Aggregation of Abnormal Memory Scores and Risk of Incident Alzheimer's Disease Dementia: A Measure of Objective Memory Impairment in Amnestic Mild Cognitive Impairment.

OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.

Baseline Amnestic Severity Predicts Progression From Amnestic Mild Cognitive Impairment to Alzheimer Disease Dementia at 3 Years.

BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.

Rapidly progressive Fronto-temporal dementia (FTD) associated with Frontotemporal lobar degeneration (FTLD) in the presence of Fused in Sarcoma (FUS) protein: a rare, sporadic, and aggressive form of FTD.

Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.

Mild Cognitive Impairment: Diagnosis and Subtypes.

Mild cognitive impairment (MCI) is a clinical diagnosis based on subjective cognitive decline, objective cognitive impairment, and relative preservation of activities of daily living. The diagnosis may be established via clinical interview, collateral history from an informant, and psychometric examination. Various consensus groups have proposed criteria for MCI in Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies, and vascular cognitive impairment. These diagnostic criteria have subtle but important differences. Criteria for subjective decline vary according to whether memory is impaired or whether impairment in any cognitive domain is sufficient. There are also differences with respect to whether the subjective decline is noted by the patient, a carer, or a clinician. The precise thresholds for classifying objective cognitive impairment also vary between various diagnostic criteria. There are also differences in the description of functional abilities. Once established, the diagnosis of MCI may be refined to 1 of 4 subtypes based on the pattern of cognitive impairment. The 4 subtypes are defined according to whether or not memory is impaired and whether 1 or more cognitive domains are impaired. Once a diagnosis of MCI has been made, the patient and the family should be counseled about social and legal implications as well as strategies for reducing the risk of progression to dementia. The main utilities of MCI as a nosology are to understand the natural history of neurodegenerative disorders such as AD, to identify those at increased risk of progressing to develop dementia, and to identifying individuals for putative treatments.

Stereotaxic localisation of the dorsolateral prefrontal cortex for transcranial magnetic stimulation is superior to the standard reference position.

OBJECTIVE: To determine whether the standard method of localisation of the dorsolateral prefrontal cortex for repetitive transcranial magnetic stimulation is accurate and reliable, and to develop an empirically based method for operational localisation of the dorsolateral prefrontal cortex with reference to the motor hand area. METHOD: We compared stereotaxic localisation of the dorsolateral prefrontal cortex with the commonly used operational definition of 6 cm anterior to the site of the abductor pollicis brevis muscle in healthy participants (n = 18). We also report the average translational distance from the site of the abductor pollicis brevis to the stereotaxically defined dorsolateral prefrontal cortex. RESULTS: The stereotaxic method was less variable than the operational method of localisation and more frequently targeted the middle frontal gyrus. The average translational distance from the site of the abductor pollicis brevis to the stereotaxically targeted dorsolateral prefrontal cortex was x = -5 mm, y = 53 mm and z = -31 mm. CONCLUSIONS: Operational localisation of the dorsolateral prefrontal cortex for repetitive transcranial magnetic stimulation with reference to the motor hand area is more variable than stereotaxic localisation. If future studies choose to use an operational definition of the left dorsolateral prefrontal cortex, we suggest it should be 5 mm lateral, 53 mm anterior and 31 mm inferior to the site of the abductor pollicis brevis.

Mild cognitive impairment: narrative review of taxonomies and systematic review of their prediction of incident Alzheimer's disease dementia.

Early detection of Alzheimer's disease is vital for developing novel treatments. Attempts to identify the intermediate state between normal cognition and dementia have evolved over the past 50 years. Current taxonomies of mild cognitive impairment (MCI) may be criticised for their imprecise operationalisation. With the advent of biomarkers such as amyloid-beta positron emission tomography imaging in established Alzheimer's disease, much research has focused on establishing which factors predict progression from MCI to Alzheimer's disease dementia. In this review, we discuss the historical context of MCI before reviewing the literature of MCI subtypes and their risk of progression to Alzheimer's disease dementia. Finally, we summarise the literature and discuss limitations and weaknesses of how the construct is operationalised and implemented, before offering suggestions for development of the concept of MCI. We conclude that MCI must be empirically defined for the sake of its predictive validity to identify Alzheimer's disease before dementia develops.