A new test to detect impairments of sequential visuospatial memory due to lesions of the temporal lobe

This study investigates visuospatial memory in patients with unilateral lesions of the temporal lobe and the hippocampus resulting from surgery to treat drug-resistant epilepsy. To detect impairments of visuospatial memory in these individuals, a memory test should be specific to episodic memory, the type of memory in which the hippocampus is crucially involved. However, most known visuospatial memory tests do not focus on episodic memory. We hypothesized that a new sequential visuospatial memory test, which has been previously developed and applied only in healthy subjects, might be suitable to fill this gap. The test requires the subject to reproduce a memorized sequence of target locations in ordered recall by typing on a blank graphics tablet. The length of the memorized sequence extended successively after repeated presentation of a sequence of 20 target positions. The test was done twice on day one and again after one week. Visual working memory was tested with the Corsi block-tapping task. The performance in the new test was also related to the performance of the patients in the standard test battery of the neuropsychological examination in the clinical context. Thirteen patients and 14 controls participated. Patients showed reduced learning speed in the new sequential visuospatial memory task. Right-sided lesions induced stronger impairments than left-sided lesions. After one week, retention was reduced in the patients with left-sided lesions. The performance of the patients in commonly used tests of the neuropsychological standard battery did not differ compared to healthy subjects, whereas the new test allowed discrimination between patients and controls at a high correct-decision rate of 0.89. The Corsi block-span of the patients was slightly shorter than that of the controls. The results suggest that the new test provides a specific investigation of episodic visuospatial memory. Hemispheric asymmetries were consistent with the general hypothesis of right hemispheric dominance in visuospatial processing

Kognition bei Down-Syndrom: Entwicklung über die Lebensspanne und neuropsychologische Diagnostik im Erwachsenenalter

Das Down-Syndrom ist die haufigste genetische Ursache einer Intelligenzminderung. Da Menschen mit einem Down-Syndrom ein erhohtes Risiko aufweisen, an einer Alzheimer-Demenz zu erkranken, ist eine umfassende Untersuchung der kognitiven Funktionen indiziert, sowohl im jungen Erwachsenenalter (zur Erhebung des kognitiven Ausgangsniveaus) als auch im Verlauf zur Demenzdiagnostik. Das weite Spektrum an kognitiver Leistungsfahigkeit bei Menschen mit einem Down-Syndrom stellt eine diagnostische Herausforderung dar. Wir mochten daher einen uberblick geben (1) uber die kognitive Entwicklung uber die Lebensspanne, (2) uber verschiedene mogliche Ursachen kognitiver Veranderungen bei erwachsenen Menschen mit einem Down-Syndrom und (3) uber neuropsychologische Diagnostik und entsprechende Verfahren fur den Erwachsenenbereich. Schlie ss lich geben wir, auf der Grundlage unserer Erfahrungen, (4) allgemeine Empfehlungen zur Untersuchung und Befundinterpretation bei Menschen mit Intelligenzminderung. Abstract Down's syndrome is the most frequent genetic cause of intellectual disability. As the risk for developing Alzheimer's disease is increased in Down's syndrome, comprehensive cognitive examination is essential, both in young adults (for baseline evaluation), as well as later for diagnosing dementia. So far, there are only a few recommendations for neuropsychological assessment in Down's syndrome. Here, we review (1) the development of cognition across the life span, (2) various causes of cognitive change in adults with Down's syndrome, and (3) procedures available for their evaluation. Furthermore, (4) we provide recommendations for the assessment and interpretation of diagnostic findings in adults with intellectual disabilities. We conclude with recommendations for cognitive assessment in intellectual disability in general

Measurement properties of the German version of the Cambridge examination for mental disorders of older people with Down syndrome and others with intellectual disabilities (CAMDEX-DS)

Background: The CAMDEX-DS is an instrument to diagnose Alzheimer's disease (AD) in Down syndrome consisting of an informant interview and a cognitive test battery (CAMCOG-DS). Measurement properties of the German CAMDEX-DS were investigated. Method: Fifty-five adults with Down syndrome (19-58 years) participated in this observational study. "Dementia" and "Alzheimer's dementia" (Alzheimer's disease) were diagnosed clinically and operationalised CAMDEX-ICD-10 criteria were applied to evaluate criterion validity. Validity and reliability of the CAMCOG-DS were analysed. Results: Specificity of the interview was 69-93%; sensitivity 0-80% for "dementia"; and 0-20% for Alzheimer's disease. A complete CAMCOG-DS score was obtained in 85% (item difficulty 0.11-0.96). Construct validity and retest-reliability were low to moderate (τ = .04-.79), inter-rater reliability excellent (τ = .70-.89), internal consistency and selectivity acceptable to excellent. Conclusions: Currently, the CAMDEX-DS including the CAMCOG-DS are the outcome assessments for assessing dementia in Down syndrome with the best psychometric properties; however, revision is recommended

Feasibility and potential diagnostic value of [18F]PI-2620 PET in patients with down syndrome and Alzheimer’s disease

Purpose of the report: Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer’s disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD. Materials and methods: Five adults with DS (40% female, aged 43–62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia. Results: Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages. Conclusion: Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD

Feasibility and potential diagnostic value of [18F]PI-2620 PET in patients with down syndrome and Alzheimer’s disease: a case series

Purpose of the reportAdults with Down Syndrome (DS) have a substantially increased risk for Alzheimer’s disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD.Materials and methodsFive adults with DS (40% female, aged 43–62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia.ResultsVisual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages.ConclusionTau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD

Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages. Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria. Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests. Discussion: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS

Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

IntroductionDown syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.MethodsWe used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria.ResultsThere were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests.DiscussionWe have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia

BACKGROUND AND OBJECTIVES: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.METHODS: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 ( c9orf72), progranulin ( GRN), or microtubule-associated protein tau ( MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. RESULTS: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( p &lt; 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( p &lt; 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. DISCUSSION: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.</p

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.</p

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.</p