Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study.

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.

Differentiation of frontotemporal dementia from dementia with Lewy bodies using FP-CIT SPECT.

INTRODUCTION: There is increasing evidence that imaging with [123I]FP-CIT SPECT is helpful in differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) but it is not known how well the scan performs in differentiating DLB from frontotemporal dementia (FTD). METHOD: We compared the striatal dopamine transporter (DAT) binding in FTD (n=12), DLB (n=10) and AD (n=9) by visually rating the caudate and putamen on [123I]FP-CIT SPECT scans. RESULTS: The majority (9/10) of DLB cases had an abnormal scan and a significant reduction of uptake of DAT binding in the putamen and the caudate. A third (4/12) of the FTD cases also had an abnormal scan and a significant reduction in uptake in the putamen and the caudate. In contrast, only one out of nine AD cases had an abnormal scan. Significant differences were found when comparisons were made between the groups for visual analysis of the entire scan (p=0.001) and the four regions of interest (p=0.001 - 0.013). In contrast to the AD group (specificity of scan 89%), the specificity of [123I]FP-CIT SPECT scans was reduced in the FTD group to 67%. Three quarters of the study population had at least one extrapyramidal motor sign (EPMS), with bradykinesia being the most common EPMS in both FTD (83%) and DLB (70%). CONCLUSIONS: This study highlights to clinicians that a positive (abnormal) [123I]FP-CIT SPECT scan, even in a patient with an EPMS, does not exclude the diagnosis of FTD and emphasises the importance of a comprehensive clinical evaluation and a detailed cognitive assessment.

An fMRI study of verbal episodic memory encoding in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is a high-risk and often prodromal state for the development of Alzheimer's disease (AD) and is characterised by isolated episodic memory impairment. Functional neuroimaging studies in healthy subjects consistently report left prefrontal cortex (PFC) activation during verbal episodic memory encoding. The PFC activation at encoding is related to semantic processing which enhances memory. The purpose of this study was to ascertain whether impaired verbal episodic memory in aMCI is related to PFC dysfunction. Using functional magnetic resonance imaging (fMRI) we compared 10 aMCI patients with 10 elderly controls during verbal encoding. The encoding task was sensitive to the effects of semantic processing. Subsequent recognition was tested to measure encoding success. Behavioural results revealed impaired recognition and a lower false recognition rate for semantically related distracters (lures) in aMCI, which suggest impaired semantic processing at encoding. Both groups activated left hemispheric PFC, insula, premotor cortex and cerebellum, but group comparisons revealed decreased activation in left ventrolateral PFC in the aMCI group. The magnitude of activation in left ventrolateral PFC during encoding was positively correlated with recognition accuracy in the control group but not in the aMCI group. We propose that verbal episodic memory impairment in aMCI is related to PFC dysfunction which affects semantic processing at encoding.

Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy.

BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone. METHODS: A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls. RESULTS: Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and specificity was 100%. CONCLUSION: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.

Long-term outcome of depressive pseudodementia in the elderly.

BACKGROUND: The term depressive pseudodementia has proved to be a popular clinical concept. Little is known about the long-term outcome of this syndrome. AIMS: To compare depressed elderly patients with reversible cognitive impairment and cognitively intact depressed elderly patients. METHODS: All patients suffering from moderate or severe depression admitted to St Margaret's Hospital, UK as inpatients or day hospital outpatients between January 1 1997 and December 31 1999 (n=182) were screened for entry into the study. Eligible patients were divided into those presenting with pseudodementia and those who were cognitively intact and followed up for 5 to 7 years. RESULTS: Seventy-one point four percent of those suffering from pseudodementia had converted into dementia at follow-up compared to only 18.2% in the cognitively intact group. The relative risk was 3.929 (95% CI: 1.985 to 7.775) and the 'number needed to harm' 1.88. CONCLUSIONS: Reversible cognitive impairment in late-life moderate to severe depression appears to be a strong predictor of dementia. Inpatients and day hospital outpatients with depressive pseudodementia should probably have a full dementia screening, comprehensive cognitive testing and ongoing monitoring of their cognitive function.

Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer's Disease: A Comparison of the Cognitive and Clinical Profiles.

BACKGROUND: Dementia must be diagnosed accurately and early in the disease course to allow pathology-specific treatments to be effective. Dementia with Lewy bodies (DLB) is often misdiagnosed as Alzheimer's disease (AD), especially at the prodromal stage. OBJECTIVE: To compare the clinical and neuropsychological profiles of Mild Cognitive Impairment (MCI) patients who, at follow-up, progressed to AD (retrospectively AD-MCI) or DLB (retrospectively DLB-MCI) or remained MCI. METHODS: This longitudinal study used an unselected sample from a memory clinic database. A total of 1,848 new patients were seen at the memory clinic between 1994-2015. Of these, 560 patients (30%) had an initial diagnosis of MCI and were considered for the study. Inclusion criteria were patients who had a diagnosis of MCI at initial assessment and a minimum of 12 months' follow-up. RESULTS: Of the 429 MCI patients with follow-up data, 164 (38%) remained MCI, 107 (25%) progressed to AD, and 21 (5%) progressed to DLB. The remainder progressed to alternative diagnoses. At baseline, DLB-MCI patients performed significantly worse on visuospatial function and letter fluency tests than both AD-MCI and stable-MCI groups, and better on episodic memory tests than the AD-MCI group. At baseline, DLB-MCI patients had a significantly higher mean UPDRS score and were more likely to have REM sleep behavior disorder and fluctuating cognition. CONCLUSION: DLB-MCI patients have a specific cognitive and neuropsychiatric profile which should alert clinicians to the possibility of prodromal DLB. This is relevant when considered in the context of early disease-specific therapy.

Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB.

OBJECTIVE: To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard. METHODS: Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria. RESULTS: Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging. CONCLUSIONS: This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.

The functional anatomy of divided attention in amnestic mild cognitive impairment.

Recent neuroimaging studies have demonstrated changes in brain function in cognitively normal subjects at increased risk of developing Alzheimer's disease. Amnestic mild cognitive impairment (AMCI) carries a high risk of developing into Alzheimer's disease. In AMCI altered cortical activation has been demonstrated during memory tasks, using functional MRI (fMRI). Memory and attention are closely related cognitive functions. It is unclear whether the memory impairment of AMCI is associated with attentional deficits of the sort likely to be revealed by tasks requiring divided attention. Ten older adults (mean age 72 years, range 57-81 years) with AMCI were compared with healthy matched controls on divided attention and passive sensory processing tasks using fMRI. During the divided attention task both groups activated similar regions of left hemispheric prefrontal and extrastriate visual cortex. However, the AMCI group had attenuated prefrontal activation compared with age matched controls. On the passive sensory processing task there was no difference between the AMCI and control groups. We conclude that there are changes in the functional network subserving divided attention in patients with AMCI as reflected in the attenuation of prefrontal cortical activation. These findings have implications for evaluating cognition in AMCI and also for monitoring the effects of future treatments in AMCI.