Manuel Baron

Event-Related Evoked Potential P300 in Frontotemporal Dementia

There are no studies on event-related cognitive potentials in frontotemporal dementia (FTD). In order to evaluate the aptitude and usefulness of the event-related P300 potential in this disease, we prospectively examined 60 cases: 11 patients with FTD diagnosed according to the Lund and Manchester criteria and Neary consensus criteria, 33 patients with a probable Alzheimer’s disease diagnosis following NINCDS-ADRDA criteria, and 16 normal controls. P300 latency, amplitude and reaction time were recorded using an auditory oddball paradigm. In this sample, P300 potential could be reliably performed by 10/11 FTD patients, notwithstanding their language or executive function deficiencies. The FTD group P300 mean latency was midway between the normal controls and the Alzheimer’s disease group (ANOVA F2, 74199 = 16.5; p = 0.00003). The latency range of the FTD patients were within normal values (average plus 1.96 standard deviation of the values of the control group), except for one case with a latency of 448 ms. Post hoc Newman-Keuls analysis showed that the P300 latencies of the control and FTD groups did not differ significantly (p = 0.15) and that the Alzheimer’s disease group had a delayed P300 latency that differed significantly from that of the FTD (p = 0.002) and control group (p = 0.0002). However, there was overlapping in P300 latency values of the three groups. Despite these differences in latencies, the reaction time was significantly increased in the FTD and the Alzheimer’s disease groups. These findings indicate that the P300 potential is less affected in patients with FTD than those with Alzheimer’s disease. This fact could aid in FTD diagnosis, differential diagnosis with Alzheimer’s disease and possibly its clinical management.

Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

We describe the clinical phenotype of nine kindred with presenile Alzheimers disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Camptocormia induced by atypical antipsychotics and resolved by electroconvulsive therapy

We present a depressive patient who developed mild parkinsonian signs and camptocormia after the introduction of olanzapine. She had been treated before with other antipsychotic drugs. When camptocormia was diagnosed, olanzapine was withdrawn and levodopa was introduced. Depressive symptoms got worse and electroconvulsive therapy was tried. When the treatment was completed, her depression substantially improved and her posture became completely upright.

A short neuropsychologic and cognitive evaluation of frontotemporal dementia.

OBJECTIVE To elaborate a brief but efficient neuropsychological assessment of frontotemporal dementia (FTD), selecting the most specific and sensitive cognitive and behavioural items for distinguish between AD and FTD in the earlier dementia stages. METHODS Retrospective study with three groups, 35 patients with FTD, 46 with AD and 36 normal subjects, were administered the MMSE, FAB, Tower of London and Stoops test along with a 98 items behavioural and cognitive questionnaire. The most sensitive items were selected and validated internally for diagnosis by lineal discriminant analysis. RESULTS From the 98 items in the questionnaire, 29 showed significant discriminatory power. Non-cognitive symptoms with higher odd-ratio for FTD compared to AD were impairment in social behaviour (disinhibition, aggressiveness), loss of insight and inappropriate acts. Language disorders, such as echolalia, verbal apraxia or aggramatism, dominate in the cognitive profile of FTD. FAB was confirmed as the best cognitive instrument to differentiate FTD and AD. A linear discriminant function with the combination of the FAB score and the items from our questionnaire with higher OR for FTD accurately classified 97% of individuals. CONCLUSIONS The neuropsychological tests allow the differentiation between FTD and AD. The combination of FAB test with the assessment of key behavioural and cognitive symptoms appears helpful in this distinction.

Extended Kindred With Recessive Late-Onset Alzheimer Disease Maps to Locus 8p22-p21.2 A Genome-wide Linkage Analysis

Late-onset Alzheimer disease (LOAD) is a complex genetic disorder. Although genes involved in early-onset forms were discovered more than a decade ago, LOAD research has only been able to point out small effect loci, with the exception of APOE. We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region (24 sampled individuals, 12 of whom are affected), completing a genome-wide screen with an Affymetrix10 K single nucleotide polymorphism microarray. Genotyping results were evaluated under model-dependent (dominant and recessive) and model-free analysis. We obtained a maximum nonparametric linkage score of 3.24 (P=0.00006) on chromosome 8p22-p21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) under a recessive model (HLOD=3.04). When we compared the results of the model-dependent analysis, a higher score was obtained in the recessive model (3.04) than in the dominant model (1.0). This is a new locus identified in LOAD, in chromosome 8p22-p21.2 and encompassing several candidate genes, among them CLU and PPP3CC that were excluded by sequencing. The finding of a recessive model of inheritance, consistent with the assumption of inbreeding as a morbidity factor in this population, supports the notion of a role of recessive genes in LOAD.

Amusia as an early manifestation of frontotemporal dementia caused by a novel progranulin mutation

Perception of music is a complex ability requiring participation of multiple brain areas, with a different manner of processing between musicians and non musicians [5, 7]. Acquired amusia has been described associated with focal cortical degeneration, particularly within the cognitive and behavioural manifestations of frontotemporal dementia [1, 3, 6]. We report herein a family with frontotemporal dementia caused by a novel progranulin gene mutation whose proband presented with impaired musical appreciation as an early symptom of the disease.

Clinical-molecular study of a family with essential tremor, late onset seizures and periodic paralysis

We report the clinical features of, and the molecular study performed on, a Spanish family with essential tremor (ET), late onset epilepsy and autosomal dominant hypokalemic periodic paralysis (hypoPP). The presence of hypoPP in this kindred suggested an ion channel as a candidate gene for ET. Our study identified an Arg528His CACNL1A3 mutation in patients with hypoPP, and excluded this mutation as the cause of tremor or epilepsy in this kindred.

Oculo‐auricular phenomenon secondary to vestibular dysfunction

The oculo‐auricular phenomenon consists of coactivation of the ocular rectus lateralis and the posterior muscles of both ears (transverse auriculae and obliquus auriculae muscles). This coactivation produces a bilateral curling of auricles during extreme lateral gaze that can be observed in as much as an 80% of the normal population. We herein describe a 26‐year‐old man who presented a transient oculo‐auricular phenomenon in the course of a vestibular vertigo.

Event related evoked potential P300 in frontotemporal dementia

There are no studies on event-related cognitive potentials in frontotemporal dementia (FTD). In order to evaluate the aptitude and usefulness of the event-related P300 potential in this disease, we prospectively examined 60 cases: 11 patients with FTD diagnosed according to the Lund and Manchester criteria and Neary consensus criteria, 33 patients with a probable Alzheimers disease diagnosis following NINCDS-ADRDA criteria, and 16 normal controls. P300 latency, amplitude and reaction time were recorded using an auditory oddball paradigm. In this sample, P300 potential could be reliably performed by 10/11 FTD patients, notwithstanding their language or executive function deficiencies. The FTD group P300 mean latency was midway between the normal controls and the Alzheimers disease group (ANOVA F(2, 74199) = 16.5; p = 0.00003). The latency range of the FTD patients were within normal values (average plus 1.96 standard deviation of the values of the control group), except for one case with a latency of 448 ms. Post hoc Newman-Keuls analysis showed that the P300 latencies of the control and FTD groups did not differ significantly (p = 0.15) and that the Alzheimers disease group had a delayed P300 latency that differed significantly from that of the FTD (p = 0.002) and control group (p = 0.0002). However, there was overlapping in P300 latency values of the three groups. Despite these differences in latencies, the reaction time was significantly increased in the FTD and the Alzheimers disease groups. These findings indicate that the P300 potential is less affected in patients with FTD than those with Alzheimers disease. This fact could aid in FTD diagnosis, differential diagnosis with Alzheimers disease and possibly its clinical management.