Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.

The International Working Group on Alzheimer's disease (AD) suggested the free and cued selective reminding test (FCSRT) to assess memory, as it showed high sensitivity and specificity in the differentiation of AD from healthy controls and other dementias. The FCSRT involves the use of selective reminding with semantic cueing in memory assessment. This study aims to validate the FCSRT for mild cognitive impairment (MCI) and AD through the analysis of the diagnostic accuracy and the suggestion of cut-off scores. Patients were classified into two groups according to standard criteria: MCI (n = 100) and AD (n = 70). A matched control group (n = 101) of cognitively healthy subjects was included. The reliability and the validity of the FCSRT were analysed on the immediate (IR) and delayed (DR) recalls. The Cronbach's alpha was 0.915 for the IR and 0.879 for the DR. The total recall measures revealed good areas under the curve for MCI (IR: .818; DR: .828) and excellent for AD (IR: .987; DR: .991). Furthermore, the MCI group was subdivided with respect to a non-similar/similar AD pattern of impairment, with almost half of the subjects showing an AD-like decline. This analysis represents a novel contribution regarding the properties of the FCSRT in illustrating the heterogeneity of MCI at baseline. The FCSRT has proved to be a very useful tool in the characterization of the memory impairment of the AD spectrum.

Mild cognitive impairment (MCI), which shows high risk for conversion to Alzheimer's disease (AD), is accompanied by progressive visual deteriorations that so far are poorly understood. Here, we compared dorsal and ventral visual stream functional magnetic resonance imaging (fMRI) activity among amnestic MCI, healthy elderly, and young participants during structure-from-motion (SFM) face categorization performance. Task performance varied with stimulus depth and duration levels and differences among groups were highly correlated with face-related fMRI activation patterns. Young participants showed larger activation to faces than scrambled faces (face sensitivity) in the right fusiform face area (FFA) and right occipital face area (OFA) whereas in elderly, this difference was reduced. Surprisingly, in MCI, scrambled faces elicited larger activation in right FFA/OFA than faces. The latter observation may be related to the additional finding of elevated depth sensitivity in left FFA/OFA of MCI, suggesting that an increased representation of low-level stimulus aspects may impair face perception in MCI. Discriminant function analysis using face and depth sensitivity indices in FFA/OFA classified MCI and healthy elderly with 88.2% accuracy, marking a fundamental distinction between groups. Potentially related findings include altered activation patterns in dorsal-ventral stream integration regions and attention-related networks of MCI patients. Our results highlight aberrant visual and additional potentially compensatory processes that identify dispositions of (preclinical) AD.

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Although patients with Alzheimer disease (AD) share clinical and histological features regardless of age of onset, the hypothesis that early onset AD constitutes a distinct subgroup prevails. Some authors suggest that early attention or language impairment constitute patterns of differentiation in terms of neuropsychological profile, between these groups. However, investigations are not consensual in terms of cognitive domains affected in each group. Aim: To investigate whether there is early neuropsychological difference between two types of AD using the conventional dividing line of 65 years. Methods: We evaluated the results obtained in the Mini-Mental State Examination (MMSE) and in a comprehensive neuropsychological battery – Battery of Lisbon for the Assessment of Dementia (BLAD), at a Dementia clinic in the University Hospital of Coimbra and a Memory Clinic. The study was developed in consecutive patients with a clinical probable diagnosis of mild to moderate AD, using standard criteria (DSMIV and NINCDS-ADRDA). Statistical analysis was performed using Qui-square and U-Mann–Whitney, for categorical and non-categorical variables. The degree of relation between variables, was measured using the coefficient of correlation rs de Spearman. Results: The total sample included 280 patients: 109 with early onset AD and 171 with a late-onset form. Groups were comparable in terms of gender, education or severity of disease, and MMSE. In BLAD, for univariate analysis the early onset group had lower scores in Naming (p = 0.025), Right–Left Orientation (p = 0.029) and Praxis (p = 0.001), and better performances in Orientation (p = 0.001) and Visual Memory (p = 0.022). After application of Bonferroni correction for multiple comparisons only Praxis and Orientation could differentiate the two groups. No significant differences were found in other tests or functions. Discussion: The results are suggestive of dissociated profiles between early and late-onset AD. Younger patients have a major impairment in Praxis and a tendency for a great impairment in neocortical temporal functions. AD patients with late-onset forms had a tendency for worse performances in Visual Memory and Orientation, suggesting a more localized disease to the limbic structures.

The nature of visual impairments in Alzheimer's disease (AD) and their relation with other cognitive deficits remains highly debated. We asked whether independent visual deficits are present in AD and amnestic forms of mild cognitive impairment (MCI) in the absence of other comorbidities by performing a hierarchical analysis of low-level and high-level visual function in MCI and AD. Since parietal structures are a frequent pathophysiological target in AD and subserve 3D vision driven by motion cues, we hypothesized that the parietal visual dorsal stream function is predominantly affected in these conditions. We used a novel 3D task combining three critical variables to challenge parietal function: 3D motion coherence of objects of unknown orientation, with constrained temporal integration of these cues. Groups of amnestic MCI (n = 20), AD (n = 19), and matched controls (n = 20) were studied. Low-level visual function was assessed using psychophysical contrast sensitivity tests probing the magnocellular, parvocellular, and koniocellular pathways. We probed visual ventral stream function using the Benton Face Recognition task. We have found hierarchical visual impairment in AD, independently of neuropsychological deficits, in particular in the novel parietal 3D task, which was selectively affected in MCI. Integration of local motion cues into 3D objects was specifically and most strongly impaired in AD and MCI, especially when 3D motion was unpredictable, with variable orientation and short-lived in space and time. In sum, specific early dorsal stream visual impairment occurs independently of ventral stream, low-level visual and neuropsychological deficits, in amnestic types of MCI and AD.

The influence of normal aging in early, intermediate and high-level visual processing is still poorly understood. We have addressed this important issue in a large cohort of 653 subjects divided into five distinct age groups, [20;30[, [30;40[, [40;50[, [50;60[and [60;[. We applied a broad range of psychophysical tests, testing distinct levels of the visual hierarchy, from local processing to global integration, using simple gratings (spatial contrast sensitivity -CS- using high temporal/low spatial frequency or intermediate spatial frequency static gratings), color CS using Landolt patches, moving dot stimuli (Local Speed Discrimination) and dot patterns defining 3D objects (3D Structure from Motion, 3D SFM). Aging data were fitted with linear or quadratic regression models, using the adjusted coefficient of determination (R2 a) to quantify the effect of aging. A significant effect of age was found on all visual channels tested, except for the red-green chromatic channel. The high temporal low spatial frequency contrast sensitivity channel showed a mean sensitivity loss of 0.75 dB per decade (R2 a = 0.17, p<0.001), while the lower intermediate spatial frequency channel showed a more pronounced decrease, around 2.35 dB (R2 a = 0.55, p<0.001). Concerning low-level motion perception, speed discrimination decreased 2.71°/s (R2 a = 0.18, p<0.001) and 3.15°/s (R2 a = 0.13, p<0.001) only for short presentations for horizontal and oblique meridians, respectively. The 3D SFM task, requiring high-level integration across dorsal and ventral streams, showed the strongest (quadratic) decrease of motion coherence perception with age, especially when the task was temporally constrained (R2 a = 0.54, p<0.001). These findings show that visual channels are influenced by aging into different extent, with time presenting a critical role, and high-level dorso-ventral dominance of deterioration, which accelerates with aging, in contrast to the other channels that show a linear pattern of deterioration.

RESUMOIntrodução: O Mini-Mental State Examination é o teste de rastreio de défice cognitivo/demência mais difundido. No nosso país têm-se utilizado pontuações de corte definidas por grupos de literacia, mas existem novas propostas sustentadas por estudos mais representativos. Propomo-nos confirmar a influência da idade e da escolaridade no desempenho, avaliar a capacidade discriminativa dos novos dados normativos e testar a acuidade diagnóstica das pontuações de corte validadas para o défice cognitivo ligeiro e para as formas mais prevalentes de demência. The Mini-Mental State Examination is the most commonly used cognitive screening test. In Portugal, the cut-off scores are defined according to literacy groups, but different proposals have been recommended by more representative studies. We therefore propose to confirm the influence of demographical variables, such as age and education, in the subject's performance; evaluating the discriminant ability of the new normative data; and to further examine the diagnostic acuity of the validated cut-off scoring for mild cognitive impairment and for the most prevalent types of dementia. Material and Methods: Our study includes 1 441 educated subjects, divided into seven subgroups: Mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, community-controls and memory cliniccontrols. Results: Altogether age and education explain 10.4% of the Mini-Mental State Examination results variance, with both variables contributing significantly to the results' prediction. The diagnostic acuity based on the most recent normative data was always higher than the one obtained through the validation cut-off scoring, revealing an overall excellent specificity (superior to 90%) and different sensitivity values: excellent for mild Alzheimer's disease (91%), good for dementia with Lewy Bodies (78%) and low for mild cognitive impairment (65%), frontotemporal dementia and vascular dementia (55%). Discussion and Conclusions:The performance on the Mini-Mental State Examination is influenced by age and education, supporting the use of normative data that consider those variables. With this approach, the Mini-Mental State Examination could be a sensitive and specific instrument for the Alzheimer's disease screening among all healthcare levels. Nevertheless, its diagnostic acuity is limited in other conditions frequently seen in memory clinics, such as Mild Cognitive Impairment and other types of dementia.