Young-onset dementia with Lewy Bodies presenting with apathy and alexithymia.

A diagnosis of young-onset dementia can pose a significant challenge for the clinician. We present a young patient with a very unusual presentation of Dementia with Lewy Bodies. The lack of motor symptoms and his marked apathy delayed his diagnosis. His symptoms were thought to be due to depression based on normal structural imaging and the psychiatric nature of his presentation. An extensive work-up was performed. Evidence of a structural neurodegenerative process was provided by the HMPAO-SPECT. Cardiac MIBG confirmed the diagnosis.

Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study.

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients <60 years. Relative to those >60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials.

Hypocupraemia-induced anaemia, sensory ataxia and cognitive impairment secondary to zinc-containing dental adhesive.

A 67-year-old man presented with 5 months of worsening memory impairment and sensory gait ataxia on the background of symptomatic anaemia. He experienced falls, agitation and became socially withdrawn over 3 weeks, resulting in hospital admission. On examination, he had sensory gait ataxia consistent with a dorsal column syndrome. He scored 13/30 on the Montreal Cognitive Assessment. Serum analysis showed normocytic anaemia and leucopenia, severe hypocupraemia, reduced caeruloplasmin and normal zinc levels. Overuse of zinc-containing denture cream was the cause of excess zinc ingestion and resultant copper deficiency, leading to blood dyscrasia and myelopathy. The cream was withdrawn and intravenous and then oral copper supplementation was implemented. Direct questions with regard to excess zinc in the diet and serological testing of copper and zinc should be considered in any patient with a dorsal column syndrome, particularly with concurrent anaemia. Copper deficiency may also have a role in exacerbating pre-existing cognitive impairment.

Multiple cerebral infarcts: a rare complication of neurosarcoidosis.

A 52-year-old man experienced a relapse of neurosarcoidosis, characterised by obstructive hydrocephalus and multiple posterior circulation infarcts. He was taking methotrexate, but his prednisolone was being weaned because of adverse effects. Stroke is rare in neurosarcoidosis and typically relates to granulomatous inflammation with a predilection for the perforator arteries. Sarcoidosis generally responds well to corticosteroids; however, patients with leptomeningeal involvement usually require additional immunosuppression as relapses can occur on weaning of corticosteroids. It is worth considering tumour necrosis factor-α antagonists for cases that progress despite first-line therapy.

The Wessex modified Richmond Sedation Scale as a novel tool for monitoring patients at risk of malignant MCA syndrome.

BACKGROUND: The Wessex Modified Richmond Sedation Scale (WMRSS) has been developed with the aim of improving the early identification of patients requiring decompressive hemicraniectomy for malignant middle cerebral artery syndrome (MMS). The objective of this study was to evaluate the WMRSS against the Glasgow Coma Scale (GCS). METHODS: A retrospective study was conducted of patients admitted to our unit for observation of MMS. Data were obtained on WMRSS and GCS recordings from admission up to 120-h post-ictus. Patients' meeting inclusion criteria were recommended for theatre based on subsequent deteriorations in consciousness on either WMRSS or GCS from a 6-h post-stroke baseline, after ruling out non-neurological causes. RESULTS: Approximately, 60% of those eligible for monitoring were not recommended for theatre, and none died; however, these patients continued to demonstrate some variability in recorded conscious level. Patients requiring surgical intervention showed earlier drops in WMRSS compared to GCS. Neither the GCS nor the WMRSS on admission predicted the subsequent need for decompressive surgery. There was no increase in mortality with the introduction of WMRSS. CONCLUSIONS: WMRSS adds value to monitoring MMS by indicating need for surgery prior to GCS. Early reduction in consciousness may not be sufficient for proceeding to surgical intervention, but subsequent reduction in consciousness may be a more appropriate criterion for surgery.

VBM with viscous fluid registration of gray matter segments in SPM.

Improved registration of gray matter segments in SPM has been achieved with the DARTEL algorithm. Previous work from our group suggested, however, that such improvements may not translate to studies of clinical groups. To address the registration issue in atrophic brains, this paper relaxed the condition of diffeomorphism, central to DARTEL, and made use of a viscous fluid registration model with limited regularization constraints to register the modulated gray matter probability maps to an intra-population template. Quantitative analysis of the registration results after the additional viscous fluid step showed no worsening of co-localization of fiducials compared to DARTEL or unified segmentation methods, and the resulting voxel based morphometry (VBM) analyses were able to better identify atrophic regions and to produce results with fewer apparent false positives. DARTEL showed great sensitivity to atrophy, but the resulting VBM maps presented broad, amorphous regions of significance that are hard to interpret. We propose that the condition of diffeomorphism is not necessary for basic VBM studies in atrophic populations, but also that it has disadvantages that must be taken into consideration before a study. The presented viscous fluid registration method is proposed for VBM studies to enhance sensitivity and localizing power.

Diffusion tensor metrics as biomarkers in Alzheimer's disease.

BACKGROUND: Although diffusion tensor imaging has been a major research focus for Alzheimer's disease in recent years, it remains unclear whether it has sufficient stability to have biomarker potential. To date, frequently inconsistent results have been reported, though lack of standardisation in acquisition and analysis make such discrepancies difficult to interpret. There is also, at present, little knowledge of how the biometric properties of diffusion tensor imaging might evolve in the course of Alzheimer's disease. METHODS: The biomarker question was addressed in this study by adopting a standardised protocol both for the whole brain (tract-based spatial statistics), and for a region of interest: the midline corpus callosum. In order to study the evolution of tensor changes, cross-sectional data from very mild (N = 21) and mild (N = 22) Alzheimer's disease patients were examined as well as a longitudinal cohort (N = 16) that had been rescanned at 12 months. FINDINGS AND SIGNIFICANCE: The results revealed that increased axial and mean diffusivity are the first abnormalities to occur and that the first region to develop such significant differences was mesial parietal/splenial white matter; these metrics, however, remained relatively static with advancing disease indicating they are suitable as 'state-specific' markers. In contrast, increased radial diffusivity, and therefore decreased fractional anisotropy-though less detectable early-became increasingly abnormal with disease progression, and, in the splenium of the corpus callosum, correlated significantly with dementia severity; these metrics therefore appear 'stage-specific' and would be ideal for monitoring disease progression. In addition, the cross-sectional and longitudinal analyses showed that the progressive abnormalities in radial diffusivity and fractional anisotropy always occurred in areas that had first shown an increase in axial and mean diffusivity. Given that the former two metrics correlate with dementia severity, but the latter two did not, it would appear that increased axial diffusivity represents an upstream event that precedes neuronal loss.

The relationship of topographical memory performance to regional neurodegeneration in Alzheimer's disease.

The network activated during normal route learning shares considerable homology with the network of degeneration in the earliest symptomatic stages of Alzheimer's disease (AD). This inspired the virtual route learning test (VRLT) in which patients learn routes in a virtual reality environment. This study investigated the neural basis of VRLT performance in AD to test whether impairment was underpinned by a network or by the widely held explanation of hippocampal degeneration. VRLT score in a mild AD cohort was regressed against gray matter (GM) density and diffusion tensor metrics of white matter (WM) (n = 30), and, cerebral glucose metabolism (n = 26), using a mass univariate approach. GM density and cerebral metabolism were then submitted to a multivariate analysis [support vector regression (SVR)] to examine whether there was a network associated with task performance. Univariate analyses of GM density, metabolism and WM axial diffusion converged on the vicinity of the retrosplenial/posterior cingulate cortex, isthmus and, possibly, hippocampal tail. The multivariate analysis revealed a significant, right hemisphere-predominant, network level correlation with cerebral metabolism; this comprised areas common to both activation in normal route learning and early degeneration in AD (retrosplenial and lateral parietal cortices). It also identified right medio-dorsal thalamus (part of the limbic-diencephalic hypometabolic network of early AD) and right caudate nucleus (activated during normal route learning). These results offer strong evidence that topographical memory impairment in AD relates to damage across a network, in turn offering complimentary lesion evidence to previous studies in healthy volunteers for the neural basis of topographical memory. The results also emphasize that structures beyond the mesial temporal lobe (MTL) contribute to memory impairment in AD-it is too simplistic to view memory impairment in AD as a synonym for hippocampal degeneration.

Atrophy, hypometabolism and white matter abnormalities in semantic dementia tell a coherent story.

Semantic dementia, in which there is progressive deterioration of semantic knowledge, is associated with focal, typically asymmetric, temporal lobe degeneration. The ventrorostral temporal lobe is most severely affected and there is concordance between atrophy and reduced metabolic activity. In this study, we confirmed the veracity of this claim using ¹8F-fluorodeoxyglucose positron emission tomography and anatomical magnetic resonance images. The principal aim, however, was to understand the impact on neuronal projections from the ventrorostral temporal cortex lesion by studying the full extent of white matter changes, with no a priori assumptions about the nature or spatial location of the tracts involved. Using an unbiased voxel-wise approach known as tract-based spatial statistics, we compared results of whole-brain diffusion tensor imaging--absolute metrics of axial, radial and mean diffusion as well as fractional anisotropy--from 10 patients with mild/moderate semantic dementia and 21 matched controls. Distributions of increased absolute diffusivity and reduced fractional anisotropy for patients with semantic dementia were spatially concordant with each other. Abnormalities in all metrics were highly statistically significant in ventrorostral temporal white matter, more extreme on the left side, thus closely matching results from structural and functional imaging of grey matter. The most sensitive marker of change was radial diffusion. Local white matter tract abnormalities extended rostrally towards the frontal lobe and dorsocaudally towards the superior temporal and supramarginal gyri. To examine more remote changes, we performed a skeletonized probabilistic tractography analysis--'seeding' the rostral temporal voxels identified as abnormal in the patient group--in a healthy control group. Three major neural pathways were found to emanate from this 'seed region': uncinate, arcuate and inferior longitudinal fasciculi. At a less conservative threshold, tensor abnormalities in the semantic dementia group mapped onto the tractographies for the uncinate and arcuate bundles well beyond the rostral temporal lobe; this was not the case for the inferior longitudinal bundle, where abnormalities in semantic dementia did not extend caudal to the atrophic/hypometabolic zone. The results offer direct evidence for how the ventrorostral temporal lesion, proposed to be responsible for deteriorating semantic knowledge in semantic dementia and separate from 'classic' language areas, is associated with degeneration of efferent white matter projections to such language areas.

MRI detection of tissue pathology beyond atrophy in Alzheimer's disease: introducing T2-VBM.

Voxel-based morphometry (VBM) of T1-weighted magnetic resonance (MR) images has been widely used to identify regional atrophy in neurodegenerative conditions such as Alzheimer's disease (AD). In theory, however, T2-weighting should be more sensitive to tissue pathology, though until recently, volumetric T2-weighted images were unavailable. We tested the hypothesis that T2-VBM would be more sensitive to grey matter pathology in AD than T1-VBM using the recently-developed SPACE acquisition, which provides true-3D, high-resolution T2-weighted images. This was contrasted to conventional T1-weighted MPRAGE images acquired at the same session and resolution. All of the atrophic regions identified with T1-VBM were also identified with T2-VBM. Additional abnormalities were, however, identified with T2-VBM and the distribution of these bore a striking resemblance to the distribution of amyloid plaque deposition in AD, suggesting that T2-VBM detects signal changes due to histopathology over and above those attributable to atrophy. In keeping with this hypothesis, the relevant statistical tests demonstrated that the difference in sensitivity was caused by an apparent change in T2-weighted signal intensity that was not present in T1-weighted images. These results suggest that T2-VBM has the potential to advance VBM beyond atrophy detection to more expansive applications in tissue pathology mapping.

What the left and right anterior fusiform gyri tell us about semantic memory.

The study of patients with semantic dementia, a variant of frontotemporal lobar degeneration, has emerged over the last two decades as an important lesion model for studying human semantic memory. Although it is well-known that semantic dementia is associated with temporal lobe degeneration, controversy remains over whether the semantic deficit is due to diffuse temporal lobe damage, damage to only a sub-region of the temporal lobe or even less severe damage elsewhere in the brain. The manner in which the right and left temporal lobes contribute to semantic knowledge is also not fully elucidated. In this study we used unbiased imaging analyses to correlate resting cerebral glucose metabolism and behavioural scores in tests of verbal and non-verbal semantic memory. In addition, a region of interest analysis was performed to evaluate the role of severely hypometabolic areas. The best, indeed the only, strong predictor of semantic scores across a set of 21 patients with frontotemporal lobar degeneration with semantic impairment was degree of hypometabolism in the anterior fusiform region subjacent to the head and body of the hippocampus. As hypometabolism in the patients' rostral fusiform was even more extreme than the abnormality in other regions with putative semantic relevance, such as the temporal poles, the significant fusiform correlations cannot be attributed to floor-level function in these other regions. More detailed analysis demonstrated more selective correlations: left anterior fusiform function predicted performance on two expressive verbal tasks, whereas right anterior fusiform metabolism predicted performance on a non-verbal test of associative semantic knowledge. This pattern was further supported by an additional behavioural study performed on a wider cohort of patients with semantic dementia, in which the patients with more extensive right-temporal atrophy (when matched on degree of naming deficit to a set of cases with more extensive left temporal atrophy) were significantly more impaired on the test of non-verbal semantics. Our preferred interpretation of this laterality effect involves differential strength of connectivity between different regions of a widespread semantic network in the human brain.

Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease.

Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.

Lost and found: bespoke memory testing for Alzheimer's disease and semantic dementia.

The neural network activated during Topographical Memory (TM) tasks in controls overlaps with the earliest affected regions in Alzheimer's disease (AD) but not with those of Semantic Dementia (SD). This suggests that clinical TM tests could be more bespoke to neural dysfunction in early AD and therefore more sensitive and specific. We hypothesized that TM impairment would be characteristic of AD but not of SD making it useful both for early diagnosis and differential diagnosis. TM was assessed in 69 patients (22 mild AD, 15 SD, 32 with mild cognitive impairment (MCI)) and 35 controls, using three tasks: the four mountains test and two novel tests in a virtual town (the Virtual Route Learning Test (VRLT) and the Heading Orientation Test). AD patients were impaired on all TM tasks. The VRLT was the most discriminatory; had the highest correlation with caregiver reports of navigation problems; and correlated strongly with memory, attention/executive function, and to a lesser degree, visuospatial ability. In contrast, SD patients performed well on the TM battery only becoming abnormal with very advanced dementia and performance correlated exclusively with attention/executive function. The VRLT achieved 95% sensitivity and 94% specificity in discriminating AD patients from controls; at the same cutoff, 70% of MCI patients were impaired. When combined with either naming performance or global dementia severity, there was complete separation of AD from SD. The VRLT is ecologically valid, highly sensitive to early AD, and useful in discriminating AD from the non-Alzheimer dementia, SD.

Focal posterior cingulate atrophy in incipient Alzheimer's disease.

Severe posterior cingulate cortex hypometabolism is a feature of incipient, sporadic Alzheimer's disease (AD). The aim was to test the hypothesis that this region is focally atrophic in very early disease by studying AD patients at the mild cognitive impairment (MCI) stage, and, if so, to determine whether the amount of atrophy was comparable to that of the hippocampus. Twenty-four patients meeting criteria for amnestic MCI, who all subsequently progressed to fulfil AD criteria, and 28 age-matched controls, were imaged with volumetric MRI. Four regions of interest were manually traced in each hemisphere: two posterior cingulate regions (BA 23 and BA 29/30), the hippocampus (as a positive control) and the anterior cingulate (as a negative control). BA 23 and BA 29/30 were both significantly atrophic and this atrophy was comparable to that found in the hippocampus, in the absence of anterior cingulate cortex (ACC) atrophy. Contrary to previous reports, there was no evidence that posterior cingulate atrophy is specifically associated with early-onset AD. The results indicate that posterior cingulate cortex atrophy is present from the earliest clinical stage of sporadic AD and that this region is as vulnerable to neurodegeneration as the hippocampus.

Self administered cognitive screening test (TYM) for detection of Alzheimer's disease: cross sectional study.

OBJECTIVE: To evaluate a cognitive test, the TYM ("test your memory"), in the detection of Alzheimer's disease. DESIGN: Cross sectional study. SETTING: Outpatient departments in three hospitals, including a memory clinic. PARTICIPANTS: 540 control participants aged 18-95 and 139 patients attending a memory clinic with dementia/amnestic mild cognitive impairment. INTERVENTION: Cognitive test designed to use minimal operator time and to be suitable for non-specialist use. MAIN OUTCOME MEASURES: Performance of normal controls on the TYM. Performance of patients with Alzheimer's disease on the TYM compared with age matched controls. Validation of the TYM with two standard tests (the mini-mental state examination (MMSE) and the Addenbrooke's cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimer's disease. RESULTS: Control participants completed the TYM with an average score of 47/50. Patients with Alzheimer's disease scored an average of 33/50. The TYM score shows excellent correlation with the two standard tests. A score of

Comparative reliability of total intracranial volume estimation methods and the influence of atrophy in a longitudinal semantic dementia cohort.

BACKGROUND AND PURPOSE: Total intracranial volume (TIV) as a measure of premorbid brain size is often used to correct volumes of interest for interindividual differences in magnetic resonance imaging (MRI) studies. We directly compared the reliability of different TIV estimation methods to address whether such methods are influenced by brain atrophy in the neurodegenerative disease, semantic dementia. METHODS: We contrasted several manual approaches using T1-weighted, T2-weighted, and proton density (PD) acquisitions with 2 automated methods (statistical parametric mapping 5 [SPM5] and FreeSurfer [FS]) in a cohort of semantic dementia subjects (n= 11) that had been imaged longitudinally. RESULTS: Novel mid-cranial sampling of either PD or T2-weighted images were least susceptible to atrophy: of these, the PD method was both more precise and more user-friendly. SPM5 also produced good results, providing automation for only a small loss in precision compared to the best manual methods. The T1 method that underestimated TIV as atrophy progressed was the least reproducible and the most labor-intensive. Fully automated FS overestimated TIV with progressive atrophy, and the results were even worse after optimizing the transformation. CONCLUSION: The mid-cranial sampling of PD images achieved the best combination of precision, reliability, and user-friendliness. SPM5 is an attractive alternative if the highest level of precision is not required.

The impact of skull-stripping and radio-frequency bias correction on grey-matter segmentation for voxel-based morphometry.

This study evaluates the application of (i) skull-stripping methods (hybrid watershed algorithm (HWA), brain surface extractor (BSE) and brain-extraction tool (BET2)) and (ii) bias correction algorithms (nonparametric nonuniform intensity normalisation (N3), bias field corrector (BFC) and FMRIB's automated segmentation tool (FAST)) as pre-processing pipelines for the technique of voxel-based morphometry (VBM) using statistical parametric mapping v.5 (SPM5). The pipelines were evaluated using a BrainWeb phantom, and those that performed consistently were further assessed using artificial-lesion masks applied to 10 healthy controls compared to the original unlesioned scans, and finally, 20 Alzheimer's disease (AD) patients versus 23 controls. In each case, pipelines were compared to each other and to those from default SPM5 methodology. The BET2+N3 pipeline was found to produce the least miswarping to template induced by real abnormalities, and performed consistently better than the other methods for the above experiments. Occasionally, the clusters of significant differences located close to the boundary were dragged out of the glass-brain projections -- this could be corrected by adding background noise to low-probability voxels in the grey matter segments. This method was confirmed in a one-dimensional simulation and was preferable to threshold and explicit (simple) masking which excluded true abnormalities.