Age-specific prevalence of the different clinical presentations of AD and FTD in young-onset dementia.

BACKGROUND: Studies have shown that the prevalence of all-variants Alzheimer's disease (AD) and frontotemporal dementia (FTD) both increase with age, even before the age of 65. However, it is not known whether their different clinical presentations all increase in prevalence with age in the same way. METHODS: We studied the prevalence of the different clinical presentations of young-onset AD and FTD by 5-year age groups in a population-based study identifying all dementia patients with a diagnosis of AD and FTD and symptoms onset before age 65 in the Modena province, Italy. By using regression models of cumulative occurrences, we also estimated age-specific prevalence and compared the growth curves of the clinical presentations. RESULTS: The prevalence of all-variants AD increased with age, from 18/1,000,000 in the 40-44 age group to 1411/1,000,000 in the 60-64 age group. The prevalence of all-variants FTD also increased with age, from 18/1,000,000 to 866/1,000,000. An estimation of age-specific prevalence functions of each clinical presentation showed that atypical non-amnestic AD and aphasic FTD grew the most in early ages, followed by the behavioural variant of FTD (bvFTD). Then, around the age of 60, amnestic AD took over and its age-specific prevalence continued to increase disproportionally compared to all the other clinical variants of AD and FTD, which, instead, started to decrease in prevalence. CONCLUSIONS: Amnestic AD is the clinical presentation that increases the most with advancing age, followed by bvFTD, suggesting that there is a differential vulnerability to the effect of ageing within the same neurodegenerative disease.

Impaired Self-Awareness in Parkinson's and Huntington's Diseases: A Literature Review of Neuroimaging Correlates.

Little is known about the brain correlates of anosognosia or unawareness of disease in Parkinson's Disease (PD) and Huntington's Disease (HD). The presence of unawareness or impaired self-awareness (ISA) of illness has profound implications for patients and their caregivers; therefore, studying awareness and its brain correlates should be considered a key step towards developing effective recognition and management of this symptom as it offers a window into the mechanism of self-awareness and consciousness as critical components of the human cognition. We reviewed research studies adopting MRI or other in vivo neuroimaging technique to assess brain structural and/or functional correlates of unawareness in PD and HD across different cognitive and motor domains. Studies adopting task or resting-state functional magnetic resonance imaging, and/or 18-F fluorodeoxyglucose positron emission tomography brain imaging and/or magnetic resonance imaging structural measures were considered. Only six studies investigating neuroimaging features of unawareness in PD and two in HD were identified; there was great heterogeneity in the clinical characteristics of the study participants, domain of unawareness investigated, method of unawareness assessment, and neuroimaging technique used. Nevertheless, some data converge in identifying regions of the salience and frontoparietal networks to be associated with unawareness in PD patients. In HD, the few data are affected by the variability in the severity of motor symptoms. Further studies are needed to better understand the mechanisms and brain correlates of unawareness in PD and HD; in addition, the use of dopaminergic medications should be carefully considered.

Neurofilaments Light Chain in Neurodegenerative Dementias: A Review of Imaging Correlates.

Neurofilaments light chain (NfLs) are currently recognized as a marker of axonal injury and degeneration. Their measurement in biological fluids has a promising role in the diagnosis, prognosis, and monitoring of the therapeutic response in neurological diseases, including neurodegenerative dementias. In recent years, their relationship with clinical phenotypes and measures of disease severity has been extensively studied. Here, we reviewed studies investigating the association between NfLs and imaging measures of grey matter (GM) and white matter (WM) damage in neurodegenerative dementias. We identified a large number of studies investigating this association in Alzheimer's disease (AD) and disorders of the frontotemporal dementia (FTD) spectrum. Results were heterogeneous, possibly due to different methodological approaches-both in NfL measurements and imaging analyses-and inclusion criteria. However, a positive association between NfL levels and GM atrophy, WM microstructural disruption, glucose hypometabolism, and protein accumulation emerged invariably, confirming the role of NfLs as a reliable biomarker for neurodegenerative dementias, albeit not specific.

Greenness and neuropsychiatric symptoms in dementia.

OBJECTIVES: It is acknowledged that living in a green environment may help mental well-being and this may be especially true for vulnerable people. However, the relationship between greenness and neuropsychiatric symptoms in dementia has not been explored yet. METHODS: We collected clinical, neuropsychiatric, and residential data from subjects with dementia living in the province of Modena, Northern Italy. Neuropsychiatric symptoms were measured with the Neuropsychiatry Inventory, a questionnaire administered to the caregiver who assesses the presence and severity of neuropsychiatric symptoms, including delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, sleep disturbances, and appetite/eating changes. Normalized Difference Vegetation Index (NDVI) was used as a proxy of greenness. Regression models were constructed to study the association between greenness and neuropsychiatric features. RESULTS: 155 patients with dementia were recruited. We found that greenness is variably associated with the risk of having neuropsychiatric symptoms. The risk of apathy was lower with lower levels of greenness (OR = 0.42, 95% CI 0.19-0.91 for NDVI below the median value). The risk of psychosis was higher with lower levels of greenness but with more imprecise values (OR = 1.77, 95% CI 0.84-3.73 for NDVI below the median value). CONCLUSION: Our results suggest a possible association between greenness and neuropsychiatric symptoms in people with dementia. If replicated in larger samples, these findings will pave the road for identifying innovative greening strategies and interventions that can improve mental health in dementia.

The association between lifelong personality and clinical phenotype in the FTD-ALS spectrum.

Introduction: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients' personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients' personality in their premorbid life. Methods: We first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient's personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI). Results: A significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy. Discussion: Our proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum.

Multimodal nonlinear correlates of behavioural symptoms in frontotemporal dementia.

Background: Studies exploring the brain correlates of behavioural symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioural symptoms. Methods: We analysed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behaviour Scale, and Neurobehavioral Rating Scale. We used a data-driven approach to identify the principal components underlying behavioural variability, then related the identified components to brain variability using a newly developed method fusing maps of grey matter volume and FDG metabolism. Results: A component representing apathy, executive dysfunction, and emotional withdrawal was associated with atrophy in bilateral anterior insula and putamen, and with hypometabolism in the right prefrontal cortex. Another component representing the disinhibition versus depression/mutism continuum was associated with atrophy in the right striatum and ventromedial prefrontal cortex for disinhibition, and hypometabolism in the left fronto-opercular region and sensorimotor cortices for depression/mutism. A component representing psychosis was associated with hypometabolism in the prefrontal cortex and hypermetabolism in auditory and visual cortices. Discussion: Behavioural symptoms in FTD are associated with atrophy and altered metabolism of specific brain regions, especially located in the frontal lobes, in a hierarchical way: apathy and disinhibition are mostly associated with grey matter atrophy, whereas psychotic symptoms are mostly associated with hyper-/hypo-metabolism.

Automated detection of cerebral microbleeds on MR images using knowledge distillation framework.

Introduction: Cerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate automated detection of CMBs would help to determine quantitative imaging biomarkers (e.g., CMB count) on large datasets. In this work, we propose a fully automated, deep learning-based, 3-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g., GRE/SWI/QSM) for their accurate detections. Methods: In our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. Results: On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of <2 false positives per subject. The knowledge distillation framework improves the cluster-wise TPR of the student model by 15%. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and better cluster-wise precision compared to existing state-of-the-art methods. When evaluating across different datasets, our method showed good generalizability with a cluster-wise TPR >80 % with different modalities. The python implementation of the proposed method is openly available.

Outdoor artificial light at night and risk of early-onset dementia: A case-control study in the Modena population, Northern Italy.

Background: Dementia is a neurological syndrome characterized by severe cognitive impairment with functional impact on everyday life. It can be classified as young onset dementia (EOD) in case of symptom onset before 65, and late onset dementia (LOD). The purpose of this study is to assess the risk of dementia due to light pollution, and specifically outdoor artificial light at night (LAN). Methods: Using a case-control design, we enrolled dementia patients newly-diagnosed in the province of Modena in the period 2017-2019 and a referent population from their caregivers. We geo-referenced the address of residence on the date of recruitment, provided it was stable for the previous five years. We assessed LAN exposure through 2015 nighttime luminance satellite images from the Visible Infrared Imaging Radiometer Suite (VIIRS). Using a logistic regression model adjusted for age, sex, and education, we calculated the risk of dementia associated with increasing LAN exposure, namely using <10 nW/cm2/sr as reference and considering ≥10-<40 nW/cm2/sr intermediate and ≥40 nW/cm2/sr high exposure, respectively We also implemented non-linear assessment using a spline regression model. Results: We recruited 58 EOD cases, 34 LOD cases and 54 controls. Average LAN exposure levels overlapped for EOD cases and controls, while LOD cases showed higher levels. Compared with the lowest exposure, the risk of EOD associated with LAN was higher in the intermediate exposure (OR = 1.36, 95% CI 0.54-3.39), but not in the high exposure category (OR = 1.04, 95% CI 0.32-3.34). In contrast, the risk of LOD was positively associated with LAN exposure, with ORs of 2.58 (95% CI 0.26-25.97) and 3.50 (95% CI 0.32-38.87) in the intermediate and high exposure categories, respectively. The spline regression analysis showed substantial lack of association between LAN and EOD, while almost linear although highly imprecise association emerged for LOD. Conclusions: Although the precision of the estimates was affected by the limited sample size and the study design did not allow us to exclude the presence of residual confounding, these results suggest a possible role of LAN in the etiology of dementia, particularly of its late-onset form.

Young Onset Alzheimer's Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of patients carrying this expansion varies widely and includes diseases beyond the FTD-ALS spectrum. Although a few cases of patients with C9ORF72 expansion and a clinical or biomarker-supported diagnosis of Alzheimer's disease (AD) have been described, they have been considered too sparse to establish a definite association between the C9ORF72 expansion and AD pathology. Here, we describe a C9ORF72 family with pleomorphic phenotypical expressions: a 54-year-old woman showing cognitive impairment and behavioral disturbances with both neuroimaging and cerebrospinal fluid (CSF) biomarkers consistent with AD pathology, her 49-year-old brother with typical FTD-ALS, and their 63-year-old mother with the behavioral variant of FTD and CSF biomarkers suggestive of AD pathology. The young onset of disease in all three family members and their different phenotypes and biomarker profiles make the simple co-occurrence of different diseases an extremely unlikely explanation. Our report adds to previous findings and may contribute to further expanding the spectrum of diseases associated with C9ORF72 expansion.

The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis.

Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases, the discovery of this gene has been crucial for amyotrophic lateral sclerosis research. Since the identification of superoxide dismutase 1 in 1993, the field of amyotrophic lateral sclerosis genetics has considerably widened, improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis. In this review, we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients. Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients, but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations. We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation. Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis, enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes, which is important for the therapeutic strategy targeting genetic mutations. Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors, including environment and other unidentified agents including modifier genes.

Neuroanatomical Correlates of Cognitive Tests in Young-onset MCI.

BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous condition characterised by cognitive changes that do not affect everyday functioning and may represent a predementia phase. Research on the neuroanatomical correlates of cognitive tests used to diagnose MCI is heterogeneous and has mainly focused on elderly populations of patients with MCI, usually well above the age of 65. However, the effect of ageing on brain structure is known to be substantial and to affect brain-behaviour associations in older people. We explored the brain correlates of different cognitive tests in a group of young-onset MCI (i.e., with symptoms onset before the age of 65) to minimise the effect of ageing on brain-behaviour associations. METHODS: Patients with a clinical diagnosis of young-onset MCI underwent extensive cognitive assessment and multimodal Magnetic Resonance Imaging (MRI) including high-resolution T1-weighted and Diffusion Tensor Imaging (DTI) sequences. Their scores on cognitive tests were related to measures of grey matter (GM) density and white matter (WM) integrity using, respectively, Voxel Based Morphometry (VBM) and Tract-Based Spatial Statistics (TBSS). RESULTS: 104 young-onset MCI were recruited. VBM and TBSS whole-brain correlational analyses showed that between-subject variability in cognitive performance was significantly associated with regional variability in GM density and WM integrity. While associations between cognitive scores and focal GM density in our young-onset MCI group reflected the well-known lateralization of verbal and visuo-spatial abilities on the left and right hemispheres respectively, the associations between cognitive scores and WM microstructural integrity were widespread and diffusely involved most of the WM tracts in both hemispheres. CONCLUSIONS: We investigated the structural neuroanatomical correlates of cognitive tests in young-onset MCI in order to minimise the effect of ageing on brain-behaviour associations.

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-ß burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-ß in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. METHODS: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates (M mulatta) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months). RESULTS: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, P=0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD (P<0.017), including age as a covariate and either clinical hypertension (P<0.030) or neuropathological SVD diagnosis (P<0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals (P=0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. CONCLUSIONS: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.

Selenoprotein P Concentrations in the Cerebrospinal Fluid and Serum of Individuals Affected by Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment and Alzheimer's Dementia.

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case-control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status.

Why can spontaneous intracranial hypotension cause behavioral changes? A case report and multimodality neuroimaging comparison with frontotemporal dementia.

Frontotemporal Brain Sagging Syndrome (FBSS) is a rare condition characterized by the presence of spontaneous intracranial hypotension associated with behavioural disturbances mimicking the behavioural variant of Frontotemporal dementia (bvFTD). It has been suggested that behavioural symptoms are caused by damage to the connectivity of the frontal lobes due to the brain sagging. However, no studies have directly explored brain connectivity in patients with FBSS. Here, we report a new case of FBSS with persistent behavioural disturbances, whom we compared to 20 patients with bvFTD and to 13 cognitively healthy controls using Magnetic Resonance Imaging (MRI). We explored differences related to grey matter (GM) volume with voxel-based morphometry, functional connectivity with seed-based analysis, and white matter (WM) microstructural integrity with tract-based spatial statistics. We found that the FBSS patient, like the controls, had greater GM volume relative to the bvFTD patients. Moreover, the FBSS patient had greater functional connectivity from a left inferior frontal gyrus seed than both the bvFTD patients and healthy controls groups in dorsolateral frontal areas. Like the bvFTD group the FBSS patient had decreased WM integrity relative to the controls, especially in the posterior part of the corpus callosum, and the magnitude of these abnormalities correlated with measures of apathy across the FBSS and bvFTD patients. Our results suggest that behavioural changes associated with SIH are mainly due to altered WM connectivity.

Predictive value of phospho-tau/total-tau ratio in amyloid-negative Mild Cognitive Impairment.

BACKGROUND: In patients with Mild Cognitive Impairment and normal biomarkers of amyloid-ß deposition, prognostication remains challenging. METHODS: We aimed at identifying clinical features, patterns of brain atrophy, and risk of subsequent conversion to dementia in a clinical cohort of consecutive patients with Mild Cognitive Impairment and normal CSF amyloid-ß1-42 presenting to our Cognitive Neurology Clinic who were followed prospectively over an average of 25 months. We stratified them as Converters/Non-Converters to dementia based on clinical follow-up and compared baseline clinical features, CSF biomarkers, and pattern of atrophy on MRI data between groups. RESULTS: Among 111 eligible patients (mean age 65,61 years; 56,8% were male), 41 patients developed a clinical diagnosis of dementia. Subjects with low baseline p/t-tau had twofold risk of future conversion compared to high p/t-tau ratio subjects (HR = 2.0, p = 0.026). When stratifying converters according to CSF p/t-tau ratio cut off value (0,17), those with values lower than the cut-off had significantly more MRI atrophy at baseline relative to Non-Converters in limbic structures. CONCLUSION: In Mild Cognitive Impairment patients with negative CSF amyloid biomarker, CSF p/t-tau ratio may be useful to identify those at greater risk of subsequent conversion, possibly because of TDP43-related underlying pathology.

Pure word deafness: a case report of an atypical manifestation of Alzheimer's disease.

BACKGROUND: Auditory agnosia refers to the impairments in sound recognition despite intact hearing and written language abilities. When auditory agnosia is specific to spoken language, it can be indicated as pure word deafness (PWD), which is characterized by the isolated difficulty in understanding spoken language, despite preserved reading comprehension, recognition of nonverbal sounds, and production of written and spoken language. CASE: A middle-aged man with a high level of education developed a progressive speech disorder initially characterized by isolated phonemic errors during spontaneous speech and later enriched by difficulties in comprehending long sentences. The patient's past medical history was unremarkable except for hypertension. The neuropsychological picture was suggestive of PWD, while cerebrospinal fluid (CSF) analyses lead to a biomarker-based diagnosis of Alzheimer's disease (AD). PWD remained the prevalent cognitive deficit over the subsequent 4 years. CONCLUSIONS: This case report shows that the presence of isolated auditory agnosia or PWD should prompt consideration of a diagnosis of AD. It also suggests that the spectrum of atypical presentations of early-onset AD may be larger than what we currently think.

Eliciting Implicit Awareness in Alzheimer's Disease and Mild Cognitive Impairment: A Task-Based Functional MRI Study.

Background: Recent models of anosognosia in dementia have suggested the existence of an implicit component of self-awareness about one's cognitive impairment that may remain preserved and continue to regulate behavioral, affective, and cognitive responses even in people who do not show an explicit awareness of their difficulties. Behavioral studies have used different strategies to demonstrate implicit awareness in patients with anosognosia, but no neuroimaging studies have yet investigated its neural bases. Methods: Patients with amnestic mild cognitive impairment and dementia due to Alzheimer's disease underwent functional magnetic resonance imaging (fMRI) during the execution of a color-naming task in which they were presented with neutral, negative, and dementia-related words (Dementia-Related Emotional Stroop). Results: Twenty-one patients were recruited: 12 were classified as aware and 9 as unaware according to anosognosia scales (based on clinical judgment and patient-caregiver discrepancy). Behavioral results showed that aware patients took the longest time to process dementia-related words, although differences between word types were not significant, limiting interpretation of behavioral results. Imaging results showed that patients with preserved explicit awareness had a small positive differential activation of the posterior cingulate cortex (PCC) for the dementia-related words condition compared to the negative words, suggesting attribution of emotional valence to both conditions. PCC differential activation was instead negative in unaware patients, i.e., lower for dementia-related words relative to negative-words. In addition, the more negative the differential activation, the lower was the Stroop effect measuring implicit awareness. Conclusion: Posterior cingulate cortex preserved response to dementia-related stimuli may be a marker of preserved implicit self-awareness.

The impact of transfer learning on 3D deep learning convolutional neural network segmentation of the hippocampus in mild cognitive impairment and Alzheimer disease subjects.

Research on segmentation of the hippocampus in magnetic resonance images through deep learning convolutional neural networks (CNNs) shows promising results, suggesting that these methods can identify small structural abnormalities of the hippocampus, which are among the earliest and most frequent brain changes associated with Alzheimer disease (AD). However, CNNs typically achieve the highest accuracy on datasets acquired from the same domain as the training dataset. Transfer learning allows domain adaptation through further training on a limited dataset. In this study, we applied transfer learning on a network called spatial warping network segmentation (SWANS), developed and trained in a previous study. We used MR images of patients with clinical diagnoses of mild cognitive impairment (MCI) and AD, segmented by two different raters. By using transfer learning techniques, we developed four new models, using different training methods. Testing was performed using 26% of the original dataset, which was excluded from training as a hold-out test set. In addition, 10% of the overall training dataset was used as a hold-out validation set. Results showed that all the new models achieved better hippocampal segmentation quality than the baseline SWANS model (ps < .001), with high similarity to the manual segmentations (mean dice [best model] = 0.878 ± 0.003). The best model was chosen based on visual assessment and volume percentage error (VPE). The increased precision in estimating hippocampal volumes allows the detection of small hippocampal abnormalities already present in the MCI phase (SD = [3.9 ± 0.6]%), which may be crucial for early diagnosis.