Atypical Alzheimer's Disease Research Articles

Rates of longitudinal change in 18 F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease.

IntroductionLongitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD.MethodsWe assessed regional and interindividual variation in longitudinal change on 18F‐flortaucipir PET imaging in 24 amyloid beta (Aβ)+ patients with atypical, early‐onset amnestic or non‐amnestic AD plus 62 Aβ– and 132 Aβ+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants.ResultsIn atypical AD, 18F‐flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late‐stage areas.DiscussionResults suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.

Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease

The apolipoprotein E (APOE) ε4 allele is the most well-established risk factor for Alzheimer's disease (AD), although its relationship to age at onset and clinical phenotype is unclear. We aimed to assess relationships between APOE genotype and age at onset, amyloid-beta (Aβ) deposition and typical versus atypical clinical presentations in AD. Frequency of APOE ε4 carriers by age at onset was assessed in 447 AD patients, 138 atypical AD patients recruited by the Neurodegenerative Research Group at Mayo Clinic, and 309 with typical AD from ADNI. APOE ε4 frequency increased with age at onset in atypical AD but showed a bell-shaped curve in typical AD where highest frequencies were observed between 65 and 70 years. Typical AD showed higher APOE ε4 frequencies than atypical AD only between the ages of 57 and 69 years. Global Aβ standard uptake value ratios did not differ according to APOE e4 status in either group. APOE genotype varies by both age at onset and clinical phenotype in AD, highlighting the heterogeneous nature of AD.

More Atypical than Atypical Alzheimer's Disease Phenotypes: A Treviso Dementia (TREDEM) Registry Case Report.

Background:A 57-year-old right-handed man was admitted to the Treviso Memory Clinic due to the presence of memory forgetfulness, repetition of the same questions, episodes of confusion, initial difficulties in performing complex tasks and easy distraction over the past two years, as well as recurrent and never-happened-before car accidents.Objective:We report a peculiar case of an early onset Alzheimer’s disease (AD) with an unusual symptomatology, apparently not fitting in any of the categorized atypical forms of AD nor being representative of a typical amnestic AD.Methods:The patient underwent a neuropsychological, structural, and metabolic cerebral evaluation by MRI and 18F-FDG PET, together with the search for cerebral amyloid (amyloid PET), a genetic testing for dementia related genes and the dosage of CSF protein biomarkers of neurodegenerative conditions.Results:We observed a convergence of predominant frontal (dysexecutive, verbal disinhibition) and posterior (visuospatial) features of cognitive impairment. Structural MRI sequences showed subarachnoid spaces of the vault enlarged in the fronto-parietal region with anterior and posterior cortical atrophy. The hippocampus appeared preserved. The 18F-FDG PET scans showed hypometabolism in the prefrontal, lateral temporal, posterior parietal, and occipital regions bilaterally. The 18F-Flutemetamol scan showed a diffused uptake of the amyloid tracer at the cerebral cortex. CSF biomarkers were compatible with Alzheimer’s disease (AD).Conclusion:This case report presented with clinical phenotypic aspects atypical of AD, both frontal and posterior, never described as concomitant in the most accredited criteria for atypical AD, and appeared therefore more atypical than each of the atypical AD phenotypes already reported.

Reduced synchrony in alpha oscillations during life predicts post mortem neurofibrillary tangle density in early-onset and atypical Alzheimer's disease.

Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD. In a well-characterized clinicopathological cohort of AD patients (n=13), we quantified neuronal synchrony within alpha (8-12Hz) and delta-theta (2-8Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination. Abnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination. Reduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

Bridging the Gap between Neurology and Psychiatry- Psychiatric Symptoms in the course of Neurodegenerative Disorders

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories in Alzheimer's disease as well as Lewy Body and Vascular dementia. Relatively common neurodegenerative disorder, Lewy Body Dementia (LBD) presents with psychiatric features. Mood disorders are common and often precede core symptoms of LBD. Patient with LBD especially early in the course of disease are at increased risk for suicide. Psychosis is one of the most debilitating symptoms of LBD as it is an independent risk factor for nursing home placements, increased caregiver distress and mortality. Visual hallucinations are the most common psychotic manifestation in LBD. Auditory, olfactory, tactile and gustatory hallucinations and delusions are less frequently found. Global cognitive deficits including attention, frontal executive dysfunction, visuospatial abnormalities, language and verbal memory were associated with the presence of psychosis in Lewy Body Dementia. Glucocerebrosidase gene (GBA) mutations and polymorphisms found to be associated with LBD. Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Frontal signs and symptoms are often seen in Alzheimer's disease especially in patients with early onset. In those clinical situations differential diagnosis especially distunguising between Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau and phosphorylated tau181. MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. We will review atypical forms of AD from these varied perspectives to help improve diagnostic confidence among clinicians. Cerebral amyloid angiopathy (CAA) is a highly prevalent pathologic finding in the elderly contributing to cognitive loss, neuropsychiatric symptoms and morbidity. It is characterized by predominantly vascular deposition of beta amyloid protein Its prevalence varies across different populations. Initially conceptualized as vascular dementia syndrome CAA was proved to overlap with AD pathology and is thought to affect over 80% of AD patients. Lobar intracerebral hemorrhage and infarction are the well-known striking clinical manifestations, but CAA has multiple other clinical phenotypes: Inflammatory disease in the form of vasculitis known as amyloid beta related angiitis (ABRA) and inflammatory leukoencephalopathy, also known as CAA related inflammation (CAA-RI). Due to multiple clinical phenotypes CAA remains clinically underdiagnosed and underreported especially in elderly with dementia and other psychiatric symptoms. The underlying pathophysiological mechanism for the spectrum of CAA will be discussed.

Deepen into sleep and wake patterns across Alzheimer's disease phenotypes.

Although, the clinical variants of Alzheimer's disease (AD) show distinct patterns of cognitive and behavioral decline, disease progression, and neuropathological features, it is unclear if this clinical heterogeneity extends to sleep-wake patterns. Sleep and wake disturbances are frequent in typical AD, often preceding memory loss and negatively impacting the quality of life of patients and caregivers alike. Still, sleep and wake disorders are often misdiagnosed and undertreated in typical AD. Better characterization of sleep-wake features in AD clinical variants is an unmet gap of high importance because these differing patterns may require tailored treatment strategies. Moreover, as wake-promoting neurons are located in subcortical nuclei and degenerate early in typical AD, contrasting the profiles of sleep-wake patterns in typical and atypical AD aids diagnosis and brings a unique opportunity to uncover the mechanisms underlying AD clinical variants at the subcortical level and mechanisms for selective neuronal vulnerability.

A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms.

Alzheimer's disease (AD) is the commonest cause of dementia, characterized by the clinical presentation of progressive anterograde episodic memory impairment. However, atypical presentation of patients is increasingly recognized. These atypical AD include logopenic aphasia, behavioural variant AD, posterior cortical atrophy, and corticobasal syndrome. These atypical AD are more common in patients with young onset AD before the age of 65 years old. Since medical needs (including the behavioural and psychological symptoms of dementia) of atypical AD patients could be different from typical AD patients, it is important for clinicians to be aware of these atypical forms of AD. In addition, disease modifying treatment may be available in the future. This review aims at providing an update on various important subtypes of atypical AD including behavioural and psychological symptoms.

The semantic storage loss score: An Algorithm for measuring an individual's level of semantic storage loss due to temporal lobe damage in neurodegenerative disease.

Anomia is common in Primary Progressive Aphasia (PPA), and there is considerable evidence that semantic problems (as opposed to impaired access to output word phonology) exist in many PPA individuals irrespective of their strict subtype, including a loss of representations from semantic memory, which is typical for people with the semantic variant of PPA. In this manuscript we present a straightforward novel clinical algorithm that quantifies this degree of semantic storage impairment. We sought to produce an algorithm by employing tasks that would measure key elements of semantic storage loss: a) whether an unrecalled name could be retrieved with cues; b) if performance for items was consistent across tasks; and c) the degree to which a participant’s performance was related to general severity of cognitive impairment rather than semantic loss. More specifically, these tasks were given to 28 individuals with PPA (12 participants had a clinical diagnosis of atypical Alzheimer’s Disease with the logopenic variant of PPA; the remaining 16 participants received a clinical diagnosis of Frontotemporal dementia (11 were classified as the non-fluent variant of PPA and five were the semantic variant of PPA). Scores from these tasks produced a single omnibus semantic memory storage loss score (SSL score) for each person that ranged from 0.0 to 1.0, with scores closer to 0 more indicative of semantic storage loss. Indeed, supporting the hypothesis that our scores measure the degree of semantic storage loss, we found participants with the semantic variant of PPA had the lowest scores, and SSL scores could predict the degree of hypometabolism in the anterior temporal lobe; even when only people with the logopenic variant of PPA were examined. Thus, these scores show promise quantitating the degree of a person’s semantic representation loss.

Longitudinal neuroimaging biomarkers differ across Alzheimer's disease phenotypes.

Alzheimer's disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer's disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer's disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer's disease (18 with typical amnestic Alzheimer's disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer's disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer's disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer's disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer's disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer's disease.

BRIDGING THE GAP BETWEEN NEUROLOGY AND PSYCHIATRY- PSYCHIATRIC SYMPTOMS IN THE COURSE OF NEURODEGENERATIVE DISORDERS

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories in Alzheimer's disease as well as Lewy Body and Vascular dementia. Relatively common neurodegenerative disorder, Lewy Body Dementia (LBD) presents with psychiatric features. Mood disorders are common and often precede core symptoms of LBD. Patient with LBD especially early in the course of disease are at increased risk for suicide. Psychosis is one of the most debilitating symptoms of LBD as it is an independent risk factor for nursing home placements, increased caregiver distress and mortality. Visual hallucinations are the most common psychotic manifestation in LBD. Auditory, olfactory, tactile and gustatory hallucinations and delusions are less frequently found. Global cognitive deficits including attention, frontal executive dysfunction, visuospatial abnormalities, language and verbal memory were associated with the presence of psychosis in Lewy Body Dementia. Glucocerebrosidase gene (GBA) mutations and polymorphisms found to be associated with LBD. Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Frontal signs and symptoms are often seen in Alzheimer's disease especially in patients with early onset. In those clinical situations differential diagnosis especially distunguising between Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau and phosphorylated tau181. MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. We will review atypical forms of AD from these varied perspectives to help improve diagnostic confidence among clinicians. Cerebral amyloid angiopathy (CAA) is a highly prevalent pathologic finding in the elderly contributing to cognitive loss, neuropsychiatric symptoms and morbidity. It is characterized by predominantly vascular deposition of beta amyloid protein Its prevalence varies across different populations. Initially conceptualized as vascular dementia syndrome CAA was proved to overlap with AD pathology and is thought to affect over 80% of AD patients. Lobar intracerebral hemorrhage and infarction are the well-known striking clinical manifestations, but CAA has multiple other clinical phenotypes: Inflammatory disease in the form of vasculitis known as amyloid beta related angiitis (ABRA) and inflammatory leukoencephalopathy, also known as CAA related inflammation (CAA-RI). Due to multiple clinical phenotypes CAA remains clinically underdiagnosed and underreported especially in elderly with dementia and other psychiatric symptoms. The underlying pathophysiological mechanism for the spectrum of CAA will be discussed

Longitudinal Amyloid-β PET in Atypical Alzheimer's Disease and Frontotemporal Lobar Degeneration.

Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer's dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer's disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). We aimed tocharacterize longitudinal Aβ accumulation anddetermine the influence of age, apolipoprotein E (APOE) genotype, disease duration, and sexin atypical AD and FTLD. 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serialPiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOEɛ4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET≤4 years. Female sex was associated with faster rates of accumulation in atypical AD. Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influence accumulation in these diseases providing insight into potentially different biological mechanisms of Aβ deposition.

Word retrieval across the biomarker-confirmed Alzheimer's disease syndromic spectrum

Alzheimer's disease (AD) is now conceptualized as a biological entity defined by amyloid and tau deposition and neurodegeneration, with heterogeneous clinical presentations. With the aid of in vivo biomarkers, clinicians are better poised to examine clinical syndromic variability arising from a common pathology. Word retrieval deficits, measured using verbal fluency and confrontation naming tests, are hallmark features of the early clinical stages of the amnestic presentations of AD, specifically in category fluency and naming with relatively spared letter fluency. As yet, there is no consensus regarding performance on these tests in atypical clinical phenotypes of AD, including posterior cortical atrophy (PCA) and logopenic primary progressive aphasia (lvPPA), in individuals who are amyloid-positive (Aβ+) but present with different clinical profiles and patterns of neurodegeneration compared to amnestic AD. The goal of the current study is to determine how Aβ+ individuals across the syndromic spectrum of AD perform on three different word retrieval tasks. A secondary goal is to determine the neuroanatomical substrates underlying word retrieval performance in these Aβ+ individuals. Thirty-two Aβ+ participants with the amnestic presentation, 16 with Aβ+ PCA, 22 with Aβ+ lvPPA, and 99 amyloid-negative (Aβ-) control participants were evaluated with verbal fluency and visual confrontation naming tests as well as high-resolution MRI. The Aβ+ patient groups were rated at very mild or mild levels of severity (CDR 0.5 or 1) and had comparable levels of global cognitive impairment (average MMSE = 23.7 ± 3.9). Behaviorally, we found that the word retrieval profile of PCA patients is comparable to that of amnestic patients, characterized by intact letter fluency but impaired category fluency and visual confrontation naming, while lvPPA patients demonstrated impairment across all tests of word retrieval. Across all AD variants, we observed that letter fluency was associated with cortical thickness in prefrontal, central precuneus, lateral parietal and temporal cortex, while category fluency and naming were associated with cortical thickness in left middle frontal gyrus, posterior middle temporal gyrus, and lateral parietal cortex. Visual confrontation naming was uniquely associated with atrophy in inferior temporal and visual association cortex. We conclude that a better understanding of the word retrieval profiles and underlying neurodegeneration across the AD syndromic spectrum will help improve interpretation of neuropsychological profiles with regard to the localization of neurodegeneration, particularly in the atypical AD variants.

Brain metabolic signatures across the Alzheimer's disease spectrum.

Given the challenges posed by the clinical diagnosis of atypical Alzheimer's disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

Tau PET Distributional Pattern in AD Patients with Visuospatial Dysfunction.

Visuospatial dysfunction is one predominant symptom in many atypical Alzheimer's disease (AD) patients, however, until now its neural correlates still remain unclear. For the accumulation of intracellular hyperphosphorylated tau proteins is a major pathogenic factor in neurodegeneration of AD, the distributional pattern of tau could highlight the affected brain regions associated with specific cognitive deficits. We investigated the brain regions particularly affected by tau accumulation in patients with visuospatial dysfunction to explore its neural correlates. Using 18F-AV-1451 tau positron emission tomography (PET), voxel-wise two-sample t-tests were performed between AD patients with obvious visuospatial dysfunction (VS-AD) and cognitively normal subjects, AD patients with little-to-no visuospatial dysfunction (non VS-AD) and cognitively normal subjects, respectively. Results showed increased tau accumulations mainly located in occipitoparietal cortex, posterior cingulate cortex, precuneus, inferior and medial temporal cortex in VS-AD patients, while increased tau accumulations mainly occurred in the inferior and medial temporal cortex in non VS-AD patients. These findings suggested that occipitoparietal cortex, posterior cingulate cortex and precuneus, which were particularly affected by increased tau accumulation in VS-AD patients, may associate with visuospatial dysfunction of AD.

Effects of Electrical Stimulation on Verbal Learning in Typical and Atypical Alzheimer's Disease

Effects of Electrical Stimulation on Verbal Learning in Typical and Atypical Alzheimer's Disease

Astrocytic Tau Deposition Is Frequent in Typical and Atypical Alzheimer Disease Presentations.

Typical Alzheimer disease (AD) features an amnestic syndrome that reflects the progression of pathology through specific neural networks. However, a subset of patients exhibits atypical onset with prominent language, behavioral, or visuospatial deficits that are not explained by current neuropathological staging schemes. Astrogliopathy featuring tau inclusions with thorn-shaped and granular fuzzy morphologies is common in the aging brain and collectively known as aging-related tau astrogliopathy (ARTAG). Prior studies have identified tau-positive thorn-shaped astrocytes in the white matter that associate with a primary progressive aphasia phenotype in an AD cohort. However, a possible contribution of ARTAG copathology to AD clinical heterogeneity has yet to be systematically examined. To investigate whether ARTAG pathology contributes to atypical presentations, we mapped the presence and density of ARTAG subtypes throughout cortical and subcortical regions in a well-characterized cohort of AD cases enriched for atypical presentations. In our cohort, ARTAG pathology is frequent and correlates with older age and higher Braak stage. ARTAG subtypes exhibit distinct distribution patterns with subpial and subependymal deposition occurring in the amygdala, while white and grey matter astrocytic deposition are distributed throughout cortical regions. However, ARTAG pathology is equally prevalent in cases with typical and atypical clinical presentations.

Does the Right Focal Variant of Alzheimer's Disease Really Exist? A Literature Analysis.

Alzheimer's disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated. To explore the existence of focal RAD on the basis of existing literature. We performed a literature search for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD. Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome. Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition.

Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer's Disease.

Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels. We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD. Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOEɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates. Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOEɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants. Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

Cross-sectional associations between [18F]GTP1 tau PET and cognition in Alzheimer's disease

The regional relationships between tau positron emission tomography (PET) imaging and cognitive impairment in Alzheimer's disease (AD) remain uncertain. We examined cross-sectional associations between cognitive performance, cerebral uptake of the novel tau PET tracer [18F]GTP1, and other neuroimaging indices ([18F]florbetapir amyloid PET, magnetic resonance imaging) in 71 participants with normal cognition, prodromal AD, or AD dementia. Greater [18F]GTP1 uptake was seen with increasing clinical severity and correlated with poorer cognition. [18F]GTP1 uptake and cortical volume (but not [18F]florbetapir uptake) were independently associated with cognitive performance, particularly within the temporal lobe. Delayed memory was more specifically associated with temporal [18F]GTP1 uptake; other domains correlated with a broader range of regional [18F]GTP1 uptake. These data confirm that [18F]GTP1 tau PET uptake significantly correlates with cognitive performance in AD, but regional correlations between performance in non-memory cognitive domains were less specific than reported by tau PET imaging studies that included participants with atypical focal cortical AD syndromes. Tau PET imaging may have utility as a surrogate biomarker for clinical AD progression in therapeutic trials of disease-modifying interventions.

The role of age on tau PET uptake and gray matter atrophy in atypical Alzheimer's disease

IntroductionLittle is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD). MethodsRegional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model. ResultsAge was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance. DiscussionAge is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.