Carlo Abbate

Mild Cognitive Impairment Subtypes and Vascular Dementia in Community-Dwelling Elderly People: A 3-Year Follow-Up Study

OBJECTIVES: To investigate whether mild cognitive impairment (MCI) with multiple impaired cognitive domains (mcd‐MCI) is a prodromal manifestation of vascular dementia (VaD).

Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions: Frequency in a cohort of geriatric non-demented subjects

We genotyped for the C9ORF72 hexanucleotide repeat expansion a population of 156 non-demented elderly subjects, recruited in a geriatric unit as control group for association studies in patients with Alzheimers disease (AD), and found two carriers (1.2%). The first was referred for subjective memory complaints, at age 81. He was followed up until age 84 and did not develop dementia. The second was an 80-year old volunteer (spouse and caregiver of a patient with AD), non-demented at time of recruitment. We have not had information on her condition since that time. These results suggest that the penetrance of the mutation is definitely incomplete.

Different Adenosine A2A Receptor Expression in Peripheral Cells from Elderly Patients with Vascular Dementia and Alzheimer's Disease

The line between vascular dementia (VaD) and Alzheimers disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2AR) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2AR mRNA in VaD compared to AD subjects. These data suggest that A2AR expression may help in the differential diagnosis between VaD and AD.

GRN Thr272fs clinical heterogeneity: a case with atypical late onset presenting with a dementia with Lewy bodies phenotype.

We describe a case of late onset frontotemporal dementia carrying the g.1977_1980 delCACT (Thr272fs) mutation in progranulin (GRN) gene, characterized by a positive family history for dementia and a clinical phenotype resembling dementia with Lewy bodies. Symptoms included prominent visuospatial impairment, complex misidentification syndrome, visual zooptic hallucinations, hypersomnia, mental fluctuations, and signs of parkinsonism. The patient showed normal cerebrospinal fluid levels of amyloid-β, tau, and Ptau biomarkers, an asymmetric pattern of cerebral atrophy and hypoperfusion, and parietal hypometabolism. A major contributing factor to the diagnosis was the testing of plasmatic progranulin levels (extremely low), which prompted us to sequence GRN.

Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease

Frontotemporal Dementia (FTD) and Alzheimers Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.

Transcriptional and epigenetic phenomena in peripheral blood cells of monozygotic twins discordant for alzheimer’s disease, a case report

Target genes in Alzheimers disease (AD) have been identified. In monozygotic twins discordant for AD we analysed the expression of selected genes, and their possible regulation by epigenetic mechanisms in peripheral blood mononuclear cells, possibly useful to discover biomarkers. Amyloid precursor protein, sirtuin 1 and peptidyl prolyl isomerase 1 gene expressions were highly up-regulated in the AD twin versus the healthy one. Consistently with sirtuin 1 role in controlling acetylation status, we observed a substantial reduction of the acetylation on histone 3 lysine 9, associated with gene transcription in the AD twin. Noteworthy in the AD twin we also observed an increased gene expression in two histone deacetylases (HDACs) isoforms: HDAC2 and HDAC9. A general DNA hypomethylation of all gene promoters studied was also observed in both twins. Our results unravel transcriptional and epigenetic differences potentially helpful to better understand environmental factors and phenotypic differences in monozygotic twins.

Phenotypic Variability associated with the C9ORF72 Hexanucleotide Repeat Expansion: A Sporadic Case of Frontotemporal Lobar Degeneration with Prodromal Hyposmia and Predominant Semantic Deficits

We describe a sporadic case of frontotemporal lobar degeneration, associated with the C9ORF72 mutation, with prominent behavioral changes and semantic deficits. Predominant deficits in naming, vocabulary, word comprehension, and face and object recognition emerged on neuropsychological assessment. Amnesia, behavioral changes, and isolated psychotic symptoms were also present. Hyposmia was an unspecific prodromal sign. Brain imaging showed basofrontal and temporopolar hypometabolism bilaterally, and predominantly left-sided atrophy. Levels of cerebrospinal fluid biomarkers (amyloid-β, tau and p-tau) were normal. This description further confirms the heterogeneous presentation of the C9ORF72 mutation.

Reversible Parkinson's Dementia Associated with Withdrawal of Androgen‐Deprivation Therapy for Prostate Cancer

To the Editor: An 80-year-old man presented because of an approximately 10-month history of increasingly slow gait, leg stiffness with nocturnal cramps, and very fine hand tremor, associated with depression. A single visual hallucination, mild apathy, rapid eye movement sleep behavior disorders, and subtle cognitive impairment were reported. His past medical history included prostate carcinoma in 1996 (Gleason score 3–4; prostate-specific antigen 12 ng/mL), treated using radical radiotherapy, and subsequent long-term androgen-deprivation therapy (ADT) with cyproterone acetate (100 mg/d) and intramuscular injections of triptorelin (3.75 mg/month). His family history was positive for Parkinson’s disease (PD) and late-onset dementia. Neurological examination (March 2013) showed mild extrapyramidal syndrome with bradykinesia, increased upper limb tone (left>right), decreased left arm swing, mild camptocormia, very mild rest and postural tremor, and reduced eye blinking. A diagnosis of PD was

Test delle matrici: il rapporto target/distrattori e il ruolo della memoria a breve termine

Digit cancellation test: target-to-distractor ratio and short term memory involvement - We studied the effect of the target-to-distractor ratio (T/D) and short term memory on a matrix test performance. Higher performance on a visual search test with rising T/D ratio was found. An overall performance score improvement from the first to the third matrix is expected, because of the T/D ratio increase. In a previous study we found a significant difference on accuracy scores between the first and the following matrixes. In this article we demonstrate that an involvement of the short term memory processes could account for this result. Two hundred and twenty seven subjects from the Geriatric Unit of Ospedale Policlinico of Milan were considered. The subjects were 159 female and 68 male, aged 58 to 94 years with 3 to 18 years of education. Patients suffering from acute or chronic neurological diseases, sensorial impairment and alcoholism were excluded. We examined retrospectively the performance obtained by the subjects on a matrix test and a bisyllabic words span test. Correlation between accuracy scores obtained for the different matrixes of the attention test and the span score was then calculated. We found: 1) a significant difference on overall performance score between the three matrixes of the attention test: scores increase with the rise of T/D ratio; 2) a significant correlation between the accuracy score of the second and third matrix and the score of the span test; 3) no correlation between accuracy scores on the first matrix and the short-term memory score. In conclusion our data confirm the positive effect of a larger target-to-distractor ratio on the visual search performance in elderly people. The hypothesis that short-term memory is involved in the execution of the second and third matrix is preliminarly confirmed. The results are discussed in terms of the signal detection theory.

RESPONSE LETTER TO DR. VISSER

mentia (AD), whereas subjects with multiple impaired cognitive domains MCI (mcd-MCI) who developed dementia all had subcortical vascular dementia (VaD). They concluded that mcd-MCI can be considered to be an early stage of subcortical VaD, although they admitted that these data should be interpreted cautiously because of the possibility of selection bias. It would be useful to compare their findings with those of similar studies performed in other settings. In a population-based study, it was shown that 67% of the subjects with mcd-MCI who developed dementia after a follow-up of 2.6 years had AD, whereas only 12% had VaD. Two longitudinal studies performed in a memory clinic setting with a follow-up of 2 to 3.8 years found that all subjects with mcd-MCI who developed dementia at follow-up had AD. Moreover, 71% to 80% of the cases with AD at follow-up had mcd-MCI at baseline, and only 15% to 29% had a-MCI. Thus, the outcome of subjects with mcd-MCI may be more heterogeneous than appears from the study of Zanetti, and mcd-MCI may also represent early AD. It would be useful if the authors could provide some additional information regarding the classification of MCI used in the study. The definition of absence of impairments in nonmemory domains for subjects with a-MCI is not fully described, such that it is not clear whether subjects with a memory score below 1.5 standard deviations (SDs) and performance on nonmemory tests between 1 SD and 1.5 SDs were classified as having a-MCI or mcdMCI. In addition, it would be interesting to learn how many subjects in the group with mcd-MCI also had memory impairment. Maybe the authors could also comment on some of the findings presented in the tables. First, Table 1 shows that subjects with mcd-MCI have a very high score of 73 on the ‘‘Neuropsychological Inventory’’ (which presumably is the ‘‘Neuropsychiatric Inventory’’). Second, I wondered why the difference between the time needed to complete the Trail Making Test (TMT) B and that needed to complete TMT A (TMT B–A, seconds) in Table 3 is not the same as the difference between the variables TMT B and TMT A in that table.