The Clock Drawing Test (CDT) is a popular neuropsychological instrument for the identification of cognitive decline, particularly Alzheimer’s disease (AD). The use of this test lacked specific validation studies for the Portuguese population, and that was the purpose of this project. The CDT showed good psychometric properties in all parameters assessed. The three selected scoring systems (Rouleau, Cahn and Babins) presented an adequate internal consistency, always higher for the Babins scoring system: α=.548 and α=.560 (Rouleau); α=.547 and α=.559 (Cahn); α=.883 and α=.901 (Babins). Interrater reliability was addressed in a subsample of 70 Mild Cognitive Impairment (MCI) patients and revealed a high correlation between two raters with opposite experience in neuropsychology. The analysis of construct validity of the CDT was conducted through exploratory and confirmatory factor analysis. The Rouleau and Cahn scoring systems presented a factorial structure of a single factor, while the Babins scoring system revealed a three factor structure: time-setting (representation of time), display characteristics (representation of numbers and global gestalt), and planning (clock face and correct placement of numbers). The scores according to the three factors were statistically different between the three groups, following an expected pattern: controls>MCI>AD. The CDT showed overall high convergent validity with the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), as well as good concurrent validity with specific measures of depression, psychopathology and functionality. The performance of controls and MCI patients on the CDT was also significantly correlated with frontal/executive, memory, attentional, visuoconstructive and language tasks, as well as with the different MoCA domains. The CDT was able to discriminate the most common types of degenerative dementia, particularly AD, Frontotemporal dementia, dementia with Lewy bodies (DLB), vascular dementia and Parkinson’s disease dementia. The presence of specific qualitative errors (conceptual deficit and stimulus-bound) confirmed its sensitivity for AD and DLB. Unfortunately, the discrimination between MCI patients and controls was in line with the tendency of international results, revealing a poor diagnostic accuracy for milder forms of cognitive impairment. Following an international recommendation, we analysed the association of the CDT with the MMSE. We developed adequate norms (according to age and education) and conducted a validation study for MCI and AD patients. Our results showed that the association of both scores significantly differentiated all groups with good to excellent diagnostic accuracy for AD (84 to 87%), although with lower values for MCI (64 to 67% for MCI). The study of the CDT was complemented with the correlation with biological variables and biomarkers of disease in MCI patients. By correlating CDT scores with regional cerebral blood flow (rCBF) measured by single-photon emission computed tomography (SPECT), we observed that the performance of MCI patients who later developed dementia correlated with brain perfusion median 3 years before the onset of dementia; also, stimulus-bound and conceptual deficit errors correlated with decreased rCBF in regions of interest for AD. On the other hand, the analysis of cerebrospinal fluid biomarkers showed that CDT scores correlated with Aβ42, an association that supports the value of the CDT as a state marker. The longitudinal assessment of these patients showed that the Babins scoring system was able to distinguish patients who converted from patients who remained stable, and was able to detect changes from baseline to follow-up in our sample. Also, future converters presented a higher rate of stimulus-bound and conceptual deficit errors at baseline, a result that was in line with our previous studies. The second part of this project focused on a preliminary approach to a biopsychosocial perspective. We presented the relevance of comprehensive geriatric assessment in dementia and developed a first validation study of the Biopsychosocial Assessment Method (Portuguese acronym MAB), an instrument created with the purpose of collecting multidimensional information about the individual. Such data may then be used for the development of a personalized intervention plan. The results with cognitively healthy population and clinical groups with cognitive impairment (MCI and mild AD) showed that the MAB has good psychometric properties. The MAB total score presented 93% sensitivity and 57% specificity for the identification of AD patients, while the score on the psychological area resulted in a diagnostic accuracy of 67% for MCI and 87% for AD. We concluded that the MAB is a valid instrument for use in clinical contexts and it is brief and easy to administer to healthy and cognitively impaired older patients.

Introdução: 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. Material e Métodos: O estudo incluiu 1 441 participantes escolarizados, divididos em sete subgrupos: Défice cognitivo ligeiro, doença de Alzheimer, demência fronto-temporal, demência vascular, demência com corpos de Lewy, controlo-comunidade e controlo-clínicamemória. Resultados: Em conjunto, idade e escolaridade explicam 10,4% da variância dos resultados no Mini-Mental State Examination, com ambas contribuindo significativamente para a predição dos resultados. A acuidade diagnóstica com base nos dados normativos mais recentes foi sempre superior à conseguida com as pontuações de corte de validação, revelando uma especificidade excelente (superior a 90%) e uma sensibilidade também excelente para a doença de Alzheimer ligeira (91%), boa para demência com corpos de Lewy (78%), baixa para o défice cognitivo ligeiro (65%) e demência fronto-temporal e demência vascular (55%). Discussão e Conclusões: O desempenho no Mini-Mental State Examination é influenciado pela idade e pela escolaridade, apoiando a utilização de dados normativos que considerem estas variáveis. Com esta abordagem, o Mini-Mental State Examination poderá ser um instrumento sensível e específico para o rastreio da doença de Alzheimer em todos os níveis de cuidados de saúde, mas a acuidade de diagnóstico é limitada noutras situações frequentes em consultas especializadas, como o défice cognitivo ligeiro ou outras formas de demência.

Introduction: 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 clinic-controls.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.

Introduction: The Alzheimer’s Disease Assessment Scale – Cognitive Subscale is a brief battery developed to assess cognitive functioning in Alzheimer’s disease that encompasses the core characteristics of cognitive decline (e.g. memory, language, praxis, constructive ability and orientation). The early detection, as well as the monitoring of cognitive decline along disease progression, is extremely important in clinical care and interventional research. The main goals of the present study were to analyze the psychometric properties of the Portuguese version of the Alzheimer’s Disease Assessment Scale – Cognitive Subscale, and to establish normative values for the Portuguese population.Material and Methods: The Portuguese version of Alzheimer’s Disease Assessment Scale – Cognitive Subscale was administered to 223 cognitively healthy participants according to a standard assessment protocol consisting of the Mini-Mental State Examination, the Montreal Cognitive Assessment and the Adults and Older Adults Functional Assessment Inventory. Normal performance on the assessment protocol was the inclusion criteria for the study.Results: The Alzheimer’s Disease Assessment Scale – Cognitive Subscale revealed good psychometric properties when used in the Portuguese population. Age was the main predictor of the Alzheimer’s Disease Assessment Scale – Cognitive Subscale total score (R2 = 0.123), whereas the influence of education level was lower (R2 = 0.027). These two variables explained 14.4% of the variance on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale scores and were used to stratify the normative values for the Portuguese population presented here.Conclusion: On the total sample, the average total score in the Alzheimer’s Disease Assessment Scale – Cognitive Subscale was 6 points. The normative data were determined according to age and educational level as these were the sociodemographic variables that significantly contributed to the prediction of the Alzheimer’s Disease Assessment Scale – Cognitive Subscale total scores, explaining 14.4% of their variance. The normative data are of the utmost importance to ensure proper use of this battery in Portugal.

Background: The previously described and validated Erlangen Score (ES) algorithm enables interpretation of the cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), ordering them on an ordinal scale: from neurochemically normal (ES = 0) through improbable AD (ES = 1), possible AD (ES = 2 or 3), to probable AD (ES = 4). Here we assess the accuracy of the ES in predicting hazards of progression from the mild cognitive impairment (MCI) stage of AD to the dementia stage of the disease (Alzheimer’s disease dementia (ADD)) in a novel, single-center cohort. Methods: Baseline CSF biomarkers (amyloid beta (Aβ) 1–42, Aβ42/40, Tau, and pTau181), interpreted according to the ES, were used to estimate time to progression from the MCI stage of AD to ADD, conditional on age, gender, APOE ε4 genotype, and Mini Mental State Examination score in 144 MCI subjects, using the Extended Cox Model; the subjects were followed-up until they developed dementia or until they had been cognitively stable for at least 2 years. In addition, ES distributions were studied in 168 ADD cases and 66 neurologic controls. Further, we stratified MCI patients into those who progressed to ADD faster (within 3 years, n = 47) and those who progressed slower (n = 74). Results: The distributions of the ES categories across the four diagnostic groups (Controls, MCI-Stable, MCI-AD, and ADD) were highly significantly different (Kruskal–Wallis χ2(df = 3) = 151.4, p < 0.001), with significant contrasts between each pair (p < 0.005), except between the ADD and the MCI-AD groups (p = 1.0). MCI patients with ES = 2 or 3 had 6–8 times higher hazards to progress to ADD compared to patients with ES = 0 or 1 in the first 3 follow-up years, and then their hazards decreased to those of the group with ES = 0 or 1. Patients with ES = 4 had hazards 8–12 times higher compared to the ES = 0 or 1 group. Faster progressors with ES = 2 or 3 had, in comparison to slower progressors, significantly lower Aβ1–42, Aβ1–40, and Aβ42/40, but comparable Tau and pTau181. A highly significant difference of the ES distributions between these two groups was observed (p < 0.001). Conclusions: Our current results reconfirm and extend the conclusions of the previously published report that the Erlangen Score is a useful tool facilitating interpretation of a complex pattern of the CSF AD biomarkers.

Despite having the same histopathological characteristics, early-onset and late-onset Alzheimer’s disease (AD) patients show some distinct clinical and neuropsychological profiles. Early Onset Mild Cognitive Impairment (EOMCI) is a less characterized group. The aim of this study is to characterize MCI probably due to AD in terms of the clinical, genetic, Cerebrospinal fluid (CSF) biomarkers profile and conversion rate of EOMCI, compared to the late-onset form (LOMCI). Methods: 159 MCI patients were divided in two groups: 52 EOMCI (onset < 65 years) and 107 LOMCI (onset ¥ 65 years). We investigated differences in neuropsychological scores, clinical variables, ApoE genotype, CSF biomarkers (A 42, t-Tau and p-Tau) in both groups. Conversion was ascertained during follow-up. Results: EOMCI showed a longer duration of symptoms prior to the first evaluation (EOMCI = 4.57 vs. LOMCI = 3.31, p = 0.008) and scored higher on the subjective memory complaints scale (9.91 vs. 7.85, p = 0.008), but performed better in brief cognitive tests (27.81 vs. 26.51, p < 0.001 in Mini-Mental State Examination; 19.84 vs. 18.67, p = 0.005 in Montreal Cognitive Assessment) than LOMCI. ApoE genotype distribution and CSF biomarker profile were similar in both groups, as was the conversion risk. Lower A 42 (Hazard ratio (HR): 0.998, 95% Confidence Interval (CI) = [0.996–1.000], p = 0.042), higher t-Tau levels (HR: 1.003, 95%CI = [1.000–1.005], p = 0.039) and higher scores in the Alzheimer Disease Assessment Scale-Cognitive (HR: 1.186, 95%CI = [1.083–1.299], p = 0.002) increased the risk of conversion. Discussion: Despite differences in memory performance and memory complaints, EOMCI and LOMCI seem to represent indistinct biological groups that do not have a higher risk of conversion to AD or differ in risk factors for conversion.

The distinction between sporadic and genetic behavioural-variant frontotemporal dementia (bvFTD) regarding some neuropsychological (NP) features remains challenging. Specifically, progranulin (GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer's disease (AD) diagnosis. In this context, we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia (Mini-Mental State Examination score ≥ 17 and Clinical Dementia Rating Scale score ≤ 1. We identified 21 patients at Centro Hospitalar e Universitário de Coimbra, Portugal with GRN mutations belonging to fifteen different families. As our focus was bvFTD variants, FTD-related aphasic forms (3 patients) were excluded. The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging, age and education. All patients completed the Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and a comprehensive NP assessment battery. Results were converted into z-scores. Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests (Kruskal-Wallis test analysis) and eta squared (ŋ2) was calculated as a measure of effect size. Group comparisons show that GRN patients have worse performances on verbal retrieval processes (P = 0.039, ŋ2 = 0.110) and visuoconstructive abilities (P = 0.039, ŋ2 = 0.190) than sporadic bvFTD forms. When compared to AD, GRN patients present a higher impairment in frontal (P = 0.001, ŋ2 = 0.211) and parietal (P = 0.041, ŋ2 = 0.129) measures and a better performance in memory tasks (P = 0.020, ŋ2 = 0.120). Sporadic-bvFTD forms are worse than AD in frontal measures (P = 0.032, ŋ2 = 0.200), being better in both memory (P = 0.010, ŋ2 = 0.131) and visuospatial skills (P = 0.023, ŋ2 = 0.231). Considering these results, we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits. This is particularly expressive in visuoconstructive abilities, which was the more discriminative feature between groups, followed by episodic verbal memory. This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra, Portugal (CE-029/2019) on June 24, 2019.

Germline and 2-hit brain somatic variants in DEPDC5 gene, a negative regulator of the mammalian target of rapamycin (mTOR) pathway, are increasingly recognized in patients with focal cortical dysplasia (FCD). Next-generation targeted sequencing identified a heterozygous germline variant in DEPDC5 gene (c.3241A>C, p.Thr1081Pro), classified as of unknown significance, in a patient with clinical features compatible with DEPDC5 phenotype (FCD, focal epilepsy, attention-deficit/hyperactivity disorder and borderline intellectual functioning). This missense variant has previously been reported in two other epileptic patients. Although interpretation of missense variants remains a challenge, DEPDC5 variants in patients with FCD and epilepsy cannot be neglected. Null variants were the most frequently reported in FCD patients, but missense variants have been described as well. The recognition of DEPDC5 phenotype and the appropriate interpretation of the detected variants are essential, since it may have important treatment implications in the near future, namely the use of mTOR inhibitors.

Frontotemporal lobar degeneration, the neuropathological substrate of frontotemporal dementia (FTD), is characterized by the deposition of protein aggregates, including tau. Evidence has shown concomitant amyloid pathology in some of these patients, which seems to contribute to a more aggressive disease. Our aim was to evaluate cerebrospinal fluid (CSF) amyloid-beta as a predictor of the mortality of FTD patients. We included 99 patients diagnosed with FTD-both behavioral and language variants-with no associated motor neuron disease, from whom a CSF sample was collected. These patients were followed prospectively in our center, and demographic and clinical data were obtained. The survival analysis was carried through a Cox regression model. Patients who died during follow up had a significantly lower CSF amyloid-beta1-42 than those who did not. The survival analysis demonstrated that an increased death rate was associated with a lower CSF amyloid-beta1-42 (HR = 0.999, 95% CI = [0.997, 1.000], p = 0.049). Neither demographic nor clinical variables, nor CSF total tau or p-tau were significantly associated with this endpoint. These results suggest that amyloid deposition in FTD patients may be associated with a higher mortality.