Non-amnestic Alzheimer's Disease Research Articles

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). Participants were NormCog (n=132) and ImpCog (n=461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression. Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC=0.87) and ImpCog (ROCAUC=0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR]=2.94; p=8.1e-06) and Aβ- individuals (HR=3.11; p=2.6e-09). Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals.

Greater white matter degeneration and lower structural connectivity in non-amnestic vs. amnestic Alzheimer's disease.

Multimodal evidence indicates Alzheimer's disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes. Participants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics. Both amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals' brain graphs. We have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread.

The Relationship Between Cognitive Impairments and Sleep Quality Measures in Persistent Insomnia Disorder.

Persistent insomnia disorder (pID) is linked to neurocognitive decline and increased risk of Alzheimer's Disease (AD) in later life. However, research in this field often utilizes self-reported sleep quality data - which may be biased by sleep misperception - or uses extensive neurocognitive test batteries - which are often not feasible in clinical settings. This study therefore aims to assess whether a simple screening tool could uncover a specific pattern of cognitive changes in pID patients, and whether these relate to objective aspect(s) of sleep quality. Neurocognitive performance (Montreal Cognitive Assessment; MoCA), anxiety/depression severity, and subjective sleep quality (Pittsburgh Sleep Quality Index: PSQI; Insomnia Severity Index: ISI) data were collected from 22 middle-aged pID patients and 22 good-sleepers. Patients underwent overnight polysomnography. Compared to good-sleepers, patients had lower overall cognitive performance (average: 24.6 versus 26.3 points, Mann-Whitney U = 136.5, p = <0.006), with deficits in clock drawing and verbal abstraction. In patients, poorer overall cognitive performance correlated with reduced subjective sleep quality (PSQI: r(42) = -0.47, p = 0.001; and ISI: r(42) = -0.43, p = 0.004), reduced objective sleep quality (lower sleep efficiency: r(20) = 0.59, p = 0.004 and less REM-sleep: r(20) = 0.52, p = 0.013; and increased sleep latency: r(20) = -0.57, p = 0.005 and time awake: r(20) = -0.59, p = 0.004). Cognitive performance was not related to anxiety/depression scores. Using a simple neurocognitive screening tool, we found that pID patients showed cognitive deficiencies that related to both subjective/self-reported and objective/polysomnographic measures of sleep quality. Furthermore, these cognitive changes resembled those seen in preclinical non-amnestic AD, and thus could indicate incumbent neurodegenerative processes in pID. Interestingly, increased REM-sleep was correlated with better cognitive performance. However, whether REM-sleep is protective against neurodegeneration requires further investigation.

Bridging the Gap between Psychiatry and Neurology: Alzheimer's disease- symptoms beyond memory impairment

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories in Alzheimer's disease.Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Recently subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau (t-tau) and phosphorylated tau181 (p-tau), MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. Special attention will be given to language variant of Alzheimer's disease. A predominant deficit in the language domain is a key feature of primary progressive aphasia but language impairment is commonly present in Alzheimer's disease. International diagnostic criteria for PPA and its three variants (agrammatic, logopenic, semantic) were published in 2011. Since then, studies have investigated the validity of these criteria in classifying patients which includes clinical symptoms, neurocognitive presentations, distinct MRI signatures, and neuropathological differences. In this session special attention will be given of logopenic PPA a syndrome frequently seen in atypical Alzheimer's disease. Even though Alzheimer's disease is most notable for memory impairment, language impairments are also found early in the disease course. Indeed, neuropsychological testing shows changes in confrontation naming and semantic fluency. However, there is an additional body of research that shows that changes in spontaneous language, including idea density, speech quantity, fluency, and tempo can differentiate between normal aging and Alzheimer's disease.A physiologic sleep pattern is essential in the process of memory formation. Inadequate sleep results in cognitive impairment. MCI has an increased rate of sleeping problems compared to healthy people of the same age. In MCI, primary sleep disorders like sleep-disordered breathing, PLMS, RLS, RBD are more common, and also associated with a high rate of progression from MCI to AD. MCI also showed shorter total sleep time (longer in non-amnestic MCI), sleep efficiency, and cyclic alternating pattern. There is increased nighttime behavior. EEG power in amnestic MCI showed a reduction in the power of delta and theta frequency. There is a reduction in fast spindle counts on frontal location. Blunted and delayed onset with a duration of REM sleep reduced. A growing body of evidence supports the hypothesis that people with sleep disorders have a higher risk of developing Alzheimer's disease AD. Insomnia, self-reported sleep disturbances, decline in sleep duration, impaired sleep consolidation, delayed or decreased circadian rhythms and sleep-disordered breathing have been shown to increase AD risk, supporting the hypothesis that a chronically disrupted sleep-wake cycle can drive AD pathogenesis. Associations of sleep disorders and neurodegeneration in Alzheimer's are complex. Its understanding however is crucial for proper AD prevention, diagnosis, as well as management.Psychosis is a core syndrome in other than Alzheimer's disease and neurodegenerative disorders. It is however present in a large percentage of patients with AD. Psychosis most commonly presents as a delusional process and is linked to disruptive behavior, rapid progression, and overall morbidity. Psychotic syndromes in AD are complex but necessary to be diagnosed and managed properly.

TREM2 risk variants are associated with atypical Alzheimer's disease.

Alzheimer's disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes.

Sleep patterns differ across Alzheimer's disease phenotypes: Implications for selective vulnerability and customized treatment.

Sleep-wake disturbances are a prominent feature in Alzheimer's Disease (AD), negatively impacting patients and caregivers' quality of life. Growing evidence suggests that sleep-wake dysregulation happens early in AD due to the AD-tau degeneration of the arousal system (i.e., locus coeruleus). However, whether the pattern of sleep-wake dysfunction is different among AD clinical variants and how it is different remains unclear. It is an unmet gap of high importance because these differing patterns may require tailored treatment strategies. Since AD phenotypes with different clinical profiles have distinct regional patterns of cortical tau, we hypothesized that AD variants may also have differential sleep patterns. Therefore, we aim to contrast the behavioral sleep features within AD variants. A cohort of 24 patients, including 8 amnestic AD and 16 non-amnestic AD (7 lvPPA, 9 PCA), with a neuropathological or biomarker based diagnosis of AD, underwent an overnight EEG monitoring. Sleep stages were evaluated by PRANA software and confirmed by REM Logic spectral analyses. We performed nonparametric analyses to study group differences in the amount of each sleep stage as a percent of total sleep time. Additionally, we performed linear regression models adjusting by the age of onset, MMSE, and CDR Total. There were no differences between amnestic AD, lvPPA, and PCA groups in gender, age of onset (59±11, 55±6, 59±8, respectively), global cognition (MMSE 21±7, 23±3, 21±5), or functional performance (CDR Total 0.9±0.5, 0.7±0.3, 1±0.4). Compared to non-amnestic AD, amnestic AD had more REM sleep (p<0.05) and a trend toward lower NREM sleep stages 1 and 3. In the same line, this pattern was still observed when comparing the three clinical variants (amnestic AD, lvPPA, and PCA) (p<0.05). Regression models confirmed that clinical AD variants accounted for differences in REM sleep (p<0.01). We are continuing to evaluate additional AD participants and age-matched healthy controls. Preliminary results suggest that sleep profiles might differ between AD variants. The existence of specific sleep-wake profiles would suggest differential degeneration patterns of the arousal system within AD phenotypes, which would open the door to uncover the selective vulnerability of subcortical structures for the first time.

Heterogeneity and Factorial Structure in Alzheimer's Disease: A Cognitive Perspective.

Alzheimer's disease (AD) patients show heterogeneous cognitive profiles which suggest the existence of cognitive subgroups. A deeper comprehension of this heterogeneity could contribute to move toward a precision medicine perspective. In this study, we aimed 1) to investigate AD cognitive heterogeneity as a product of the combination of within- (factors) and between-patients (sub-phenotypes) components, and 2) to promote its assessment in clinical practice by defining a small set of critical tests for this purpose. We performed factor mixture analysis (FMA) on neurocognitive assessment results of N = 230 patients with a clinical diagnosis of AD. This technique allowed to investigate the structure of cognitive heterogeneity in this sample and to characterize the core features of cognitive sub-phenotypes. Subsequently, we performed a tests selection based on logistic regression to highlight the best tests to detect AD patients in our sample. Finally, the accuracy of the same tests in the discrimination of sub-phenotypes was evaluated. FMA revealed a structure characterized by five latent factors and four groups, which were identifiable by means of a few cognitive tests and were mainly characterized by memory deficits with visuospatial difficulties ("Visuospatial AD"), typical AD cognitive pattern ("Typical AD"), less impaired memory ("Mild AD"), and language/praxis deficits with relatively spared memory ("Nonamnestic AD"). The structure of cognitive heterogeneity in our sample of AD patients, as studied by FMA, could be summarized by four sub-phenotypes with distinct cognitive characteristics easily identifiable in clinical practice. Clinical implications under the precision medicine framework are discussed.

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.

ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration.

Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-β1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-β1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-β1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-β1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-β1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-β1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic 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

Diagnostic Accuracy of MRI Visual Rating Scales in the Diagnosis of Early Onset Cognitive Impairment.

The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker. We aim to determine the distribution and diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias. We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer's disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients [11 with behavioral variant (bvFTD), nine with semantic variant of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA)], 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed. Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders. The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker.

Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer's disease.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenic-variant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease. 10.1093/brain/awz091_video1 awz091media1 6041544065001.

BRIDGING THE GAP BETWEEN NEUROLOGY AND PSYCHIATRY-ATYPICAL PRESENTATION OF COMMON NEURODEGENERATIVE DISORDERS: Session 418

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories both in Alzheimer's as well as in Parkinson's disease. Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Recently subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau (t-tau) and phosphorylated tau181 (p-tau), MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. We will review the typical and atypical forms of AD from these varied perspectives to help improve diagnostic confidence among clinicians. Special attention will be given to language variant of Alzheimer's disease. A predominant deficit in the language domain is a key feature of primary progressive aphasia but language impairment is commonly present in Alzheimer's disease. International diagnostic criteria for PPA and its three variants (agrammatic, logopenic, semantic) were published relatively recently in 2011. Since then, studies have investigated the validity of these criteria in classifying patients which includes clinical symptoms, neurocognitive presentations, distinct MRI signatures, and neuropathological differences. In this session, we will review the subtypes of PPA using the above parameters to assist clinicians in diagnosis of these conditions. Special attention will be given of logopenic PPA a syndrome frequently seen in atypical Alzheimer's disease. Another common neurodegenerative disorder, Parkinson's disease (PD) conceptualized as predominantly movement disorder presents with myriad of atypical features predominantly psychiatric in nature. Psychosis is one of the most debilitating symptoms of PD, 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 PD. Auditory, olfactory, tactile and gustatory hallucinations are infrequently found and usually coexist with visual ones. Delusions occur in about 5% of Parkinson's disease patients. Cognitive correlates of hallucinations and delusions appear to be different in PD. They may have distinct pathogenic mechanisms and possibly anatomical substrates. Global cognitive deficits including attention, frontal executive dysfunction, visuospatial abnormalities, language and verbal memory were associated with the presence of hallucinations in Parkinson's disease, but did not correlate with the presence of delusions. APOE and glucocerebrosidase gene (GBA) mutations and polymorphisms found to be associated with a distinct cognitive profile of changes characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. During this session new findings on pathognomonic, cognitive and genetic correlates of psychosis in PD will be presented.

Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy.

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia.

TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease

Amnestic Alzheimer's disease (AD) is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to the neocortex. In contrast, nonamnestic Alzheimer's patients have relative sparing of the hippocampus, but the pattern in which the disease spreads is unclear. We examined spreading disease in nonamnestic AD using a novel magnetic resonance imaging–based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included the hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipitoparietal cortex for posterior cortical atrophy (51 scans); temporoparietal cortex for corticobasal syndrome (31 scans); and frontotemporal cortex for behavioral/dysexecutive variant AD (37 scans). In nonamnestic patients, atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, beta amyloid, neuronal loss, and gliosis for the subset of patients (n = 17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients' disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated nonamnestic phenotypes from each other and from amnestic AD. The frequency-based phase assignment algorithm used in the present study thus represents a promising approach for studying the neocortical origin and spread of disease in nonamnestic AD.

Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease.

Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). 18 F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between 18 F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs). 18 F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between 18 F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms.

18F-Flortaucipir PET/MRI Correlations in Nonamnestic and Amnestic Variants of Alzheimer Disease.

Nonamnestic Alzheimer disease (AD) variants, including posterior cortical atrophy and the logopenic variant of primary progressive aphasia, differ from amnestic AD in distributions of tau aggregates and neurodegeneration. We evaluated whether 18F-flortaucipir (also called 18F-AV-1451) PET, targeting tau aggregates, detects these differences, and we compared the results with MRI measures of gray matter (GM) atrophy. Methods: Five subjects with posterior cortical atrophy, 4 subjects with the logopenic variant of primary progressive aphasia, 6 age-matched patients with AD, and 6 control subjects underwent 18F-flortaucipir PET and MRI. SUV ratios and GM volumes were compared using regional and voxel-based methods. Results: The subgroups showed the expected 18F-flortaucipir-binding patterns. Group effect sizes were generally stronger with 18F-flortaucipir PET than with MRI volumes. There were moderate-to-high correlations between regional GM atrophy and 18F-flortaucipir uptake. 18F-flortaucipir binding and GM atrophy correlated similarly to cognitive test performance. Conclusion:18F-flortaucipir binding corresponds to the expected neurodegeneration patterns in nonamnestic AD, with potential for earlier detection of pathology than is possible with MRI atrophy measures.

DISTINGUISHING NON-AMNESTIC FROM AMNESTIC VARIANTS OF EARLY-ONSET ALZHEIMER’S DISEASE ON NEUROPSYCHOLOGICAL TESTS

Patients with early-onset Alzheimer's disease (AD) include those with typical amnestic AD and those with atypical, non-amnestic presentations, including language, visuospatial, or executive disturbances, who have more focal neocortical localization early in the disease. There are no neuropsychological profiles to distinguish these non-amnestic variants as a group from typical amnestic presentations. We compared neuropsychological measures of 41 patients meeting AA-NIA criteria for AD and having an age of onset of <65 years of age. Based on the initial extensive physician clinical evaluation, these 41 patients were divided into amnestic (n=22 including 14 male/8 female; mean years for age-58.4, disease duration-3.2, education-16.1 years) vs. non-amnestic (n=19 including 8 male/11 female; mean years for age-59.7, disease duration-4.0, education-16.2). The two patient groups were of comparable severity on functional measures and had fluorodeoxyglucose positron emission tomography (FDG-PET) or cerebrospinal fluid biomarker confirmation of their disease. We then analyzed neuropsychological differences between these two groups. Six measures emerged as having either sensitivities of ≥0.8 or specificities of ≥0.9 for typical amnestic vs. non-amnestic AD (See Table 1). The amnestic EOAD patients were worse on the California Verbal Learning Test (CVLT) delayed recall scores, including “Savings Score” (free long-delayed recall/last registration trial) especially because of better memory registration and had many more false positives on CVLT recognition memory testing. In comparison, the non-amnestic AD patients were worse on Forward Digit Span, Trailmaking B time, Boston Naming Test (uncued), CVLT memory registration, and the Southern California Figure-Ground Test. 17 of the 19 non-amnestic EOAD patients were abnormal on all 6 tests, and the Trailmaking B added the highest specificity at 0.92. These results reveal significantly different neuropsychological profiles for the non-amnestic variants of AD, as a group, from typical AD. The findings suggest neuropsychological measure for differentiation of these variants that including measures of early impairment in mental control and executive abilities, uncued naming, memory registration, and mid-level visuospatial processing.

YOUNG-ONSET DEMENTIA IN A SOUTHEAST ASIAN POPULATION FROM SINGAPORE: CLINICAL AND BIOMARKER CHARACTERIZATION

Patients with Young onset dementia (YOD) are less likely to have mixed pathology, have a higher genetic predisposition and thus detailed characterization of this cohort may offer an opportunity for biomarker development and discovery of novel drug interventions. Existing Asian YOD cohorts are largely from Japan and thus little is known about the clinical and biomarker profile of YOD in Southeast Asia. We present the clinical and biomarker characteristics of Southeast Asian YOD patients from multiethnic Singapore. Patients were recruited from the National Neuroscience Institute beginning January 2012. Beginning July 2015, additional biomarker data including volumetric MRI, genetics and cerebrospinal fluid (CSF) were collected. Volumetric MRI was performed on a 3T Siemens machine. CSF Amyloidβ, total tau and phosphor-tau were performed using ELISA techniques. Diagnosis of dementia was made at consensus meetings comprising of cognitive neurologists, neuroradiologists, psychologists and dementia nurses. Alzheimer's disease (AD) was diagnosed based on the NIA-AA criteria, Vascular Dementia (VaD) based on the NINDS-ADRDA criteria and Frontotemporal Dementia (FTD) based on the Rascovsky criteria. MCI was diagnosed based on the Petersen's criteria. A total 309 patients were recruited between 2012 and Dec 2016. There were 250 patients with dementia (N, AD=145, VaD=30, FTD=48) and 59 patients with MCI. Mean (SD) age of onset for AD, VaD and FTD was 56.77 (5.06), 56.84 (5.61) and 56.60 (5.32) respectively. Family history of YOD among first degree relatives were present in 28.7% of AD, 10.0% of VAD and 22.9% of FTD. Of the 143 patients with Young Onset AD, 90.9% had amnestic AD, 2.1 % had behavioral variant AD and 1.4% had logopenic variant and 5.6% had Posterior Cortical Atrophy type of AD. 39.0% consented for CSF analyses. Further analyses with clinical, neuropsychological, volumetric MRI and CSF findings are on-going. This is the first report of YOD in Southeast Asians. AD continues to be the major subtype of YOD. Non-amnestic AD is present in about 10% and 29% of Young AD have a positive family history. Greater awareness on the clinical presentation of YOD among Southeast Asians is needed for earlier diagnosis and timely intervention.