Pulsatile tympanic membrane displacement is associated with cognitive score in healthy subjects.

To test the hypothesis that pulsing of intracranial pressure has an association with cognition, we measured cognitive score and pulsing of the tympanic membrane in 290 healthy subjects. This hypothesis was formed on the assumptions that large intracranial pressure pulses impair cognitive performance and tympanic membrane pulses reflect intracranial pressure pulses. 290 healthy subjects, aged 20-80 years, completed the Montreal Cognitive Assessment Test. Spontaneous tympanic membrane displacement during a heart cycle was measured from both ears in the sitting and supine position. We applied multiple linear regression, correcting for age, heart rate, and height, to test for an association between cognitive score and spontaneous tympanic membrane displacement. Significance was set at P < 0.0125 (Bonferroni correction.) A significant association was seen in the left supine position (p = 0.0076.) The association was not significant in the right ear supine (p = 0.28) or in either ear while sitting. Sub-domains of the cognitive assessment revealed that executive function, language and memory have been primarily responsible for this association. In conclusion, we have found that spontaneous pulses of the tympanic membrane are associated with cognitive performance and believe this reflects an association between cognitive performance and intracranial pressure pulses.

The impact of smoking cessation on multiple sclerosis disease progression.

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis.

Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia.

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke's Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome.

Clinical nurse specialist's role in young-onset dementia care.

Post-diagnostic care in young-onset dementia (YoD) varies, from something that is occasionally structured, to improvised, to frequently non-existent depending on geographic region. In a few regions in England, a nurse designated to helping families may exist. This study aimed to describe this seldom-observed nursing role and its content. It used an investigative qualitative case study design based on the analysis of two YoD clinical nurse specialists (CNSs) describing the work they did in providing post-diagnostic care to YoD service users. The CNSs address various areas affected by mid-life dementia, including patients' mental health, caregiver stress and families' psycho-social problems. They use various approaches in delivering care, including making home visits, acting as a personal contact for service users and liaising with other health and social care services. Desirable attributes of a CNS service include service users having access to the same CNS throughout their care, receiving timely care and experiencing longer-term support and reassurance. In the post-diagnostic period, service user needs are often more psycho-social than medical, and the CNS role can complement and add value to clinical appointments. The role allows service users to be managed in the community, to receive information, guidance and advice and can prevent and de-escalate problems.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-ß from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy.

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aß), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aß plaques in the brain in Alzheimer's disease (AD) and deposition of Aß within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aß in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

UK neurology response to the COVID-19 crisis.

COVID-19 has led to seismic changes in neurological practice in a matter of weeks. The Association of British Neurologists has supported neurology specialists and patients during this rapid reorganisation and its attendant challenges. We have written guidance on structured service transformation, considering the need to sustain long term care while responding to acute developments; we have recognised that staff experience differs and that this, as well as individual risk factors should be considered when redeployment occurs. Appreciating that there may be understandable anxiety when facing a working routine outside normal practice, we have signposted ethical and psychological support for individuals. We have also focused on our patients: we have facilitated a national alert system to register all neurological COVID cases, coordinating research efforts on this new disease; finally we have defined how to identify the most vulnerable patients under our care. When this initial wave of the pandemic subsides, we will have planned for return to the new 'norm', ready to embrace innovation where appropriate, aiming to minimise fall-out in our chronic disease population, and potentially having enhanced and modernised our services.

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Variably protease-sensitive prionopathy mimicking frontotemporal dementia.

Sporadic prion diseases are fatal neurodegenerative disorders characterized clinically by rapidly progressive dementia and myoclonus. Variably protease-sensitive prionopathy (VPSPr) is a recently identified sporadic human prion disorder that may present with a lengthy atypical clinical history. Here, we describe a case of VPSPr in a patient with a long history of suspected frontotemporal dementia (FTD). A 61-year-old man presented with speech difficulties, including naming objects and constructing multipart sentences, while there was no difficulty in comprehension. Movement abnormalities included slightly jerky pursuit, minor dysmetria of saccades and brisk reflexes. There was no family history of dementia. Later he developed swallowing difficulties and the possibility of FTD with motor neuron disease was suspected. He died at the age of 71 and his brain was donated to the London Neurodegenerative Diseases Brain Bank. The brain (1004 g) showed mild to moderate atrophy, predominantly in the frontal lobe. Histology revealed moderate spongiform microvacuolation mostly affecting the frontal and parietal cortices, but also present focally in the basal ganglia and the cerebellum. Only mild Alzheimer pathology was found by extensive immunohistochemistry, in keeping with BrainNet Europe stage II. Trans-activation response DNA-binding protein 43 kDa and α-synuclein immunostains were negative. Immunostaining for prion protein (PrP) showed granular/synaptic positivity in a patchy distribution, mainly within the deeper cortex, and also revealed microplaques in the cerebellum and basal ganglia. Western blotting confirmed a low molecular weight protease-resistant PrP band with a faint ladder-like pattern in the absence of types 1 and 2 isoforms. These features are diagnostic of VPSPr. VPSPr can mimic various neurodegenerative conditions; diagnosis requires both PrP immunohistochemistry and Western blotting. The presence of patchy spongiform change in the absence of other neurodegenerative pathology should raise suspicion of VPSPr, even in elderly patients with a lengthy clinical history.

Imaging Care Requirements: Use of Functional Neuroimaging to Predict Dementia Caregiver Burden.

BACKGROUND: Dementia caregivers frequently report high stress, with increased burden associated with worse outcomes for both patients and caregivers. Although many studies relate clinical phenotypes to burden, the relationship between imaging pathology and burden, irrespective of diagnosis, is unknown. This study investigated the relationship between caregiver burden and patient regional cerebral blood flow in dementia. METHODS: Seventy-sev en patients with cognitive impairment undergoing brain perfusion single-photon emission computed tomography imaging in normal clinical care and their caregivers were recruited. Caregiver burden was ranked from "little" to "severe" using the Zarit Burden Interview and perfusion values extracted from the patient images for predefined regions of interest. The associations between burden score and regional function on imaging were tested. RESULTS: Burden score was significantly higher for caregivers of patients with abnormal perfusion compared to those with normal perfusion in the left and right frontal, right parietal, and right temporal lobes. No difference in burden was found in the left parietal or temporal groups. Correlations showed that a higher caregiver burden was associated with lower patient perfusion scores in the same regions. CONCLUSION: Caregiver burden is strongly related to the extent of frontal or right-predominant parietal or temporal lobe dysfunction. Regional abnormality on perfusion imaging can be used to facilitate identification of individuals who are likely to create a high burden on caregivers.

Understanding important issues in young-onset dementia care: the perspective of healthcare professionals.

AIM: Psychosocial research on the lived experiences of young-onset dementia patients and caregivers has identified salient issues about their care, however, views on care from the perspective of young-onset dementia healthcare professionals is less well known. The aim of this study was to investigate and identify important issues in young-onset dementia care provision from a healthcare provider perspective. METHODS: The design was an exploratory qualitative interview study. In-depth semistructured interviews were conducted with healthcare professionals with clinical expertise in young-onset dementia drawn from medicine, nursing and allied health. Thematic analysis was applied to interview transcripts to identify themes representing important underlying issues in care across the dementia clinical pathway (i.e., prediagnosis, diagnosis and postdiagnosis). RESULTS: In prediagnosis, it is important for healthcare professionals to recognize symptoms as organic and degenerative and more than psychological, and to refer patients to an appropriate clinical facility for assessment. During diagnosis, it may be challenging to determine dementia, and methods are employed to manage diagnostic uncertainty. Following diagnosis, optimizing routine clinical care is important and can include the provision of practical informational guidance, empathic concern and psychoeducational support. Meeting service-user requirements in the community is an important aspect of care, and may be facilitated by the involvement of clinical nurse specialists. CONCLUSION: The findings are presented as a paradigm for holistic young-onset dementia care. The paradigm offers a framework for contemplating and evaluating the criteria and quality of young-onset dementia care.

Occipital lobe and posterior cingulate perfusion in the prediction of dementia with Lewy body pathology in a clinical sample.

OBJECTIVE: The aim of this study was to investigate the diagnostic value of occipital lobe and posterior cingulate perfusion in predicting dopamine transporter imaging outcome using a quantitative measure of analysis. PATIENTS AND METHODS: In total, 99 patients with cognitive complaints who had undergone both technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography (Tc-HMPAO SPECT) and I ioflupane (I-FP-CIT also called DaTSCAN) imaging in a dementia diagnostic center were analyzed. Measures of perfusion were calculated from HMPAO SPECT images for the medial and lateral occipital lobe, the posterior cingulate cortex, precuneus and cuneus regions of interest using statistical parametric mapping 8. DaTSCAN images were quantified and specific binding ratios were calculated independent from HMPAO SPECT results. Statistical parametric mapping and tests of associations between perfusion and I-FP-CIT imaging were completed. RESULTS: Regions of interest on HMPAO yielded poor predictive values when used independently to predict I-FP-CIT status; however, the combination of normal posterior cingulate perfusion with medial and lateral occipital hypoperfusion was associated significantly with I-FP-CIT status, χ (1, N=99)=9.72, P=0.002. This combination also yielded a high positive likelihood ratio and specificity (11.1, 98%). Sensitivity was, however, low (22%). No significant perfusion differences were found when abnormal and normal I-FP-CIT groups were compared directly using voxel-based morphometry (P<0.05, family-wise error). CONCLUSION: The combination of medial and lateral occipital hypoperfusion with preserved posterior cingulate gyrus perfusion is highly specific for individuals with a positive I-FP-CIT scan in a clinical sample where diagnostic doubt exists. This regional combination, however, lacks sensitivity; therefore, absence of the sign cannot be used to rule out dementia with Lewy bodies. A positive finding provides strong evidence to rule in dementia with Lewy bodies.

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the 'bvFTD phenocopy syndrome'.

PURPOSE OF REVIEW: The clinical features of behavioural variant frontotemporal dementia (bvFTD) are well established; however, recent work has identified patients fulfilling diagnostic criteria for the disease who do not appear to progress clinically. This review describes means of distinguishing this group at an early stage from patients who are likely to deteriorate. RECENT FINDINGS: Despite indistinguishable clinical profiles, studies in a cohort of bvFTD patients showed a particularly good prognosis in a subgroup of predominantly male patients in whom initial structural imaging was normal. This could not be explained by differences in disease duration, and was confirmed by subsequent PET studies. Retrospective review of clinical data in these groups verified that the current clinical diagnostic criteria are both insensitive to true progressive bvFTD, particularly in the early stages, and also poorly specific. In contrast, measures of activity of daily living performance, executive function and tests of social cognition appear to have better discriminatory value for patients who show clear clinical progression, with many individual diagnoses verified by post mortem examination in this group. SUMMARY: It remains doubtful that the nonprogressive group have a neurodegenerative disease. The implication for the current clinical diagnostic criteria and their proposed revision is discussed.

Is the pathology of corticobasal syndrome predictable in life?

Corticobasal syndrome (CBS) has been associated with a heterogeneous spectrum of pathologies with an increasing number of reports of Alzheimer's type pathology. There is, however, no means of predicting pathology of CBS in vivo at present. We compared the clinical features of patients presenting with CBS who have either pathologic changes of classic corticobasal degeneration (CBD) or Alzheimer's disease (AD) at post-mortem to identify predictors of the specific pathological processes in life. Twelve patients with CBS were followed prospectively; six had AD and six had classic CBD neuropathology. After review of the presenting clinical features, we identified nine potential predictor variables, compared their frequency in the two groups, and performed a discriminant function analysis. Initial episodic memory complaints and poor performance on the combined orientation-memory subtest of the Addenbrooke's Cognitive Examination (ACE) reliably predicted AD pathology while varying combinations of early frontal-lobe type behavioral symptoms, nonfluent language disturbance, orobuccal apraxia, and utilization behavior predicted CBD pathology ante-mortem. CBS is frequently associated with Alzheimer's disease pathology. Early episodic memory impairment versus early behavioral symptomatology appears to best predict AD or CBD pathology in life.

Activities of daily living in behavioral variant frontotemporal dementia: differences in caregiver and performance-based assessments.

Patients with the behavioral variant of frontotemporal dementia have marked impairment in everyday life, yet little is known about factors underlying this impairment. Moreover, a recently identified subgroup with normal brain imaging has an excellent prognosis (phenocopy cases) and their performance on activities of daily living (ADL) tasks is unknown. Eighteen behavioral variant frontotemporal dementia patients were assessed on 2 ADL measures, the Disability Assessment for Dementia, a caregiver-based interview, and the Assessment of Motor and Process Skills, a performance-based instrument. Behavior change, global cognition, executive function, and magnetic resonance imaging brain atrophy were also evaluated. There was no association between the 2 ADL measures. A model combining the Addenbrooke's Cognitive Examination Revised (global cognition) and Frontal Systems Behavior Scale (frontal dysfunction) explained the variance on ADL performance. A qualitative rating distinguished between pathologic and phenocopy patients better than the performance-based assessment. Degree of frontal dysfunction and overall dementia determined the level of ADL impairment. The phenocopy patients were clearly distinguishable when evaluated using a performance-based, and even better with a qualitative rating assessment.

Emotion, social functioning and activities of daily living in frontotemporal dementia.

Social functioning in FTD is profoundly affected, and forms the basis for the clinical diagnosis of the behavioural variant of the disease (bv-FTD). In particular, there are deficits in emotional processing, but the inter-relationship of such deficits to other aspects of social functioning remains unclear. We studied patients with bv-FTD (n = 14) and AD (n = 14), and compared their performance on a test of emotion recognition with their scores on two carer-based assessments: the Disability Assessment for Dementia (DAD) of activities in daily living (ADL), and the Cambridge Behavioural Inventory (CBI). The bv-FTD group had significantly greater impairments in ADLs, and had higher scores on the CBI, compared to the AD group. Despite a deficit in emotion recognition, particularly involving negative emotions, in the FTD group relative to AD and controls, performance on this task did not correlate with ADL ratings which instead, correlated highly with carer-rated apathy levels on the CBI. The study highlights the multifactorial nature of social dysfunction in FTD which is important in the management of these patients and in designing effective behavioural and therapeutic interventions. The relationship of emotional processing to other aspects of social cognition in FTD is reviewed.

Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions.

The most widely established diagnostic criteria for the behavioral variant of frontotemporal dementia have now been in use for almost a decade. Although consensus criteria have provided a much needed standard for frontotemporal dementia research, a growing body of evidence suggests that revisions are needed to improve their applicability. In this article, we discuss the limitations of current diagnostic criteria and propose the establishment of an international consortium to revise diagnostic and research criteria for the behavioral variant of frontotemporal dementia.

Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale.

BACKGROUND/AIMS: The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain; while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large sample of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. METHODS: We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. RESULTS: The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. CONCLUSIONS: MRI findings should form part of the diagnostic criteria for SD; the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.

The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia.

Structural brain imaging and neuropsychological data implicate the orbital aspects of prefrontal cortex in the developing neuropathology of fvFTD. Damage to this region is associated with deficient performance on laboratory tasks assessing theory of mind (ToM) and affective decision-making (DM), but the relationship between these two capacities in patients with prefrontal cortex dysfunction is unclear. We studied a group of patients with early/mild fvFTD (n=20) and a group of matched normal controls (n=10) on the Iowa gambling task (IGT) of affective decision-making, and the "reading the mind in the eyes" (MIE) and "faux pas" (FP) tests of ToM. The fvFTD group was impaired in both ToM tasks and the IGT. While performance measures from the two ToM tasks were significantly correlated, they were not associated with IGT performance. This suggests that whilst similar prefrontal circuitry is implicated in ToM and DM tasks, these cognitive domains may be independent. In clinical settings, the IGT may be useful as a complementary tool to the frontal test battery for patients with early/mild fvFTD. Deficits in decision-making and ToM observed in this study have distinct but additive effects upon the development of social behaviour in patients with prefrontal dysfunction.

Frontotemporal dementia.

PURPOSE OF REVIEW: The syndromes of frontotemporal lobar degeneration are increasingly recognized as an important cause of early-onset dementia. Diagnostic consensus criteria have now been established for almost a decade, and form the framework for its clinical classification. While these criteria remain useful, a growing body of evidence suggests that revisions may be necessary to improve their validity and applicability. RECENT FINDINGS: In each individual syndrome, the core features are not uniformly present, and criteria that are currently used to exclude a condition, such as impaired episodic memory, are often present. Imaging, however, may warrant increased diagnostic prominence, particularly for diagnosis in semantic dementia and prognosis in behavioural syndromes. There is clinical and pathological overlap between the syndromes, but the clinical distinction between progressive nonfluent aphasia and semantic dementia is strengthening. Several series have refined our understanding of the correspondence between clinical syndromes and histopathological subtype: strong for tau-negative, ubiquitin-positive forms and more variable for tau-positive forms, yet prospective studies are still rare. The influence of genetic factors varies substantially across the syndromes. SUMMARY: Further research should aim to integrate detailed clinical, radiological, pathological and genetic information.