Accuracy of MRI Classification Algorithms in a Tertiary Memory Center Clinical Routine Cohort.

BACKGROUND: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers have been evaluated mostly in the artificial setting of research datasets. OBJECTIVE: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic. METHODS: We studied 239 patients with cognitive troubles from a single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria. RESULTS: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM. CONCLUSION: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis.

Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers.

INTRODUCTION: In vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers profiles are still unknown. METHODS: Twenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain 18F-FDG PET. RESULTS: All patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients. CONCLUSION: Our findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients.

COGEVIS: A New Scale to Evaluate Cognition in Patients with Visual Deficiency.

We evaluated the cognitive status of visually impaired patients referred to low vision rehabilitation (LVR) based on a standard cognitive battery and a new evaluation tool, named the COGEVIS, which can be used to assess patients with severe visual deficits. We studied patients aged 60 and above, referred to the LVR Hospital in Paris. Neurological and cognitive evaluations were performed in an expert memory center. Thirty-eight individuals, 17 women and 21 men with a mean age of 70.3 ± 1.3 years and a mean visual acuity of 0.12 ± 0.02, were recruited over a one-year period. Sixty-three percent of participants had normal cognitive status. Cognitive impairment was diagnosed in 37.5% of participants. The COGEVIS score cutoff point to screen for cognitive impairment was 24 (maximum score of 30) with a sensitivity of 66.7% and a specificity of 95%. Evaluation following 4 months of visual rehabilitation showed an improvement of Instrumental Activities of Daily Living (p = 0.004), National Eye Institute Visual Functioning Questionnaire (p = 0.035), and Montgomery-Åsberg Depression Rating Scale (p = 0.037). This study introduces a new short test to screen for cognitive impairment in visually impaired patients.

Alzheimer's Disease Diagnosis Relies on a Twofold Clinical-Biological Algorithm: Three Memory Clinic Case Reports.

The International Working Group recently provided revised criteria of Alzheimer's disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an "amnesic syndrome of the hippocampal type" (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight that the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice.

Free and Cued Selective Reminding Test - accuracy for the differential diagnosis of Alzheimer's and neurodegenerative diseases: A large-scale biomarker-characterized monocenter cohort study (ClinAD).

INTRODUCTION: The International Working Group recommended the Free and Cued Selective Reminding Test (FCSRT) as a sensitive detector of the amnesic syndrome of the hippocampal type in typical Alzheimer's disease (AD). But does it differentiate AD from other neurodegenerative diseases? METHODS: We assessed the FCSRT and cerebrospinal fluid (CSF) AD biomarkers in 992 cases. Experts, blinded to biomarker data, attributed in 650 cases a diagnosis of typical AD, frontotemporal dementia, posterior cortical atrophy, Lewy body disease, progressive supranuclear palsy, corticobasal syndrome, primary progressive aphasias, "subjective cognitive decline," or depression. RESULTS: The FCSRT distinguished typical AD from all other conditions with a sensitivity of 100% and a specificity of 75%. Non-AD neurodegenerative diseases with positive AD CSF biomarkers ("atypical AD") did not have lower FCSRT scores than those with negative biomarkers. DISCUSSION: The FCSRT is a reliable tool for diagnosing typical AD among various neurodegenerative diseases. At an individual level, however, its specificity is not absolute. Our findings also widen the spectrum of atypical AD to multiple neurodegenerative conditions.

Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology. METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

Deciphering logopenic primary progressive aphasia: a clinical, imaging and biomarker investigation.

Within primary progressive aphasia the logopenic variant remains less understood than the two other main variants, namely semantic and non-fluent progressive aphasia. This may be because of the relatively small number of explored patients and because of the lack of investigations with a comprehensive three-level characterization of cognitive, brain localization and biological aspects. The aim of the present study was to decipher the logopenic variant through a multimodal approach with a large cohort of 19 patients (age 66.5 ± 8.7 years, symptom duration 3.2 ± 0.6 years) using detailed cognitive and linguistic assessments, magnetic resonance imaging and perfusion single-photon emission computed tomography as well as cerebrospinal fluid biomarkers screening for Alzheimer pathology. The linguistic assessment unveiled that language dysfunction is not limited to the typical feature of word finding and verbal working memory impairments but that it extends into the language system affecting to some degree syntactic production, phonological encoding and semantic representations. Perfusion tomography revealed damage of the temporal-parietal junction with a peak of significance in the superior temporal gyrus (Brodmann area 42), and of some less significant prefrontal areas (Brodmann areas 8, 9 and 46), whereas hippocampal cortices were unaffected. Magnetic resonance imaging, which was visually assessed in a larger group of 54 patients with logopenic, non-fluent, semantic variants as well as with posterior cortical atrophy, confirmed that the logopenic variant demonstrates predominant atrophy of left temporal-parietal junction, but that this atrophy pattern has a relatively poor sensitivity and specificity for clinical diagnosis. Finally, the biomarker study revealed that two-thirds of the logopenic patients demonstrated a profile indicative of Alzheimer pathology whereas one-third had a non-Alzheimer profile. Splitting the two groups showed that logopenic aphasia due to probable Alzheimer pathology is a more aggressive variant characterized by more extensive language/cognitive disorders affecting, in addition to lexical processes and verbal working memory, also phoneme sequencing, semantic processing and ideomotor praxis. Concordantly, logopenic aphasia due to probable Alzheimer pathology demonstrated more extensive brain hypoperfusion involving larger regions throughout the inferior parietal, the posterior-superior and the middle temporal cortex. These findings allow for unfolding logopenic aphasia into two subvariants differing by disease severity, lesion nature and lesion distribution, which has important implications for diagnosis, patient management and for potential future trials with anti-Alzheimer drugs. The present data therefore provide novel insight into the cognition and brain damage of logopenic patients while unveiling the existence of distinct diseases constituting a 'logopenic aphasia complex'.

Frontal presentation of Alzheimer's disease: a series of patients with biological evidence by CSF biomarkers / Apresentação frontal da doença de Alzheimer: uma série de pacientes com evidência biológica por biomarcadores no LCR

Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.

Além da típica forma amnésica, apresentações focais atípicas da doença de Alzheimer (DA) foram descritas em estudos anatomopatológicos. Essas variantes fenotípicas da DA ("DA atípica") não seguem o padrão amnésico convencional e incluem síndromes corticais focais não amnésicas, tais como a atrofia cortical posterior e a variante frontal da DA. Essas variantes apresentam lesões histológicas características da DA ao exame patológico post-mortem. O uso de marcadores fisiopatológicos da DA, como os biomarcadores do líquido cefalorraquidiano, permite estabelecer in vivo um diagnóstico biológico de DA nessas síndromes corticais focais. Reportamos uma série de oito pacientes que foram clinicamente diagnosticados como portadores da variante comportamental da demência frontotemporal (de acordo com critérios clínicos, neuropsicológicos e de neuroimagem), mas nos quais a investigação dos biomarcadores do líquor mostrou um perfil biológico de DA, de modo que o diagnóstico da variante frontal de DA foi finalmente estabelecido.

Frontal presentation of Alzheimer's disease: a series of patients with biological evidence by CSF biomarkers.

Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.

Além da típica forma amnésica, apresentações focais atípicas da doença de Alzheimer (DA) foram descritas em estudos anatomopatológicos. Essas variantes fenotípicas da DA ("DA atípica") não seguem o padrão amnésico convencional e incluem síndromes corticais focais não amnésicas, tais como a atrofia cortical posterior e a variante frontal da DA. Essas variantes apresentam lesões histológicas características da DA ao exame patológico post-mortem. O uso de marcadores fisiopatológicos da DA, como os biomarcadores do líquido cefalorraquidiano, permite estabelecer in vivo um diagnóstico biológico de DA nessas síndromes corticais focais. Reportamos uma série de oito pacientes que foram clinicamente diagnosticados como portadores da variante comportamental da demência frontotemporal (de acordo com critérios clínicos, neuropsicológicos e de neuroimagem), mas nos quais a investigação dos biomarcadores do líquor mostrou um perfil biológico de DA, de modo que o diagnóstico da variante frontal de DA foi finalmente estabelecido.

Visuospatial deficits and hemispheric perfusion asymmetries in posterior cortical atrophy.

We studied visuospatial performance and obtained brain perfusion scintigraphy in 27 patients with posterior cortical atrophy (PCA) and 24 healthy controls, with two aims: (1) to determine inter-hemispheric perfusion imbalances underlying signs of spatial neglect and (2) to establish the functional substrates of patients' performance on distinct visuospatial tasks (line bisection and target cancellation). Between-groups and correlation analyses were performed on a voxel-wise basis with Statistical Parametric Mapping, and right-to-left hemispheric perfusion ratios were calculated in anatomical regions of interest. Nineteen patients had pathological spatial biases. Compared with controls, patients with signs of left-sided and right-sided neglect presented prominent hypoperfusion in the right and left parietal cortex, respectively. Importantly, hypoperfusion extended to the ipsilateral prefrontal regions. Correlation analyses between task scores and brain perfusion showed that shifts in line bisection correlated with hypoperfusion in parieto-frontal regions, whereas omissions on target cancellation mainly correlated with hypoperfusion in prefrontal structures. Overall, the results indicate that spatial neglect in PCA is related to inter-hemispheric perfusion asymmetries in fronto-parietal networks, with partially different neural correlates for line bisection and target cancellation.

Visuospatial deficits in posterior cortical atrophy: structural and functional correlates.

OBJECTIVE: To determine the neural substrates of biased spatial orienting in posterior cortical atrophy (PCA) by using a combined structural and functional neuroimaging approach. BACKGROUND: Patients with spatial neglect typically bisect horizontal long lines towards their brain lesions but the precise neural substrates of this spatial bias remain controversial and poorly explored in neurodegenerative disorders such as PCA. METHODS: 15 patients with PCA underwent brain MRI and single photon emission computed tomography (SPECT) and were required to bisect five 20 cm long lines, each centred on an A4 horizontal sheet. Direct correlations between average deviations on the bisection task and both (1) the degree of grey matter density, as estimated by voxel based morphometry and (2) regional cerebral blood flow, as assessed by SPECT, were performed. RESULTS: Seven patients (47%) had pathological bias on the bisection task, deviating consistently towards the non-neglected side for each of the five lines. Rightward bias (sign of left-sided neglect) was more frequent and severe than leftward bias (sign of right-sided neglect). Correlation analyses showed that rightward deviations correlated with atrophy and hypoperfusion exclusively in the right hemisphere, involving a large scale fronto-parietal network; cortical atrophy was prominent in the parieto-temporal cortex but extended to the frontal region; hypoperfusion was substantial both in the middle frontal gyrus and in the postcentral region. No correlations emerged from leftward deviations. CONCLUSION: The results indicate that rightward bias (sign of left-sided neglect) in PCA depends on dysfunction of a large fronto-parietal network in the right hemisphere, related to both cortical atrophy and decreased cerebral perfusion.

Brain networks in posterior cortical atrophy: a single case tractography study and literature review.

Posterior cortical atrophy (PCA) is rare neurodegenerative dementia, clinically characterized by a progressive decline in higher-visual object and space processing. After a brief review of the literature on the neuroimaging in PCA, here we present a study of the brain structural connectivity in a patient with PCA and progressive isolated visual and visuo-motor signs. Clinical and cognitive data were acquired in a 58-years-old patient (woman, right-handed, disease duration 18 months). Brain structural and diffusion tensor (DT) magnetic resonance imaging (MRI) were obtained. A voxel-based morphometry (VBM) study was performed to explore the pattern of gray matter (GM) atrophy, and a fully automatic segmentation was assessed to obtain the hippocampal volumes. DT MRI-based tractography was used to assess the integrity of long-range white matter (WM) pathways in the patient and in six sex- and age-matched healthy subjects. This PCA patient had a clinical syndrome characterized by left visual neglect, optic ataxia, and left limb apraxia, as well as mild visuo-spatial episodic memory impairment. VBM study showed bilateral posterior GM atrophy with right predominance; DT MRI tractography demonstrated WM damage to the right hemisphere only, including the superior and inferior longitudinal fasciculi and the inferior fronto-occipital fasciculus, as compared to age-matched controls. The homologous left-hemisphere tracts were spared. No difference was found between left and right hippocampal volumes. These data suggest that selective visuo-spatial deficits typical of PCA might not result from cortical damage alone, but by a right-lateralized network-level dysfunction including WM damage along the major visual pathways.

Similar amyloid-ß burden in posterior cortical atrophy and Alzheimer's disease.

While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-ß burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. ¹¹C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased ¹¹C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global ¹¹C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-ß deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-ß accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

Neural correlates of cognitive impairment in posterior cortical atrophy.

With the prospect of disease-modifying drugs that will target the physiopathological process of Alzheimer's disease, it is now crucial to increase the understanding of the atypical focal presentations of Alzheimer's disease, such as posterior cortical atrophy. This study aimed to (i) characterize the brain perfusion profile in posterior cortical atrophy using regions of interest and a voxel-based approach; (ii) study the influence of the disease duration on the clinical and imaging profiles; and (iii) explore the correlations between brain perfusion and cognitive deficits. Thirty-nine patients with posterior cortical atrophy underwent a specific battery of neuropsychological tests, mainly targeting visuospatial functions, and a brain perfusion scintigraphy with 99mTc-ethyl cysteinate dimer. The imaging analysis included a comparison with a group of 24 patients with Alzheimer's disease, matched for age, disease duration and Mini-Mental State Examination, and 24 healthy controls. The single-photon emission computed tomography profile in patients with posterior cortical atrophy was characterized by extensive and severe hypoperfusion in the occipital, parietal, posterior temporal cortices and in a smaller cortical area corresponding to the frontal eye fields (Brodmann areas 6/8). Compared with patients with Alzheimer's disease, the group with posterior cortical atrophy showed more severe occipitoparietal hypoperfusion and higher perfusion in the frontal, anterior cingulate and mesiotemporal regions. When considering the disease duration, the functional changes began and remained centred on the posterior lobes, even in the late stage. Correlation analyses of brain perfusion and neuropsychological scores in posterior cortical atrophy highlighted the prominent role of left inferior parietal damage in acalculia, Gerstmann's syndrome, left-right indistinction and limb apraxia, whereas damage to the bilateral dorsal occipitoparietal regions appeared to be involved in Bálint's syndrome. Our findings provide new insight into the natural history of functional changes according to disease duration and highlight the role of parietal and occipital cortices in the cognitive syndromes that characterize the posterior cortical atrophy.

Visual neglect in posterior cortical atrophy.

BACKGROUND: In posterior cortical atrophy (PCA), there is a progressive impairment of high-level visual functions and parietal damage, which might predict the occurrence of visual neglect. However, neglect may pass undetected if not assessed with specific tests, and might therefore be underestimated in PCA. In this prospective study, we aimed at establishing the side, the frequency and the severity of visual neglect, visual extinction, and primary visual field defects in an unselected sample of PCA patients. METHODS: Twenty-four right-handed PCA patients underwent a standardized battery of neglect tests. Visual fields were examined clinically by the confrontation method. RESULTS: Sixteen of the 24 patients (66%) had signs of visual neglect on at least one test, and fourteen (58%) also had visual extinction or hemianopia. Five patients (21%) had neither neglect nor visual field defects. As expected, left-sided neglect was more severe than right-sided neglect. However, right-sided neglect resulted more frequently in this population (29%) than in previous studies on focal brain lesions. CONCLUSION: When assessed with specific visuospatial tests, visual neglect is frequent in patients with PCA. Diagnosis of neglect is important because of its negative impact on daily activities. Clinicians should consider the routine use of neglect tests to screen patients with high-level visual deficits. The relatively high frequency of right-sided neglect in neurodegenerative patients supports the hypothesis that bilateral brain damage is necessary for right-sided neglect signs to occur, perhaps because of the presence in the right hemisphere of crucial structures whose damage contributes to neglect.