 vascular dementia (VaD) patients, 30 Alzheimer's disease (AD) patients, and 30 normal elderly (NE) controls. They were administered a complex reaction time test, a continuous performance test (CPT), and a neuropsychological battery. Compared to NE, both dementia groups had significantly slower motor reaction times and made more errors on the CPT. Compared to AD patients, the VaD patients were slower in stimulus categorization time and had increasing omission errors and persistent commission errors throughout the CPT trial, VaD, which usually includes frontal-subcortical circuit injury, can impair mental speed and stimulus response initiation.

OBJECTIVE: After Alzheimer's disease, vascular dementia (VaD) and frontotemporal dementia (FTD) are among the most common dementing illnesses. FTD may have a neuropsychological profile similar to that of VaD, and patients with these dementias may be difficult to distinguish on clinical examination. The purpose of this study was to elucidate distinct cognitive profiles of a large group of FTD and VaD patients on a brief, clinical mental status examination. DESIGN: A comparison of 39 FTD patients and 39 VaD patients on a brief, clinical mental status examination. SETTING: A Dementia Research Center and affiliated, university hospitals. METHODS: The FTD patients were diagnosed by noncognitive clinical and neuroimaging criteria, and the VaD patients met NINDS-AIREN criteria for vascular dementia. The two dementia groups were comparable on three dementia assessment scales. MEASUREMENTS: The mental status measures included the neuropsychological battery from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), plus supplementation from the Neurobehavioral Cognitive Status Examination (NCSE) for cognitive areas not assessed by the CERAD). RESULTS: The FTD and VaD groups differed significantly on the mental status examination measures. FTD patients performed significantly better than the VaD patients on digit span and constructions, despite comparable performance by both groups on calculations. Although not statistically significant, the FTD group performed worse than the VaD group on verbal fluency and abstractions. These differences were not explained by group differences in age and education. CONCLUSION: These results suggest that cognitive differences between FTD and VaD groups reflect greater frontal pathology in contrast to relative sparing of posterior cortex and subcortical white matter in FTD. These cognitive differences as measured by a mental status examination may help distinguish between these two dementia syndromes.

Investigators have reported high sensitivity and specificity values for single photon emission computerized tomography (SPECT) when distinguishing Alzheimer's disease (AD) patients from normal elderly controls or from selected patient groups. The role of SPECT in identifying AD among unselected patients with memory complaints requires investigation. We examined 139 consecutive patients with 99Tc-HMPAO SPECT. NINCDS-ADRDA diagnoses were determined blind to SPECT results, and scans were read and classified by visual inspection blind to clinical diagnoses. Bilateral temporoparietal hypoperfusion (TP) occurred in 75% of probable, 65% of possible, and 45% of unlikely AD patients, yielding a sensitivity of 75% and a specificity of 52% when comparing probable AD versus unlikely AD groups. A positive predictive value of 78% was obtained based on a 69% prevalence of AD in our total clinic population. Patients with false-positive results included a variety of dementing illnesses; all patients with bilateral hypoperfusion had dementia. A pattern of TP on SPECT scans is seen in most patients with AD, but could be found in other dementias as well and cannot be regarded as specific to AD. Reduced TP perfusion discriminated between demented and nondemented individuals. Further strategies for SPECT interpretation that improve diagnostic specificity should be sought.

White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting.We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants.Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group.The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

Mendez et al.1 found that distinguishing between pathologically confirmed bvFTD and AD can be determined by personality changes, problem-solving, and episodic memory deficits. This could have implications on future bvFTD diagnostic criteria. The higher incidence of episodic memory problems in AD raises the controversial issue: is a memory deficit a reliable diagnostic criterion in distinguishing between the pathologies? There is increasing evidence that an episodic memory deficit is a poor diagnostic predictor for bvFTD and AD, even in pathologically proven cases.2–5 Closer inspection of the authors' findings reveals that their neuropsychological memory measures confirm these findings by showing no episodic memory difference between bvFTD and AD. The authors based their recommendation on the binary informant-based decision of episodic memory deficits presence, which does not converge with their more objective neuropsychological findings. This discrepancy is concerning. The recommendation to discriminate between bvFTD and AD on the basis of memory deficits may not be warranted by their data. The authors should have mentioned this caveat in their publication.

Semantic dementia impairs semantic autobiographical memory, but tends to spare its episodic components that are critical for the sense of self. Investigators have recently discovered disturbances in the "future self" in semantic dementia. We report a 63-year-old man with semantic dementia who was hospitalized after suicide attempts that he attributed to his loss of a sense of future self. He complained of a decreased sense of being human, because he could not imagine doing things in the future that he had done in the past. Suicidal thinking and inability to place himself in future tasks persisted despite resolution of depression. Clinical assessment revealed a crossmodal loss of semantic knowledge, and neuroimaging showed bilateral anterior temporal atrophy and hypometabolism. On specific tests of autobiographical memory, identity, attribute knowledge, and future projection, the patient could return to the past and visualize himself in familiar scenarios, but he could not visualize himself even passively in these scenarios in the future. His future self was impaired not from seeing himself disabled; it was from an absence of semantic details of potential experiences, associated with impaired semantic autobiographical memory. His self-representations were concrete and specific rather than abstract and generalizable. This patient and recent publications indicate that semantic dementia impairs the ability to imagine oneself as capable in the future, leading some patients to suicidal behavior. We discuss possible mechanisms for these findings, including the potential role of abstract construals for future thinking. Language: en

Objective: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). Methods: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. Results: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy. Conclusions: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Summary Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. Methods We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. Findings Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI −3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, −0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Interpretation Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Funding Forest Research Institute.

Objective: To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy. Methods: This study reviewed all patients entered as clinical bvFTD in the National Alzheimer9s Coordinating Center9s database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups. Results: The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems. Conclusion: During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD.

Background/Aims: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. Methods: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. Results: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. Conclusion: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.

Recently, Coppola and colleagues demonstrated that a rare microtubule-associated protein tau (MAPT) sequence variant, c.454G>A (p.A152T) significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer disease (AD) in a screen of 15,369 subjects. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (n=2); 2 patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathologic correlation to elucidate the influence of this genetic variant on neurodegenerative disease. Copyright © 2013 by Lippincott Williams & Wilkins.

Abnormal depth perception contributes to visuospatial deficits in Alzheimer's disease. Disturbances in stereopsis, motion parallax, and the interpretation of static monocular depth cues may result from neuropathology in the visual cortex. We evaluated 15 patients with mild Alzheimer's disease and 15 controls matched for age, sex, and education on measures of local stereopsis (stereoscopic testing), global stereopsis (random dots), motion parallax (Howard-Dolman apparatus), and monocular depth perception by relative size, interposition, and perspective. Compared to controls, the patients were significantly impaired in over-all depth perception. This impairment was largely due to disturbances in local stereopsis and in the interpretation of depth from perspective, independent of other visuospatial functions. Patients with Alzheimer's disease have disturbed interpretation of monocular as well as binocular depth cues. This information could lead to optic interventions to improve their visual depth perception.

Studies suggest a high frequency of epileptic auras with intellectual content among epileptic patients with psychopathology and personality disorders. This study compared measures of personality and psychosocial functioning between epileptic patients with cognitive auras and epileptic patients with noncognitive auras. Ten patients with complex partial seizures who experienced cognitive auras had consistently more depressive traits and psychosocial difficulties than 50 patients with other psychic or nonpsychic auras, particularly if the patients with cognitive auras had left hemisphere epileptiform foci. Cognitive auras may be associated with depressive traits among epileptic patients. The findings were also in agreement with studies that relate the left hemisphere to depression.

Lesions in the left supplementary motor area (SMA) can result in a transcortical motor aphasia with nonfluent spontaneous verbal output and relatively preserved repetition. Reading and writing are proportionally affected. We report a patient with an ischemic lesion in the right SMA. He had impaired articulation and normal repetition plus preserved reading and writing, consistent with an aphemia. This patient supports the dissociation of articulatory fluency and linguistic fluency and suggests that both SMAs affect the initiating of articulatory movements required to produce words whereas the left SMA also affects linguistic aspects of speech.

Huntington’s disease-like 2 (HDL2) is a rare neuropsychiatric disorder that resembles HD but results from a distinct mutation. The authors present a patient with HDL2, hospitalized for psychiatric management, and they review the neuropsychiatric manifestations of this disorder. Depression, irritability/aggression, and frontal lobe personality changes are common presentations of HDL2 and are comparable to classic HD. Patients with HDL2 may differ from those with HD in having a lower incidence of obsessive-compulsive acts, known suicides, antisocial acts, and changes in sexuality. Clinicians should be aware of the psychiatric presentations of this disorder, when to obtain genetic testing, and how to manage problematic behaviors.

Objective: To review the neuropsychiatry of boxing. Method: This update considers the clinical, neuropsychological, diagnostic, neurobiological, and management aspects of boxing-related brain injury. Results: Professional boxers with multiple bouts and repeated head blows are prone to chronic traumatic encephalopathy (CTE). Repeated head blows produce rotational acceleration of the brain, diffuse axonal injury, and other neuropathological features. CTE includes motor changes such as tremor, dysarthria, and parkinsonism; cognitive changes such as mental slowing and memory deficits; and psychiatric changes such as explosive behavior, morbid jealousy, pathological intoxication, and paranoia. Screening with neuropsychological tests and neuroimaging may help predict those boxers at risk for CTE. Conclusions: Boxing results in a spectrum of CTE ranging from mild, nonprogressive motor changes to dementia pugilistica. Recent emphasis on safety in the ring, rehabilitation techniques, and other interventions do not eliminate the risk for CTE. For this reason, there is an active movement to ban boxing.

Objective: This article examines the cognitive and psychiatric features of multiple sclerosis. MS can manifest as a neuropsychiatric disturbance even in the absence of physical disabilities. Method: Two MS patients with predominant behavioral symptoms are described, and the literature is reviewed. Results: The first patient had an interhemispheric disconnection syndrome, and the second patient had cognitive fatigue and depression. Other patients have slowed information processing speed, memory retrieval difficulty, frontal-executive dysfunction, and visuospatial difficulty. Conclusions: MS results in specific cognitive deficits and mood disorders. These two patients had organic mental disorders from cerebral demyelination particularly affecting the corpus callosum. Other patients have neuropsychiatric symptoms from extensive demyelination of prefrontal-subcortical circuits. Evaluation and management strategies are discussed.

Objective Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. Methods Eleven patients with bvFTD and 10 with AD completed the Delis–Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. Results The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right). Conclusions Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs.

Patients with Alzheimer's disease (AD), the most prevalent neurodegenerative dementia, are usually elderly; however, ∼4–5% develop early-onset AD (EOAD) with onset before age 65. Most EOAD is sporadic, but about 5% of patients with EOAD have an autosomal dominant mutation such as Presenilin 1, Presenilin 2, or alterations in the Amyloid Precursor Protein gene. Although most Alzheimer's research has concentrated on older, late-onset AD (LOAD), there is much recent interest and research in EOAD. These recent studies indicate that EOAD is a heterogeneous disorder with significant differences from LOAD. From 22–64% of EOAD patients have a predominant nonamnestic syndrome presenting with deficits in language, visuospatial abilities, praxis, or other non-memory cognition. These nonamnestic patients may differ in several ways from the usual memory or amnestic patients. Patients with nonamnestic EOAD compared to typical amnestic AD have a more aggressive course, lack the apolipoprotein E ɛ 4 (APOE ɛ 4) susceptibility gene for AD, and have a focus and early involvement of non-hippocampal areas of brain, particularly parietal neocortex. These differences in the EOAD subtypes indicate differences in the underlying amyloid cascade, the prevailing pathophysiological theory for the development of AD. Together the results of recent studies suggest that nonamnestic subtypes of EOAD constitute a Type 2 AD distinct from the usual, typical disorder. In sum, the study of EOAD can reveal much about the clinical heterogeneity, predisposing factors, and neurobiology of this disease.

Early-onset Alzheimer’s disease (EOAD) beginning before the age of 65 may differ from late-onset AD (LOAD) in clinical course and frequency of nonamnestic presentations. In a 10-year retrospective review, 125 patients with EOAD, diagnosed clinically and verified by functional neuroimaging, were compared with 56 patients with LOAD and further classified depending on predominant cognitive difficulty on presentation. Eighty (64%) of the patients with EOAD had a nonamnestic presentation, compared with only 7 (12.5%) of the patients with LOAD. Compared with LOAD, the patients with EOAD had a shorter duration with lower Mini-Mental State Examination scores. The neuroimaging reports among the patients with EOAD showed more hippocampal atrophy with an amnestic presentation, more left parietal changes with impaired language presentations, and more right parietal and occipital changes with impaired visuospatial presentations. These findings indicate that EOAD differs from LOAD in a more aggressive course and in having predominantly nonamnestic presentations that vary in neuropathological location.

ARTICLE Sir, We are grateful for the opportunity to respond to correspondence from Dr Schroeter on the revised criteria for behavioural variant frontotemporal dementia (bvFTD). We thank Dr Schroeter for his interest and the points he raises for discussion. Based on his work using meta-analytic methods, Schroeter suggests that imaging criteria for probable bvFTD should be restricted to atrophy or hypometabolism in frontomedian brain regions, anterior insula and thalamus (Schroeter et al ., 2007, 2008; Schroeter and Neumann, 2011). He argues that beside frontal areas, no temporal clusters were identified, indicating that bv FTD is mainly a frontomedian disease. As the work of Schroeter and others illustrates, meta-analytical imaging studies can provide important information about the brain regions most consistently affected in neurodegenerative disorders. The meta-analyses conducted by Schroeter and colleagues (Schroeter et al ., 2007, 2008; Schroeter and Neumann, 2011) were restricted to nine bvFTD studies published from 1980 to 2005, thus excluding large and more recent bvFTD neuroimaging series …

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.